Lichens Anti Cancer 2

Seminars in Cancer Biology xxx (xxxx) xxx
Contents lists available at ScienceDirect
Seminars in Cancer Biology

journal homepage: www.elsevier.com/locate/semcancer
Lichens as a repository of bioactive compounds: an open window for green

therapy against diverse cancers
Tanvir Ul Hassan Dar a, **, 1, Sajad Ahmad Dar b, 1, Shahid Ul Islam a, Zahid Ahmed Mangral a,
Rubiya Dar c, Bhim Pratap Singh d, Pradeep Verma e, Shafiul Haque b, *
a
Department of Biotechnology, School of Biosciences and Biotechnology, BGSB University, Rajouri, Jammu and Kashmir, India
b
Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, Saudi Arabia
c
Centre of Research for Development, University of Kashmir, Srinagar, Jammu and Kashmir, India
d
Department of Agriculture & Environmental Sciences, National Institute of Food Technology Entrepreneurship & Management (NIFTEM), Sonepat, Haryana, India
e
Bioprocess and Bioenergy Laboratory, Department of Microbiology, Central University of Rajasthan, Ajmer, Rajasthan, India
A R T I C L E I N F O A B S T R A C T
Keywords: Lichens, algae and fungi-based symbiotic associations, are sources of many important secondary metabolites,
Lichens such as antibiotics, anti-inflammatory, antioxidants, and anticancer agents. Wide range of experiments based on
Secondary metabolites in vivo and in vitro studies revealed that lichens are a rich treasure of anti-cancer compounds. Lichen extracts and
Anti-cancer activity
isolated lichen compounds can interact with all biological entities currently identified to be responsible for tumor
Cell cycle arrest
Metabolic networks
development. The critical ways to control the cancer development include induction of cell cycle arrests,
blocking communication of growth factors, activation of anti-tumor immunity, inhibition of tumor-friendly
inflammation, inhibition of tumor metastasis, and suppressing chromosome dysfunction. Also, lichen-based
compounds induce the killing of cells by the process of apoptosis, autophagy, and necrosis, that inturn posi
tively modulates metabolic networks of cells against uncontrolled cell division. Many lichen-based compounds
have proven to possess potential anti-cancer activity against a wide range of cancer cells, either alone or in
conjunction with other anti-cancer compounds. This review primarily emphasizes on an updated account of the
repository of secondary metabolites reported in lichens. Besides, we discuss the anti-cancer potential and possible
mechanism of the most frequently reported secondary metabolites derived from lichens.
1. Introduction cancers in men, whereas colorectal, lung, thyroid, cervical, and breast
cancers are the most prevalent in women [2]. Despite advances in di
The World Health Organization (WHO) describes a broad group of agnostics, care, and preventive tools, the number of cases is increasingly
diseases marked by an unchecked proliferation of abnormal cells that expanding and expected to hit an incidence of 29.5 million by 2040.
can invade neighbouring areas of the body and spread to other organs as Food and Drug Administration (FDA)-approved anti-cancer medications
a generic term for cancer [1]. According to global cancer figures pro are majorly categorized into four main groups: a) cytotoxic medicines,
vided by the Global Cancer Observatory (GCO) (https:/gco.iarc.fr/), b) target-based agents, c) hormones and hormone antagonists, and d)
cancer is the second leading cause of death globally, with a reported 9.6 immunomodulators [3]. More than 70 % of these treatments are from
million deaths in 2018. The most common cancers worldwide were lung either natural ingredients or synthetic to semi-synthetic products [4].
and breast cancers, each contributing about 12 % to the total count of Although current advancements in the production of anticancer drugs,
new cases reported in 2018 [1].The third most common cancer was moving from traditional non-specific cytotoxic agents to specific
colorectal cancer, with 1.8 million new cases occurring in 2018. Lung, target-based therapies and immune-related modulators, are going on
kidney, colorectal, stomach, and liver cancers are the most prevalent [3]; still, the identification of new anticancer drugs from nature remains
* Corresponding author at: Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, 45142, Saudi Arabia.
** Corresponding author at: Department of Biotechnology, School of Biosciences & Biotechnology, Baba Ghulam Shah Badshah University, Rajouri, 185234 Jammu
& Kashmir, India.
E-mail addresses: tanvirulhasan@gmail.com (T.U.H. Dar), shafiul.haque@hotmail.com (S. Haque).
1
The authors contributed equally.
https://doi.org/10.1016/j.semcancer.2021.05.028
Received 16 March 2021; Received in revised form 10 May 2021; Accepted 24 May 2021
Available online 27 May 2021
1044-579X/© 2021 Elsevier Ltd. All rights reserved.
Please cite this article as: Tanvir Ul Hassan Dar, Seminars in Cancer Biology, https://doi.org/10.1016/j.semcancer.2021.05.028
T.U.H. Dar et al. Seminars in Cancer Biology xxx (xxxx) xxx
critical for modern cancer science, as many alternative sources of nat biotin, vitamin-A, vitamin-C, vitamin-E, vitamin-D and folic acid. Ni
ural substances remain mostly unexplored [5]. trogen concentrations range from 1.6 to 11.4 % of the lichen thallus’ dry
Lichens are the symbiotic associations between photoautotrophic weight [15]. Lichen secondary metabolites, also called as lichen acids,
algae or cynobacteria and fungi, which act as photobionts and myco are small chemically complex substances, classified as per their chemical
bionts, respectively. Algae and fungi are two different kinds of organ structure into the following classes: a) S-containing compounds, b)
isms, and their nature is quite different as well. Still, they lose their P-containing compounds, c) N-containing compounds, d) quinines, e)
nature to act as a single organism, the lichen, which differs morpho aromatic compounds, f) aliphatic and cycloaliphatic compounds, g)
logically and physiologically from its contributors [6]. About 90 % of a chromanes and chromones, h) depsidones, I) dibenzofurans, j) diphenyl
lichens is contributed by the fungus serving as the primary source of ethers, k) xanthones, l) diphenylmethanes, m) nostoclines, n) biphenyls,
shape, size, structure, and colour, whereas the remaining 10 % of its depsides, o) terpenoids, p) depsones, q) pulvinic acid derivatives, r)
inside is contributed by the alga. In lichen associations, 98 % fungi cleavage products of depsides and depsidones, and s) naphthopyranes
belong to Ascomycota and the remaining to Basidiomycota [7]. Upon [16,17].
keen examination of the lichen structure, it is evident that the fungus Lichens contain a significant amount of secondary metabolites,
mostly contributes the visible part called lichenized fungus [8,9]. The generally between 0.1 and 10 % of the dry weight, but often up to 30 %
abundance of mycobiont protects the photobiont from intense light and [18,19]. To date, lichens have recorded more than 800 specific sec
serves as a shelter for it to take nutrients from the underlying substrate. ondary metabolites, and most of them do not occur in other fungi or
Photobiont also helps in synthesizing organic nutrients from carbon plants [20]. All of the lichen compounds are produced by the fungal
dioxide and ammonium via nitrogen fixation [10]. About 21 % of all activity [21–23]. These compounds are found in either the cortex or
fungi act as mycobionts and, accordingly, lichens are considered the medulla of lichens. Secondary metabolites such as usnic acid, fungal
largest mutualistic group among fungi. As against this, only 40 genera, melanins, parietin, and atranorin are located in the cortex, whereas
which include 25 from algae (forming 90 % of lichens) and 15 from physodic acid and physodalic acid are present in the medulla [24,25].
cyanobacteria (in 10 % of lichens), are involved as photosynthetic The most common cortical compounds are atranorin and usnic acid;
partners in lichens [9]. Thus both the algal and fungal partners get some other combinations are also known to occur. Except atranorin, all
benefited by forming the association in the lichen. The algal partners of them are pigmented. Certain lichen substances are usually present in a
(photobionts) are protected and benefited from the efficacious uptake of specific layer of lichen thallus, and specific cortical substances can be
mineral nutrients by the fungal partners (mycobionts). The latter also identified from those typically present only in the medulla.
enable the former to grow in conditions in which they can not succeed The dissemination of secondary metabolites within lichens is usually
alone. In turn, the fungi obtain sugars and organic nitrogen from the species-specific and is often used in lichen systematics and taxonomy
algal partners and are able to grow in nutrient-deficient environments [26–28]. Studies have revealed that the resembelence in secondary
[9]. metabolites’ chemistry may not necessarily imply close phylogenetic
The lichens show a broad spectrum of biological potential but have links [28]. For example, Neofuscelia and Xanthoparmelia, two close
been neglected by mycologists and pharmacologists, due to their slow genera in the Parmeliaceae, alter primarily in their upper pigments of the
growth and difficulty in culturing. This is the main reason that they have cortex. In the genus Xanthoparmelia, the upper cortex of the stem com
been scarcely studied from a biochemical perspective. Lichens produce prises crystallized usnic acid, while in the Neofuscelia, the stem cortex
various secondary metabolites, which act as the defensive mechanism comprises a melanin-like pigment. Besides, some other species in the
against decomposers and herbivores. The defensive nature of lichens is Parmeliaceae may include the only atranorin in the cortex. For the
the crucial point from the pharmaceutical point of view, as they have an growth and survival of lichens, secondary metabolites are not required,
excellent anti-cancer potential against a wide range of cancers [11]. The and the function of these compounds in lichen symbiosis remains poorly
latter property may be due to their anti-tumor, ant-ioxidant, understood [29]. However, it is imperative and valuable that they can
anti-invasive, anti-migrative, anti-proliferative, cytotoxic and help to shield the thalli from competitors, pathogens, herbivores, and
pro-apoptotic nature [12,13]. Several studies have been carried out on external abiotic factors, such as high UV radiation. Studies have shown
lichens based on their biological activities, and some compounds have that regional and seasonal changes can influence some lichen species [9,
been identified. Still, their medicinal properties have not been well 30].
investigated. A few secondary metabolites with anti-cancerous activity Secondary metabolites of lichens are produced by three chemical
act effectively in various in vitro models of cancers [12]. It is in this back pathways: shikimic acid pathway, mevalonic acid pathway, and acetate
drop that the present review is envisaged to understand the dynamics of polymalonate pathway [9]. The synthesis of lichen secondary metabo
recent research concerning the anti-cancerous nature of lichens and its lites is mostly by acetate polymalonate (polyketides) pathway, which is
help in cancer management in a clinical perspective. The discussed predominantly connected with the fungal part of lichen [31,32].
lichen acids can prove beneficial in oncology by increasing the stability Chemical compounds such as depsidesusnic acid and its derivatives
and preventing the body from having undesirable side effects. It will xanthonesorcinols, aromatic compounds and depsidones, e.g. lobaric
help to comprehend the molecular mechanisms concerning the drugs acid, physodic acid, lividic acid, alectoronic acid, grayanic acid, norlo
extracted from lichens at various stages. baridone, diploicin, 4-O-methylphysodic acid, variolaric acid, and
alpha-collatolic acid, are produced by this pathway through a chain of
2. Lichens: a rich repository of bioactive secondary metabolites reactions facilitated by acetate polymalonate synthase enzymes [9,32,
33]. These polyketides are bound by bonds of ester, ether, and C–C
Certain conditions in which lichens grow, allow them to produce [34]. The main biosynthesis products obtained via acetate polyaromatic
many metabolites, which facilitate them with adequate protection from pathway include gyrophoric acid, fumarprotocetraric acid, and atra
various biological and physical challenges.There are two classes of norin, in depsides [35]. Pulvinic acid and terphenylquinone compounds
metabolites synthesized by lichens: primary and secondary metabolites are predominantly associated with the shikimic acid pathway [35].
[8,12]. The primary metabolites found within them include vitamins, Several studies have also demonstrated how elevation affects sec
proteins, polysaccharides, carotenoids, and amino acids. These com ondary metabolites’ production and content in lichens [36–38]. It has
pounds can be extracted from the lichens on boiling. Some of the pri been reported for some lichen species that several metabolites are pro
mary metabolites are non-specific and are found in free-living fungi, duced with increasing elevation [9,39]. The variances in the synthesis of
higher plants, and algae. Polysaccharides and their related groups are phenolic compounds by lichens are affected by environmental factors
located in lichens in trace amounts, accounting for roughly 3 % of dry and their interaction. Some lichen metabolites maintain the symbiotic
weight [14]. Lichens are a rich source of vitamins, such as vitamin B12, equilibrium, while others dissolve rocks for better lichens’ attachment
2
[40]. It has been reported that lichen secondary metabolites exhibit the anticancer properties of lichen derived metabolites against different
diverse biological properties, including anticancer, antifungal, cancers include leukaemia (18 %), breast cancer (31 %), colorectal
anti-inflammatory, antiviral, antibacterial, antioxidant, analgesic, cancer (22 %), bone and joint cancer (1 %), myeloma (2 %), melanoma
enzyme inhibitory, antipyretic, anti-insecticidal, plant growth inhibi (13 %), lung cancer (16 %), sarcoma (13 %), brain cancer (8 %), cervical
tory, and antifungal. The detection of anti-cancer activity of lichen cancer (9 %), prostate cancer (7 %), liver cancer (8 %), pancreas cancer
substances/extracts is depicted by various techniques like MTT assay, (4 %), kidney cancer (4 %), ovary cancer (4 %), larynx cancer (2 %),
flow cytometry assay, gene expression assay, cell line based assays, uterus cancer (1 %), oral cavity and pharynx cancer (1 %), stomach
western blot, FACS analysis, microplate reader, real-time PCR and sul cancer (4 %), lymphoma (1 %), vulvar cancer (1 %), mastocytoma (1 %),
forhodamine B assay [34,41–45]. The different processes used for the head and neck cancer (1 %), endometrial cancer (1 %), and bladder
extraction and analyses of lichen based secondary metabolites are cancer (1 %). Lichen substances and their acids are analyzed through in
depicted in Fig. 1. vivo and in vitro experiments for studying anticancer activities. Many
studies have revealed the anticancer and cytotoxic effects of
3. Secondary metabolites of lichens and their anti-cancer lichen-derived compounds, such as programmed cell death (apoptosis),
properties expression of proteins or genes, invasion, migration, angiogenesis,
autophagy, and cellular senescence [12]. About 23 % of the research
Lichen secondary metabolites are potential anticancer agents articles pertaining to lichens include the in-vivo assays, in which lichen
[46–48] with varying physicochemical properties. A number of different substances are injected into tumor-bearing mice and then, after some
chemical structures reflect these bioactive secondary metabolites of li time, weight and volume of the tumor are measured [12]. Lichens
chens (Fig. 2) [49–52]. They differ according to the species and physical exhibit cytotoxicity to cancer cells through various mechanisms
factors like temperature, light, exposure to UV, altitude and seasonality including cell necrosis or cell death, autophagy, and cell-cycle arrest at
[53,54]. Lichen secondary metabolites belong to certain restricted G2/M, G0/G1 or S phase [60]. For example, physodic and physodalic
chemical families like terpenoids [55], flavonoids [34], tridepsides [56, acids result in the prevention of reactive metabolite synthesis by stop
57], aphthosin [57], orcinol tetradepsides, orsinol tridepsides, and ping the oxidation systems found in the hepatic microsomal fraction
phenolic compounds [57]. Structural identification of lichen secondary [61]. Diffractic and gyrophoric acids, the para-depsides, inhibit human
metabolite has been carried out using biochemical methods such as keratinocyte cell proliferation [12,13].
HPLC, TLC, IR, UV, MS, X-ray crystallography, and NMR [58,59]. Thus, Various in vitro assays that are mostly used for determining cell
compounds containing different aromatic, aliphatic and cyclic struc viability include Methylthiazolyldiphenyl-tetrazolium bromide (MTT)
tures, viz. gyrophoric acid, lecanoric acid, umbilicaric acid, norstic acid, assay, Trypan Blue Dye assay and Propidium Iodine (PI) assay [13].
parietin, palmitic acid, myristic acid, palmitoleic acid, oleic acid, lino Apoptosis is studied by identifying apoptosis-related genes and proteins
leic acid, stearic acid, and linolenic acid have been documented in the via Western Blotting, preceded by the caspase activity and Annexin-V
genus of Umbilicaria [31]. staining assays [12,13]. Cell Migration and cellular invasion are tested
Recently, lichens and their secondary metabolites have gained mainly by Boyden chamber assay, and healing is tested by Boyden
enough attention because of their pharmaceutical potential [31]. chamber/transwell migration assays and scratch/wound-healing assays
Among the diverse classes of unique secondary metabolites, very few [12,13]. Following sections of this review discuss the most promising
possess anti-cancerous activity upon investigation in various in vitro and frequently reported lichen metabolites and their possible anticancer
models of cancers. The percentage-wise existing literature pertaining to activities (Table 1; Fig. 2).
Fig. 1. Overview of screening process used for extraction and analysis of lichen-based secondary metabolites.
3
Fig. 2. Structure of some secondary metabolites with anti-cancer properties extracted from lichens.
3.1. Atranorin adenocarcinoma HT-29, Human cervix adenocarcinoma HeLa, Human

promyelocytic leukemia, Human T cells lymphocyte leukemia, Jurkat,
Atranorin is one of the β-orcinol products produced by different Human breast adenocarcinoma SK-BR-3, Human colon carcinoma p53
lichen families, such as Cladoniaceae, Streocaulaceae, Parmeliaceae, null HCT-116 p53, and Human colon carcinoma wild type p53 HCT-116)
and Lecanoraceae. Hesse first extracted it in 1898 and, ever since then, [57]. Kosanic et al., 2014, investigated atranorin’s anticancer activity
its biological and therapeutic properties have been thoroughly studied against FemX (human melanoma) and LS-174 (human colon carcinoma)
and evaluated [13,62]. It has shown interesting effects on cancer cells cell lines, and observed intense anticancer activity.
due to its ability to intercalate with DNA and avert the enzyme topo As documented by Kosanić et al. [12], atranorin and fumarprotoce
isomerase II without impacting topoisomerase I [44]. It exhibits traric acid both show antiproliferation activity and decline in G2/M cell
important anticancer properties, especially against cervical cancer cell- population on LS-174 cell line. However, atranorin was more effective at
Hela, breast cancer cell- MCF-7, and colon cancer cell –Widr [12]. Also, accumulating cells in the sub-G1 step than fumarprotocetraric acid.
atranorin showed strong cytotoxic and pro-apoptotic activities when Atranorin also shows inhibitory activities towards invasion and migra
used against broad spectrum of cell lines (Human breast adenocarci tion of lung cancer cells under in vivo studies [63]. Atranorin decreases
noma MCF-7, Human ovarian carcinoma A2780, Human colon the activity of β-catenin-mediated TOPFLASH and modifies the
4
Table 1
Lichen-derived bioactive compounds and their anti-cancer properties.
S. Lichen species Bioactive Chemical name Cancer cell-lines Cancer type Reference
No. compound (s)
1. Stereocaulon alpinum, Parmelia Atranorin 3-hydroxy-4-methoxycarbonyl-2,5- MCF-7, LS-174, UACC- Bone and joint, [46,67]
sulcata, Parmotrema stuppeum, dimethylphenyl 62, DLD-1, FemX, A375 colorectal, brain,
Physcia aipolia,Bacidia stipata, cervical, breast,
Cladonia fimbriata, Cladonia furcata, prostate, lung,
Cladonia subulata, Cladonia foliacea melanoma, and
ovary cancer.
2. Stereocaulon alpinum,Cladonia sp., Lobaric acid 3-hydroxy-9-methoxy-6-oxo-7-(1- T-47D, ZR-75-1, Brain, pancreas, [220,221,
Stereocaulon sasakii oxopentyl)-1-pentyl-2 -benzo[b][1,4] HCT116, K-563 breast, prostate lung 222]
benzodioxepincarboxylic acid cancer, and
leukaemia
3. Parmotrema tinctorum, Usnea Lecanoric acid 4-(2,4-dihydroxy-6-methylbenzoyl)oxy- HCT116, MCF-7, HEP-2, Colorectal cancer [223]
subvacata, Parmotrema grayana, 2-hydroxy-6-methylbenzoic acid 768-0, B16-F-10 and
Parmotrema stuppuem Vero cell lines
4. Cetraria islandica Lichenin (2S,3R,4R)-2-(hydroxymethyl)-3,4- Leukaemia [13]
dihydro-2H-pyran-3,4,5-triol
5. Cornicularia aculeata, Protolichesterinic 4-methylidene-5-oxo-2-tridecyloxolane- T-47D, ZR-75-1, SK-BR- Breast, myeloma, [105,135,
Tuckermannopsis ciliaris,Parmelia acid 3-carboxylic acid 3, LNCaP, DU-145, K562, lung, pancreatic, 224,225,
saxatilis, Parmelia sulcata, Parmelia U266, AsPC-1, colorectal, and 226]
sulcata RPMI8226 prostate cancer
6. Usnea longissimi,Usnea subcavata, Diffractaic acid 4-[(2,4-dimethoxy-3,6-dimethylbenzoyl) UACC-62, HeLa, MCF-7 Prostate, brain, [13,78,79]
Protousnea magellanica oxy]-2-hydroxy-3,6-dimethylbenzoic and HCT-116 breast, cervical and
acid colorectal cancer
3,9-dihydroxy-6-oxo-7-(2-oxoheptyl)-1- MCF-7, MDA-MB-231, T-
7 Hypogymnia physodes Physodic acid pentylbenzo[b][1,4] 47D, MMP-7, A375, Melanoma [108]
benzodioxepine-2-carboxylic acid HCT116
methyl (2E)-2-(3-hydroxy-5-oxo-4-
8. Alectoris virens Vulpinic acid BT-474, SK-BR-3 Breast cancer [124]
phenylfuran-2-ylidene)-2-phenylacetate
5,13,17-trihydroxy-12-(hydroxymethyl)-
7-methyl-9,15-dioxo-2,10,16-
Colorectal and
9. Parmelia caperata Salazinic acid trioxatetracyclo[9.7.0.03,8.014,18] LS-174, HCT116, FemX [94,227]
melanoma
octadeca-1(11),3(8),4,6,12,14(18)-
hexaene-4-carbaldehyde
Alectoria ochroleuca,Usnea diffracta,
LS-174, UACC-62, FemX,
Cladonia arbuscular, Cladonia
HTB-140 (HS294 T),
lepidophora, Cladonia fimbriata,
A549, BGC823, Breast, leukaemia,
Cladonia furcata, Cladonia subulata, 2,6-diacetyl-7,9-dihydroxy-8,9b- [125,137,
10. Usnic acid HGC7901, HepG2, HT- pancreatic and
Cladonia foliacea,Usnea florida, dimethyldibenzofuran-1,3-dione 140]
29, H1299, MCF-79, prostate cancer
Flavocetraria nivalis,Alectoria
Capan-2, HeLa, PC-3,
samentosa,Xanthoparmelia
HEK293T
chlorochroa
1,8-Dihydroxy-3-methoxy-6-methyl- MDA-MB-231, A278, P3
11. Xanthoria parietina Parietin Ovarian cancer [66]
9,10-anthrachinon × 63Ag8.653
8-chloro-9-hydroxy-3-methoxy-1,4,7-
12. Parmelia palladium Pannarin trimethyl-6-oxobenzo[b][1,4] DU-145 Prostate cancer [151]
benzodioxepine-10-carbaldehyde
10-formyl-3,9-dihydroxy-4-
Parmelia sulcata,Usnea albopunctata, (hydroxymethyl)-1,7-dimethyl-6- Human colon
13. Protocetraric acid LS-174, UACC-62, FemX [77]
Parmelia saxatilis, Parmelia caperata oxobenzo[b][1,4]benzodioxepine-2- carcinoma
carboxylic acid
13,17-dihydroxy-5-methoxy-7,12-
dimethyl-9,15-dioxo-2,10,16-
Colon and breast
14. Lobaria pulmonaria Stictic acid trioxatetracyclo[9.7.0.03,8.014,18] MCF-7, HT-29 [123]
cancer
octadeca-1(11),3(8),4,6,12,14(18)-
hexaene-4-carbaldehyde
distribution of subcellular β-catenin by limiting its nuclear import to cycle arrest at G0/G1, S phases in colorectal cancer and melanoma cell
stop cell division [64]. It has been reported that atranorin controls the lines [66,70]. Moreover, it triggers the activation of caspase-3, mito
downstream target genes of β-catenin/LEF and c-jun/AP1, thereby chondrial membrane depolarization, enhanced expression of
inhibiting cell division [63,65,66]. Besides atranorin decreases pro-apoptotic BAX, activation of the intrinsic pathway of apoptotic cell
KITENIN-mediated AP-1 activity and inhibits the downstream expres death, higher Hs p90 expression and reduced expression of
sion of c-fos and c-jun transcription factors [67,68]; atranorin anti-apoptotic Bcl-xl and Hsp70 in all tested cell lines [20,46,66,71,72].
Rho-GTPase activity and STAT activity, affecting the target genes Similarly, atranorin was tested against mouse breast cancer (4T1) cells.
correlated with metastatic potential and involved in lung cancer The reduction in the clonogenic potential of 4T1 cells was observed,
development [65]. It also reduces the expression level of STAT, compared with average mammal non-malignant epithelial (NMuMG)
GTP-RhoA and GTP-Cdc42 proteins, all of which, if overexpressed, will cells [12]. Atranorin, isolated from Stereocaulon caespitosum, also
lead to diverse types of cancers [65]. Considerable cytotoxic activity inhibited human hepatocellular carcinoma (SK-Hep1, Huh-7, SNU-182)
against all forms of cancers tested (IC50 between 12.5 and 26.5 μg/mL), cell lines when used in a high dose. It has also been reported that atra
except leukaemia cell lines (IC50 = 93.5 μg/mL) has been reported with norin arrested SK-Hep1 cells at G2/M phase, induced cell death at 24 h
atranorin [67,69]. Atranorin cytotoxicity was also correlated with cell period and suppressed invasiveness and migration of Huh-7 cells and
5
Sk-Hep1 [12]. such as Parmelia sulcata, P. saxatilis, P. caperata, Parmotrema lichex

anthonicum, and Xanthoparmelia somloensis [91,94–97]. Previously, this
3.2. Diffractaic acid acid was detected from some specific Usnea sp. [98]. Preliminary testing
has been done on brain, colorectal, sarcoma, melanoma, breast, and
Diffractaic acid is a naturally formed depside derivtive produced by vulva cancer cell lines. From this testing, it has been found that cyto
lichens such as Usnea longissima, U. diffract, Parmelia tinctorum and toxicity against colorectal and melanoma-cell lines is very highly con
P. nepalensis [73]. Research findings have shown that diffractic acid has nected with G1 cell-cycle arrest (IC50 = 35, 67 μg/mL, and IC50 = 39, 02
antiviral, anti-tumor and analgesic activities [74–76]. It has been μg/mL, respectively), and highly enhanced by structural modifications
screened for brain, cervical, breast, colorectal, melanoma, and prostate which decrease IC50 values to 1, 73 μg/mL [96,97]. The cell-cycle arrest
cancers [43,77–80]. Diffractic acid is also proposed to be an effective of sarcoma and vulvar cell-line cells shows low in cytotoxicity [94].
anti-proliferative agent against human keratinocyte development [81]. Salazinic acid was also tested in vivo (mice) against solid-type Ehrlich
It has also been reported not to be cytotoxic at small doses, but have a carcinoma and ascetic to study the effects on two forms of tumors over a
lower cytotoxic potential than 50 mg L− 1 cultured human blood cells at week [95].
higher concentrations. Related to these results, Brisdelli et al. (2013)
tested the cytotoxicity of diffractaic acid in several cancer cell lines. 3.6. Gyrophoric acid
They authenticated the cytotoxic action of diffractaic acid on HeLa,
MCF-7 and HCT-116cells [77]. It has also been shown that diffractaic Gyrophoric acid is a typical compound of the lichen genus Umbil
acid exhibits low cytotoxic and robust antioxidant properties at different icaria. It is recognized in lichen species as a strong ultraviolet filter. As
dose concentration [9]. Further, it has been investigated that diffractaic demonstrated, the cytotoxic and apoptotic behaviour of UVB in the
acid causes apoptosis, oxidative stress, and cell cycle arrest [82]. Stim radiated HaCaT cells was successfully prevented by gyrophoric acid
ulation of oxidative stress to apoptosis and cell cycle arrest can consti [99]. In addition to photoprotective operations, gyrophoric acid also
tute effective anti-cancer drugs used in single, combination or adjuvant demonstrated reasonably good antimicrobial effects on numerous fungi
cancer therapies [82]. and bacteria, including human pathogens [100]. Besides, DPPH’s (2,2,
diphenyl-1-picryl-hydrazyl-hydrate) radical-scavenging behaviour has
3.3. Lecanoric acid confirmed the antioxidant properties of gyrophoric acid [101]. Several
studies have shown the anti-proliferative effects of gyrophoric acid on
Lecanoric acid is a natural medullar lichen depside and is isolated cancer cell-lines [20,66,94]. Bačkorová et al. (2012) found that 200 μM
from several lichen species, such as Parmotrema tinctorum, Hypo of gyrophoric acid resulted in a substantial decrease in the mitochon
cenomyce scalaris and Parmelia subrudecta [49,80,83,84]. Umezawa et al. drial membrane potential of ovarian cancer cells, and that after 24 h of
(1974) revealed that lecanoric acid is a relatively low-toxicity inhibitor prolonged incubation results were not same for HT-29 colon adenocar
of histidine decarboxylase. Further, research has shown that 30, cinoma cells (A2780). Following 24 h exposure to A2780 and 72 h to
50-dichloro-2, 40-dihydroxybenzanilide, an analogue of lecanoric acid, HT-29, annexin V positive cells’ proportion increased significantly at the
exhibits inhibitory activity against skin tumours’ development [85]. same dose. After 3 and 6 h of exposure to gyrophoric acid, the devel
Gomes et al. (2002) documented the harmful activity of lecanoric de opment of reactive oxygen species (ROS) in HT-29 cells was observed,
rivatives in potent fungi. More significantly, in Parmotrema tinctorum, but effects on A2780 cells were not seen [20,66,102].The gyrophoric
the free radical activity of lecanoric acid and its derivatives has also been acid-mediated alteration in A2780 cells and proteins p52, Bcl-2, Bax,
investigated [86]. Besides, lecanoric acid can play a photo-protective and P38 in HT-29 cells was observed by Western Blot analysis [20,66].
role for lichen symbionts in Polar regions [9,87,88]. In the UV range, Gyrophoric acid also mostly impaired cell-growth and regulates the
lecanoric acid has a high absorption rate, but only a mild absorption rate expression of proteins such as Bcl-2, Bax, and Hsp70, although only at an
in the violet region’s photosynthetic photofluence band. It is hypothe increased level in A375 melanoma cancer cells [100]. Furthermore,
sized that lecanoric acid plays a significant role in shielding the lichen stains of annexin V have shown that the therapy of gyrophoric acid has
symbionts from harmful solar radiation. Axin 2 expression in HCT 116 contributed to a 24 -h increase in apoptotic cells (early stage), and a
cells was reduced only slightly by lecanoric acid derived from Hypo rapid increase in apoptosis after 48 h and 72 h (late-stage) [20,66].
cenomyce scalaris [49]. Lecanoric acid has been tested against Breast
carcinoma MCF-7, Larynx carcinoma HEP-2, Kidney carcinoma 786-0, 3.7. Protolichesterinic acid
Murine melanoma cell B16-F-10, and Vero cell lines [5,12,23].
Protolichesterinic acid was documented for the first time from Usnea
3.4. Lichenin albopunctata. It has been derived from Cetraria islandica, Cornicularia
aculeate and Rhizoplaca melanophthalma. Protolichesterinic acid was
Lichenin is derived from various lichen species, such as Acroscyphus evaluated in vitro for its possible human tumor-cell growth inhibitory
sphaerophoroides, Alectoria sarmentosa, Cetraria islandica, Cladonia activity on prostrate cancer cells such as LNCaP and DU-145, using the
furcata, Alectoria sulcata, Evernia prunastri, Gyrophora esculenta, MTT assay, to measure cell proliferation and viability [103]. It
Lasallia papulosa, L. pensylvanica, Ramalina celastri, Umbilicaria car demonstrated a robust dose-response interaction of 6.25–50 lM con
oliniana, U. polyphylla, U. angulata, and Usnea rubescens. Glucans are centrations and comparable growth inhibitory activity in DU-145 cells
among the first lichen-derived metabolites tested for its anti-cancer ac relative to LNCaP cells [103]. It induces apoptotic cell-death since
tivity [89,90]. Leukaemia cell lines were tested for lichenin that induced literature suggests that apoptosis can only be correlated with high values
reduced telomerase activity, as well as distinctive ultrastructural of TMOM (Tail Moment) [103]. TMOM is described as a product of DNA
changes, DNA fragmentation and overexpression of Bax, Fas and FasL percentage in the comet’s tail. Studies have unravelled that the proto
due to both intrinsic and extrinsic pathways of apoptotic cell death [91]. lichesterinic acid down-regulates the expression of NOS2 and, thus,
They have proven successful against carcinoma and sarcoma by plays a crucial role against these cancer-causing agents [104,105].
enabling anti-tumor immunity and inhibiting in vivo tumor growth [90, Protolichesterinic acid works in many cancer cell-lines via apoptosis
92,93]. induction by inhibition of Hsp70 protein expression in cell lines of
caspase-3 activation in HeLa cell and prostate cancer [103–105].
3.5. Depsidone-salazinic acid This acid has been used against breast cancer cell-lines, such as
SKBR-3 and T47D. It has been demonstrated that protolichesterinic acid
Salazinic acid is a depsidone extracted from different lichen species possesses anticancer properties against SK-BR-3 cell-lines. However, no
6
change was reported in T-47D cells because protolichesterinic acid had protocetraric acid and salazinic acid has resulted in a much more rise in
no effect on the ERK and AKT signaling pathways [103,104]. Similarly, the sub-G1 phase and a consequent reduction in the G2/M phase, sup
HeLa, human neuroblastoma, and leukaemia (K562) cell-lines have been porting the arrest of the G1 stage. A spike was observed in cells con
affected by protolichesterinic acid [103–105]. In the presence of pro taining sub-G1 levels of DNA, suggesting that the compound caused cell
tolichesterinic acid, upregulation of human epidermal growth factor death [95]. Protocetraric acid is the ideal candidate for in vivo melanoma
receptor-2 (HER2) and fatty acid synthase (FASN) was also observed studies as it displayed the highest selectivity index towards UACC-62
[104]. FASN is an important enzyme which catalyzes long chain fatty cells [77]. Inhibition of DXR-induced mutagenicity in somatic cells of
acids in mammalian cells [31]. It also controls the expression of HER2, Drosophila has also been reported by protocetraric acid [113]. Proto
which is a transmembrane receptor tyrosine kinase. In breast cancer, cetraric acid showed a robust cytotoxic effect on UACC-62 cells, and
both of these are over-expressed. Any target drug which stops the higher activity for melanoma cells than 3T3 normal cells. It also proved
expression of FASN can also inhibit the HER2 expression [31].The effect to be the best candidate for in vivo studies of melanoma, as it showed
of protolichesterinic acid extracted from Cetraria islandica was analyzed high activity against UACC-62 cells [12].
in human pancreatic carcinoma (AsPC-1) and human multiple myeloma
(RPMI 8226, U266). It was observed that protolichesterinic acid inhibits
the proliferation of AsPC-1 and RPMI 8226, U266, cells with shallow 3.10. Parietin
IC50 values, inducing apoptosis of RPMI 8226 and U266 cells, but not of
pancreatic AsPC-1 cells. Cell-cycle arrest of pancreatic AsPC-1 cells in G1 Parietin is an anthraquinone compound of orange-yellow hue that
phase was also observed [12]. absorbs blue light. It is synthesized with mycobiont; protects photobiont
from oxidation caused by harmful solar radiation [114]. It is extracted
3.8. Physodic acid from the lichen Xanthoria parietina to analyse its antiproliferative and
anti-cancer properties [57,66,114]. The higher anti-cancerous activity
Physodic acid is a depsidone derived from Hypogymnia physodes, of X. parietina is because of its higher antioxidant contents, including
H. lugubris and Pseudevernia furfuracea [47,49,71,106–108]. In the superoxides and peroxidases [57,114–116]. When used with acetone
acetyl-polymalonyl process, depsidones, such as physodic acid, are extract of 1.5 mg/mL, parietin resulted in blockage of cells in the G1
produced by lichens, and have been shown to have a favourable phar stage after 48 h of treatment [57,115,116]. However, parietin alone did
macological profile as well [71]. Much of the experiments performed not produce any desired results, even at high dose concentration, sug
have analyzed the anti-microbial, cytotoxic, and anti-oxidant effects of gesting that acetone extract’s multifactorial components contribute to
these compounds [20,47,71,107,108]. It has been evaluated against its anti-cancer action [57,116].
brain cancer, ovarian cancer, bladder cancer, breast cancer, melanoma, Several studies have revealed that parietin causes proliferation in
colorectal cancer, pancreatic cancer, and leukemia [71]. Physodic acid hibition and apoptosis in the MDA-MB231 cell-lines [31,57,114]. These
cytotoxicity seems to be high against colorectal cancer-cells (IC50 = two effects are followed by regulation of expression of gene products of
17.89 μg/mL), correlated with an elevated number of cells in the sub-G1 cell-cycle genes such as cyclin A, cyclin D1, p27, and p16. It also induces
phase [56], and reduced production of anti-apoptotic survival protein apoptosis by stimulating external and internal cell-death pathways,
(known as a baculoviral inhibitor of apoptosis repeat-containing 5 or upregulating tumor necrosis factor-related apoptosis-inducing TRAIL
BIRC5). It also induces apoptosis due to decreased Bcl2 levels and (Tumour necrosis factor apoptosis inducing ligand), B-cell lymphoma 2
over-expression of Bax and caspase-3 activity in melanoma cells of A375 (Bcl-2), and triggering cell-death against phosphorylation [117]. Studies
[71]. Moreover, physodic acid has contributed to a decrease in the have also shown that parientin from Xanthoria parietina has also been
expression of the matrix metalloproteinase-7 (MMP-7) and other genes used with gyrophoric acid to treat human ovarian carcinoma cells A278
of the β-catenin-dependent Wnt signalling system involved in cancer-cell [118]. Specifically, methyl-βorcinol carboxylate with IC50 of 0.25 μg/mL
migration, invasion, and growth [49]. It has also been reported that is the cause of proliferation inhibition in ovarian cancer cells. It has
physodic acid cytotoxic activity was high against melanoma cell-lines already been documented by Triggiani et al. (2009) that extract of
(IC50 = 19.52 μg/mL), and enhanced pro-apoptotic Bax expression Xanthoria parietina possesses antiproliferative property on murine
and declined anti-apoptotic Bcl-2 and Hsp70 expression [71,109]. myeloma cells (P3 × 63Ag8.653) and result in upto 75 % reduction in
The cytotoxicity effect of physodic acid was investigated on A375 cell proliferation [118].
melanoma cancer cell-lines, reduced growth of melanoma cells, and
activation of apoptotic process by a mechanism probably involving the
downregulation of HSP70 [31]. Emsen et al. (2016) showed that the 3.11. Pannarin
effect of physodic acid, olivetoric acid and psoromic acid was analyzed
by [110] on U87MG and rat PRCC cells.; and that they found a positive Pannarinis is a natural depsidone derived from species of Pannaria
relationship between the cytotoxicity (lactate dehydrogenase activity, lichen genera (Fulvesencs, Lurida, Pityrea and Rubiginosa), and extracted
and oxidative damage of DNA) associated with these metabolites and from Pityrea palladium [119,120].The right chemical structure of pan
their concentrations. Physodic acid showed moderate cytotoxicity narin was deciphered by Jackman. It has been tested in-vitro on human
against cell-lines of the bladder, breast, pancreatic, cervical cancers and prostate carcinoma DU-145 cell-lines, and findings have shown that it
leukaemia [57], whereas low cytotoxicity is seen towards cell-lines of exhibits important inhibitory action (P < 0.001) on DU-145 cell growth.
cerebral cancer [52]. It has significantly decreased the expression of axin Research studies have also unravelled that depsidones, especially pan
2 in HCT116 cells [10,49,72]. narin, are higly anti-cancerous drugs than other depsides [64,121].This
could be due to a higher penetration of depsidones into lipid micro
3.9. Protocetraric acid domains of cancer cells. Researchers have proposed that pannarin in
creases the productivity of reactive oxygen species (ROS) which initiates
Protocetraric acid, a significant lichen-compound, has been isolated a necrotic pathway in DU-145 cells [122]. It is further reported that
from Parmelia sulcata, P. caperata, P. saxatilis, and Usnea albopunctata. caspase-3 enzyme activity rises substantially in DU-145 cells by treat
There are reports that both FEM-x (human melanoma) and LS174 ment with pannarin at a concentration of 12 and 25 mmol/llinked with
(human colon carcinoma) cell-lines with IC50 show good anticancer higher DNA fragmentation, although without the plasma’s degradation
activity with protocetraric acid [96]. After analysing various in vitro membrane, as measured by the percentage of LDH release. Strong
assays, it has been documented that protocetraric acid exhibits a high cytotoxic effects were observed when pannarin extract was tested
antioxidant activity [111,112].The treatment of LS174 cells with against (Lymphocytes from ratspleens) cell-lines [56].
7
3.12. Stictic acid expression of the cleaved form of the poly ADP-ribose polymerase
(PARP), a DNA repair and apoptosis regulator and expression of the cell
Stictic acid is one of the commonly distributed depsidones found in cycle and apoptosis-related marker genes [134].Therefore, lobaric acid
lichen species with molecular formula C19H1409. It has been tested in in and lobarstin have significantly inhibited cell proliferation by halting
vitro against human cancer cell-lines like MCF-7 and HT-29. HT-29 the cell-cycle and inducing apoptosis in colon and cervix adenocarci
human colon adenocarcinoma cells are the most vulnerable to stictic noma cells via the mitochondrial pathway [5]. Lobaric acid show strong
acid (IC50 value 29.29 μg/mL); compared to MCF-7 human breast to moderate cytotoxicity against several cancer cell-lines like, breast
adenocarcinoma, the compound evaluated was 689-fold more respon cancer, brain cancer, colorectal cancer, cervical cancer, ovary cancer,
sive to cell-line HT-29 [123]. It has been reported that other secondary lung cancer, pancreas cancer, prostate cancer, stomach cancer, mela
lichen metabolites like gyrophoric acid, parietin, usnic acid, and atra noma and leukemia (IC50 value of ≤ 100 to IC50 value of ≤ 30 μg/mL).
norin, compared to stictic acid, have been less susceptible to HT-29 Several research studies have also shown that lobaric acid also exhibits a
cell-lines even after the 72 h exposure [66]. strong inhibitory effect on thioredoxin reductase [67] and is, therefore, a
potential anti-cancer drug that induces oxidative stress as cell-cycle ar
3.13. Vulpinic acid rest and apoptosis [69]. Significant reduction in DNA synthesis was
observed when lobaric acid was used against Breast cancer cell-lines
Vulpinic acid is a derivative of pulvinic acid, used as a therapeutic (T-47D, ZR-75− 1) and Erythro-leukemia cell-lines (K-563).
agent against breast cancer. After treatment with different concentra
tions of vulpinic acid, it inhibits the proliferation of breast cancer. It has 3.16. Usnic acid
been documented that vulpinic acid inhibited the development of BT-
474 and SK-BR-3 cells in a time-dependent and dose-dependent Usnic acid is dibenzofuran sub-metabolite multifunctional bioactive
fashion with IC50 values of 5 μM [124,125]. Studies have revealed lichen acid, which may have anti-cancer effects. It was first extracted by
that vulpinic acid is more harmful to keratinocytes (HaCaT) than to the German scientist W Knop in 1844 and synthesized by Curd & Rob
malignant MM98 mesothelioma cells and A543 vulvar carcinoma cells ertson between 1933 and 1937. Usnic acid is a yellow cortical pigment
[125]. However, studies have also documented that vulpinic acid is that, depending on the angular methyl group’s projection at the chiral
slightly less toxic to HUVECs than NS20Y and HepG2 cancer cells. 9b position, exists in two enantiomeric forms (+)usnic acid and (–)usnic
Vulpinic acid tends to be moreappropriate as an anti-angiogenic agent acid [136].
than (-)-usnic acid due to its poorer toxicity and more significant Usnic acid has been found in various species of lichen genera, such as
anti-angiogenic effect [125,126]. A significant result of vulpinic acid Usnea, Lecanora, Cladonia, Evernia, Parmelia, Alectoria and Ramalina.
blocks the breast cancer cell-lines and has a minimal inhibitory effect on Kupchan & Kopperman have first shown in vitro anti-cancenogenic ef
non-carcinogenic breast cells’ human epithelium. Thus,because of its fects of Usnea acid for Lewis lung carcinoma [137]. It is among the only
reduced sensitivity to non-cancerous epithelial cells, vulpinic acid has a commercially available and used lichen compounds in 50 % of the sci
more significant therapeutic edge than many traditional drugs in the entific papers on its anti-cancer properties. Natural sources of usnic acid
drug industry [17]. reported in cancer literature include Cladonia arbuscula, C. convoluta, C.
lepidophora, C. foliacea, C. leptoclada, Alectoria ochroleuca, A. samentosa,
3.14. Physciosporin Ramalina farinacea, Usnea subcavata, U. florida, U. diffracta, U. long
issima, U. barbata, Flavocetraria cucullata, F. nivalis, Parmelia subrudecta,
Physciosporin is a depsidone-derived lichen metabolite present in and Xanthoparmelia somloensis [13]. Usnic acid and usnic acid-amine
many members of the genus Pseudocyphellaria [127]. Physciosporin derivatives have demonstrated in vitro antiproliferative efficacy
isolated from P. granulate was tested against a wide range of colorectal against a wide spectrum of human cancer and murine cell-lines [66,91,
cancer cell-lines (Caco2, CT26, DLD1, SW620,HCT116). Another phys 138–141]. This acid has been used to evaluate its pro-apoptotic abilities
ciosporin, extracted from P. coriacea and tested on A549, H1650 and in human rhabdomyosarcoma (RD), human colorectal adenocarcinoma
H1975 cell-lines, revealed anti-cancer effect by inhibiting invasion and (CaCo2), human cervical carcinoma (Hep2C), mouse fibrosarcoma
migration of human lung cancer cells A549, H1650 and H1975 by (Wehi), human hepatocellular carcinoma (HepG2), as well as in mouse
downregulating KITENIN-mediated AP-1 activity, N-cadherin, Rac1, subcutaneous connective tissue (L929) cell-lines and nonmalignant Af
and Cdc42 [128]. Interestingly, the metastasis suppressor gene KAI1 was rican green monkey kidney (Vero). Studies have revealed that in cancer,
also upregulated by physciosporin [129]. It has also been reported that but not in non-malignant cells, usnic acid increases expression of Bax,
physciosporin causes apoptosis by raising the amounts of PARP and and decreases the expression of p53 and Bcl-2 genes [142]. At the
caspase-3 and inhibit the motility and tumorigenicity of CRC cell-lines concentration of 8μM, usnic acid inhibits the SCFmediated migration of
significantly [130–132]. Studies have documented that physciosporin human colorectal cancer (HCT116, LS174 c-KIT+) cells. The
modulates the expression of the EMT effectors N-cadherin and vimentin anti-proliferation activity of this acid on human gastric carcinoma cells
through deregulation of the transcription factors Twist, Slug, Snail, Zeb1 (BGC823, SGC7901) has been evaluated and confirmed, with BGC823
and Zeb2 [130,132]. being highly acid-sensitive.
Usnic acid toxicity was correlated with elevated P450 activity and
3.15. Lobaric acid and lobarstin oxidative stress in human hepatoblastoma cells [141], pancreatic cancer
Capan-2 cell-line, breast cancer T-47D cell-line [143], and mitochon
Lobaric acid and lobarstin are secondary metabolites isolated from drial dysfunction in HepG2 cells [141], with apoptotic activation in
antarctic lichens Stereocaulon alpinum and S. halei [13,78,133–135]. murine leukemia L1210 cells [139]. Due to its capacity to break down
These two secondary lichen metabolites have been shown to have high and suppress the electron transfer chain in mitochondriaand trigger
anti-cancer activity on HeLa cells of the human cervix adenocarcinoma oxidative stress in cells, it was found to be a potent hepatotoxic against
and HCT116 cells of colon carcinoma [5,133]. The effect of these two monogastric murine hepatocytes [144]. Usnic acid (commercial) was
compounds shows significant results by decreasing in a dose- and tested with Human ovarian carcinoma A2780 and Human colon
time-dependent manner. Flow cytometry analysis of these compounds adenocarcinoma HT-29 cell-lines; wherein activated programmed
shows prominant apoptosis in both the cell-lines, following cell-cycle cell-death through the mitochondrial pathway was observed [31,145].
supression and arrest in the G2/M phase [5,134]. Further, the immu No morphological changes in microtubules or increase in the mitotic
noblot assay also shows significant results in the decreased expression of index was observed when usnic acid was tested against Breast cancer
the apoptosis regulator B cell lymphoma 2 (Bcl-2) gene and increased cell-line MCF-7, and Lung cancer cell-line H1299 (null for p53). It has
8
been reported that usnic acid (isolated from Cladonia convoluta) induces prostate cancer cells [152]. Two Roccellamontagnei-isolated lichen sec
apoptotic cell-death in murine lymphocytic leukemia cells. It is ondary metabolites, evernic acid and roccellic acid, display anti-cancer
moderately cytotoxic to various cancer cell-lines, like human chronic activity, along with inhibition of cyclic dependent kinase CDK-10 in
myelogenous leukemia, murine Lewis lung carcinoma, human glio FaDu cancer cells of the neck and head [153]. Barbatic acid extracted
blastoma, human brain metastasis, prostate carcinoma and human from the lichen Cladonia aggregata was evaluated for the nasopharyngeal
breast adenocarcinoma [139]. Reduction in cell size was observed, and squamous cell carcinoma cell-line KB.
both acids inhibited cell entry into the S-phase. No apoptosis was seen,
but in Capan-2, necrosis was seen. Nguyen et al. (2014) tested the 4. Efficacy and perspective clinical use of lichen metabolites in
cytotoxic activity of 17 lichen species against several human cancer cancer management
cell-lines; HT29 (colon cancer), AGS (gastric cancer), A549 (lung can
cer), CWR22Rv-1 (prostate cancer), HaCaT (human keratinocyte), NIH Lichens are a rich source of bioactive molecules with a lot of thera
3T3 (mouse embryonic fibroblast cells), HEK293T (human embryonic peutic promise in cancer treatment. Modern methods enable the isola
kidney) cells, RIE (rat intestinal epithelial) cells, and Madin-Darby tion and characterization of lichen metabolites, as well as the
canine kidney (MDCK) cells. It was observed that usnic acid signifi visualisation of their complex biological and cellular effects, allowing
cantly decreases motility of cancer cells and inhibits in vitro and in vivo for a quick assessment of future clinical testing and the use of lichen-
tumorigenic potentials. derived anticancer drugs in medicine [97]. The dynamic structure of
In MCF-7 breast cancer cell-line, lichen acid extracted from Hypo malignant tumours differ in cell lines in numerous ways at genotype and
gymnia physodes triggers inhibition of apoptosis and cell growth [146], phenotype level. These cell lines are highly sensitive to therapies and
while as no microtubular and morphological changes are seen when the most of the cell lines develop resistance to the drugs [154]. This has
same cell-lines are treated with usnic acid. This study research contra become a serious issue in the way of treating cancer. The use of lichen
dicts the previous findings [31], where after usnic acid treatment, acid and convectional therapy in combination is not only beneficial but a
microtubular and morphological changes were seen in MCF-7 cells, good concept for targeting numerous signalling pathways that are
suggesting that the treatment effects on the cells of breast cancer can be responsible for inducing cancer [155]. Studies have revealed the po
due to the successful concentration of usnic acid in these studies. tential of lichen acids with respect to the anticancerous property both in
Exposed to usnic acid derived from Flavocetraria cucullata, human em vivo and in vitro. It can be clearly seen that usnic acid act as an inhibitor
bryonic renal cells HEK293T induced apoptosis, and declined cell of angiogenesis in vascular endothelial growth factor (VEGF) model and
movement and epithelial-mesenchymal transition (EMT) [38]. A hexane chick embryo. It also inhibits the growth of Bcap-37 BC cells inoculated
extract isolated from Parmelia caperata [14] and usnic acid from Cla in the female nude mice C57BL/6, resulting in the suppression of
donia arbuscula were tested for their anti-cancer properties on prostate angiogenesis. While as in cell based system usnic acid results in reduc
cancer cells DU 145, and showed a remarkable impact on cancer cells. tion in the human umbilical vein endothelial cells (HUVEC) cell prolif
Usnic acid also decreased the proliferation, without DNA damage, of eration, tube formation and migration. It also decreases Bcl-x1/survinin
human lung cancer cells and human breast cancer cells [140]. The levels that blocks VEGF receptor-2 (VEGFR-2) responsible for ERK1/2
synthetic derivatives of this acid, by using lipid-based nanocarriers also and AKT signalling [156]. The efficacies of various lichen extracts in vivo
show antiproliferative activity in breast cancer (MCF-7), human and in vitro are depicted in Table 2.
epithelial carcinoma (HeLa) and human prostate cancer (PC-3) cells.
This acid is encapculated into micro/nano/polymeric or lipid based 5. Molecular mechanisms involved in the anti-cancer activity of
carriers in order to enhance its usage as therapatic agent [147,148]. The lichen metabolites
synthetic derivatives of this acid also show anti-proliferative activity in
Breast cancer (MCF-7), human epithelial carcinoma (HeLa), human Uncontrolled cell-growth with several other characters like deregu
prostate cancer (PC-3) cells [147,148]. It is important to discover cancer lation of metabolism, malfunctioning of the immune system, and
therapies that do not have a DNA-damaging effect and, therefore, do not angiogenesis induction are the cancer criteria [184]. Cancer is treated by
cause the production of secondary malignancies in later years. There chemotherapy or target therapy, radiation therapy, and surgery options
fore, usnic acid can be a novel source of a natural non-genotoxic drug for in some instances. The various medicines used for cancer treatment
cancer (a chemotherapeutic agent). showed undesirable side-effects leading to the disturbance of the im
Several potential lichen-derived metabolites described in the above mune system, hematopoiesis, digestives system, etc [93]. To overcome
section have evolved our understading of their mechanism of action and such effects, targeting cancer cells using target therapy by intervening
anticancer activity on several cancer cell-lines. Upon exploring the po the cancer-signalling pathway is always needed. Small molecules and
tential anti-cancer metabolites in lichens, several additional metabolites antibiotics are used as target chemicals in this therapy; the most
with low anti-cancer activity have also been reported (Fig. 2). Ramalin, promising source seems to be the lichen products.
a secondary lichen metabolite, showed G2/M cell-cycle arrest as an The lichen products, also known as lichen acids, have great potential
indication of HCT116 cell apoptosis. In addition, there has been a raise against carcinogenesis [11]. This potential of lichen acids is due to their
in the expression of the TP53 protein and a decline in CDK1 and CCNB1 antioxidant, cytotoxic, anti-proliferative, anti-invasive, anti-magrative,
[122]. Tumidulin, another promising anti-colorectal agent, decreases anti-tumor and pro-apoptotic nature [12,13]. Most lichens’ antioxi
spheroid formation in DLD, HT29 and CSC221, mRNA expression, and in dant property is usually associated with the phenolic compounds, which
cancer markers such as CD133, aldehyde dehydrogenase-1, CD44, and possess high free-radical scavenging property [12]. The prevention of
Lgr5. Tumidulin impedes oncogene-linked glioma transcriptional ac mutagenesis and carcinogenesis by lichens is due to inhibition of
tivity (Gli1 and Gli2) [149]. In squamous lung cancer cells treated with oxidation of cellular macromolecules (Studzińska-Sroka et al., 2016).
lichen extracts of Cladonia and barbatic acid, anti-neoplastic activity These abilities are visualized by superoxide dismutase (SOD) or
with poor toxicity was observed on normal cells [150]. Treatment of malondialdehyde (MDA) stress markers [49]. The higher cytotoxic effect
olivetoric acid and psoromic acid on human U87MG-GBM cell-lines also has been reported in the cancerous cells compared to the non-cancerous
showed cytotoxic effects of these two meta-toxic acids [110]. Sphaer cells [187,188]. This ability of lichens is attributed to the processes,
ophorin, and epiphorellic acid-1, extracted from Sphaerophorus globosus, including apoptosis, autophagy and cell-cycle arrest at G2/M, S, or
and Cornicularia epiphorella, respectively, increased DNA fragmentation G0/G1 phases [12,189]. They regulate cell-cycle through multiple
and caspase-3 activity in prostate cancer cell-line DU-145 cells [151]. mechanisms by their intervention with cyclins (cyclin D1) and
Other lichen secondary metabolites, retigeric acid A and B, extracted cyclin-dependent Kinases (CDK4, CDK6) [44].
from Lobaria kurokawae, showed growth inhibition and cytotoxicity on Anti-proliferating effects of lichens can be regulated by signalling
9
Table 2
Anti-cancer effects of species/ lichen acids on different types of cancers (in vitro/in vivo).
S. Species/lichen acid Cell lines/models Effects in References
No. vitro/
in vivo
1. Extracts of Umbilicaria crustulosa, FemX, LS174 Increased Cytotoxicity in vitro [157]

Umbilicaria cylindrical and Umbilicaria
polyphylla
2. Methanol extract of Lasallia pustulata FemX,LS174 Increased cytotoxicity in vitro [158]
3 Extracts of Parmelia caperata, Parmelia FemX, LS174 Increased cytotoxicity in vitro [157]
sulcate and Parmelia saxatilis
4. Extract of Parmotrema reticulatum MCF-7,A549,WI-38 Increased cytotoxicityInduction cell cycle arrest in vitro [159]
5. Extract of Cetraria islandica FemX, LS174 Increased cytotoxicity in vitro [160]
6. Extract of Parmelia arseneana FemX, LS174, A549, K562 Increased cytotoxicity in vitro [157]
7. Extracts of Dermatocarpon vellereum, HepG2, RKO Increased cytotoxicity in vitro [54]
Umbilicaria vellea, Xanthoria elegans,
Melanelia disjuncta, Melanelia disjuncta,
Lobothallia alphoplaca and Xanthoparmelia
stenophylla
8. Extracts of Parmelia sulcata Taylor and A549, PC-3, Hep3BRat glioma C6 Increased cytotoxicityInduction in vitro [161]
Usnea filipendula Stirt genotoxicityInduction apoptotosis
9. Extract of Hypogymnia physodes MCF-7, MDA-MB-231 Increased anticancer and/or apoptosis-inducing in vitro [162]
(low concentration) effectIncreased
genotoxicity (high concentration)
10. Extracts of Cladonia rangiformis and MCF-7 Induced apoptosisDecreased in vitro [163]
Cladonia convolute proliferationIncreased cytoxicity
11. Extract of Xanthoria parietina MCF-7, MDA-MB-231 Decreased proliferationDecreased cell in vitro [114]
cycleIncreased apoptosis
12. Extract of Parmelia sulcata MCF-7, MDA-MB-231 Induced cytotoxicityInduced apoptosis in vitro [164]
13. Extracts of Xanthoparmelia chlorochroa and Human Burkitt’s lymphoma (Raji) Induced apoptosisInduced cell arrestIncreased in vitro [165]
Tuckermannopsis ciliaris p53 expression
14. Extracts of Parmotrema gardneri, Pannaria AGS, A549, MDCK Increased cytotoxicity in vitro [166]
sp., and CanoparmeliaAptata
15. Extract of Cladonia rangiformisExtract of MCF-7 Increased cytotoxicity in vitro [167]
Cladonia convoluta
16. Caloplaca pusilla (on G-LBM medium) HeLa, MCF-7, PC-3 Decreased viabilityInduce apoptosisDecreased in vitro [168]
Xanthoria parietina (on PDA and G-LBM) cancer cell viability of MCF-7 and HeLa
17. Extract of Cladonia pocillumon MCF-7 Decreased apoptosis (concentration-dependent) in vitro [169]
18. Extract of Pleurosticta acetabulum HT-29 Increased cytotoxicityDecreased in vitro [170]
(cytochalasin E) proliferationInduce apoptosis
19. Polysaccharide from Umbilicaria esculenta A875, A375, HUVEC Increased cytotoxicity of A875 and in vitro [171]
A375Increased Annexin-V positive and TUNEL
positive A875Induce apoptosis of A875 (ROS
generation followed by " caspase-3 and -9)
20. Extracts of Cladonia furcata and HeLaHuman lung carcinoma A549Human colon Extract of C. foliacea: Increased cytotoxicity of in vitro [172]
CladoniaFoliacea carcinoma LS174 A549Extract of C. furcata: Increased
cytotoxicity of HeLa
21. Extract of Candelariella vitelline Caco-2 Decreased proliferation (Ki-67)Induced in vitro [173]
apoptosis,Increased necrosisDecreased Bcl-
2Increased Bax,Increased CASP3 protein
levelIncreased Bax/Bcl-2 ratio
22. Extract of Usnea intermedia A549, H1299, MCF7, MDA-MB-231 Decresed proliferation of H1299Induced in vitro [174]
apoptosis (phophatidylserine translocation,
Icreased caspase 3/7 activity, lossof
mitochondrial membrane potential, formation
of pyknotic nuclei)
23. Nemania serpens and Nemania aenea var. HT-29, HCT116, PC-3 and DU145 Decreased anticancer activity,Induced apoptosis in vitro [175]
aureolatum (isolates of endolichenic fungi (activated caspase 3, 8, PARP cleavage,
associated with the lichen Nephroma chromatin fragmentation)
laevigatum)
24. Physcia milegrana HeLa, Vero Increased cytotoxicity of HeLa in vitro [176]
Decreased angiogenesis and VEGFR2
Bcap-37 cells inoculated into C57BL/6 female
mediatedERK1/2 and AKT signaling; Decreased
nude mice; chick embryo chorioallantoic
Bcap-37 cellsgrowth; Decreased proliferation, in vivo [156]
membraneassay; mouse corneal angiogenesis
migration, and tubeformation and Increased
model
apoptosis of HUVEC cells
Human breast cancer MCF-7 cells inoculated into Decreased tumor growth in dose dependent
in vivo [177]
Balb/c nude mouse manner;any toxic effect in animals
25. Usnic acid
Decreased toxicity of bleomycin therapy;
Increased efficacy of combined therapy vs
bleomycine alone-arrested tumor cells in G0/
H22 cells inoculated into male KunmingMice G1;Increased caspase-3 and -8; Decreased levels in vivo [51]
of MDA,hydroxyproline, TNF-_, IL-1_, IL-6 and
TGF-_1 and Increased levels of SOD; Decreased
p-Smad2/3;Increased Smad7 proteins
Human breast cancer MDA-MB-231 and MCF-7
26. Usnic acid and its benzylideneAnalogue in vivo [179]
cells inoculated into athymic nude mice
(continued on next page)
10
Table 2 (continued )
S. Species/lichen acid Cell lines/models Effects in References
No. vitro/
in vivo
Increased anticancer activity on both

xenograftmodels; Increased autophagy;
Decreased mTOR signalling
27. Usnic acid Human gastric carcinoma BGC823 cells Decreased tumor volume and weight; Increased in vivo [178]
inoculated s.c. into the flank of female BALB/C tumor ratio of Bax/Bcl-2 compared to 5-FU
nude mice
28. Usnic acid and Potassium usnate Mouse colorectal cancer CT26-Fluc Decreased tumor growth in orthotopic liver in vivo [179]
cellsinoculated by intrasplenic injection of male metastasis model; Decreased levels of EMT; PU
BALB/c mice without hepatotoxic effect in liver metastasis
model
29. Ethyl acetate extract of Usnea longissimi Gastric and esophagealadenocarcinomas of Decreased tumor formation; extract in vivo [180]
Albino Wistar male rats induced by oral N- concentrations of 50 and 100 mg/kg
methyl-N-nitro-N-nitrosoguanidin administration demonstratedselectivity to cancer tissue and
low toxicity profile in animals
Increased survival time of tumor-bearing
Mouse breast carcinoma 4T1 cells inoculated into animals;Decreased tumor volume; Increased
in vivo [181]
BALB/c mice apoptosis; Decreased oxidative stress in livers of
30. Atranorin tumor-bearing mice
Decreased tumor volume and weight; Decreased
Mouse Lewis lung carcinoma cells inoculated into
Ki-67;Decreased KITENIN, CD44, STAT, and in vivo [65]
the flanks of C57BL/6 mice
cyclin-D1
Dalton’s lymphoma ascites cells inoculated into
Albino Wistar rats and consequent cancer fluid Decreased tumor volume; effect comparable to
31. Extract of Rocella montagnei in vivo [182]
aspiration from rat peritoneal cavity injected into Vincristine
new animals
Mouse colorectal cancer CT26 cells inoculated
Endolichenic fungus EL002332 into BALB/c syngeneic mice; TMK1 cells injected Decreased tumor score and tumor volume in
32. in vivo [183]
(Endocarpon pusillum) into the abdominal cavity of BALB/c mice skin and intraperitoneal tumor-bearing animals
(intraperitoneal xenografts)
Decreased tumor volume; Decreased tumor cell
Ehrlich ascites carcinoma cells were injected i.p.
invasion and mitotic activity; Increased
33. Extract of Candelariella vitelline and consequently transferred every 5 days into in vivo [190]
formation of apoptotic bodies; Increased ratio of
new female Swiss albino mice
Bax/Bcl-2 on both mRNA and protein levels
Physciosporin (Pseudocyphellaria Mouse colorectal cancer cells CT26 implanted Decreased tumor volume and weight; without
34. in vivo [184]
granulata) into male BALB/c mice changes in body weight of animals
Sarcoma-180 cells inoculated in the right axillary
35. Barbatic acid(Cladia aggregate) Decreased tumor weight; apoptosis in vivo [185]
region of female albino Swiss mice
Hypostictic acid (Pseudoparmelia
Murine melanoma B16-F10 inoculated into male Decreased tumor volume in both acids; high
36. sphaerospora)Salazanic acid(Parmotrema in vivo [186]
BALB/c mice cancer selectivity and low toxicity in both acids
cetratum)
Human breast cancerMDA-MB-231/GFP cells Decreased tumor volume and weight; Decreased
37. Nortictic acid(Usnea strigosa) in vivo [191]
inoculated into female nude mice c-MetPhosphorylation
pathways such as Ki-67 (protein proliferation marker), ERK1/2 and Akt (fabro-sarcoma of the mouse), RD, CaCo2, Hep2C, HepG2 (human
[190]. STATs (signal transducer and activator of transcription), rhabdomyosarcoma), colorectal adenocarcinoma, cervical carcinoma
Paxillin/Rac-1(Rac-related C3 botulinum toxin substrate 1), and P13 and hepatocellular carcinoma, showed a promising impact, while as no
K/Akt (protein kinase B, also known as Akt)/ mTOR (mammalian target effect on non-cancerous L292 and Vero was observed. This is only
of rapamycin) signalling cascades are regulated by the transition factors possible because usnic acid enhanced the Bax expression and decreased
like c-Met, that are cancer-invasive and associated with pathway mod Bcl-2 and p53 genes in cancerous and non- cancerous cells, respectively
ulation maintained by the anti-cancerous potential of lichens [191]. [194].
MMP7 (matrix metalloproteinase-7), BIRC5 (Baculoviral IAP Repeat Anticancer properties of lichens are also related to the AP-1 family by
Containing 5), Axin2 genes related to cell apoptosis, and cyclin D1, regulating c-jun and c-fos, which are considered critical regulators of
c-mycgenes associated with cell-cycle regulation are actively affected gene expression. Simultaneously, as declined KITENIN- mediated AP-1
by the lichens, as it targets β-catanin or its downstream effectors [49]. activity is also associated with lichens’ anti-cancerous property [65].
Lichen acids stop the migration and invasion of various signalling Current findings have shown that the anti-cancer effects of lichens are
molecules, such as Cdc42 (cell division control protein 42), Rac1, RhoA, also associated with the regulation of inflammatory reactions through
and KITENIN, which play a crucial role in progression and development TGF- 1, TNF-, IL-1, and IL-6, [51], and the targeting of microRNA
of tumors. They also target genes including CAPN1, CFL1 (Cofilin-2 molecules [195].
human Recombinant protein), CDC42, WASF1 (Wiskott-Aldrich Syn Lichens also act as activators of apoptosis to regulate cancerous ac
drome protein family member 1) or IGF1 (insulin-like growth factor 1), tivity in cancer cells intervening through gene expression to optimize
and markers related to metastasis. On the other hand, the anti-cancer apoptosis via caspases P53 and P38 and Bcl-2 family [193]. PARP (Poly
activity of lichen induced by angiogenesis inhibitors is due to repres ADP-Ribose polymerase) increase and its cleaved nature by caspases for
sion of endothelial tube formation [192] or VEGFR-2 mediated act and DNA damage repair are also induced by lichen acids [196]. Cleaved
extracellular signal-controlled kinase (ERK) signalling [193]. Endothe PARP is used as an indicator for Western Blotting to detect DNA repair
lial tube formation or VEGFR-2 mediated Akt is also suppressed by the [44]. Apoptosis is initiated by caspase-3, activated by the liberation of
angiogenesis inhibitor activity of lichen acids [192]. The effect of lichen cytochrome c, mediated by the increase of Bax/Bcl-2 ratio. Many lichen
acid, particularly of Usnic acid, on the cancerous cell of Vero (African acids, like Usnic acids, b-glucan and galacto-mannan have great po
green monkey kidney), L292 (subcutaneous connective tissue), Wehiq tential against cancer cells [197,198].Usnic acid is reliable because no
11
effect on animals is visualized as apoptosis of cancer cells via caspase Table 3

pathway (JNK and ROS activation) leading to human MCF-7 breast Molecular mechanism of lichen-derived bioactive compounds as potential anti-
cancer [199]. The Molecular-level involvement in the anticancer activ cancer drugs.
ity of lichen metabolites is depicted in Table 3 and Fig. 3. Recently in S. Bioactive Molecular mechanism Reference(s)
2020, Goncu and his coworkers carried out the research on the identi No. compound
fying the effects of various lichen extracts in terms of apoptosis and 1. Atranorin • Arrests G0/G1and S phase of [20,65]
proliferative properties by using various methods (Western blot, LDH, cell-cycle and it also inhibits the
MTT and Annexin V assays). They concluded that the lichen extracts intrinsic pathway (mitochon
drial membrane depolarization,
showed a prominent antiproliferative and apoptotic effect on PC-3 cells
caspase-3 dependent, increased
which is the main reason for inducing apoptosis by both intrinsic and pro-apoptotic Bax expression,
extrinsic pathways. Use of low concentrations in the treatment has decreased anti-apoptotic Bcl-xl
resulted in increased apoptotic protein expression [130]. expression, increased Hsp90
expression, decreased Hsp70
expression)
6. Lichens: potential agents for combinational cancer therapies • Increases production of ROS
2. Usnic acid • Inhibits the G0/G1,G2/M and S [51,52,72,125,
As the mortality rates for all types of cancers have decreased, modern phase of cell-cycle through the 193,198,228,
therapies contribute only a tiny fraction of this improvement [200]. This modulation of CDK-cyclin-CDK1 229,230]
• Modulates p53/p21/cyclin
is partly due to laborious and expensive-to-manufacture novel pre
pathway
scription anti-cancer agents, requiring initial in vitro and in vivo clinical • Inhibits stem cell factor (SCF)
trials before FDA approval. It is predicted that a latest developed • Inhibits actin cytoskeleton
medication takes 15 years to reach the drug in the market [201]. Newer organization
• Regulation of Rho GTPase
methods, which do not rely profoundly on a single agent’s conventional
(mTOR)
cytotoxicity profile, are needed to offer a more selective, reliable and • Modulation of β-catenin
improved type of cancer treatment. For example, chemoprevention with mediated and KITENIN-
natural compounds and monoclonal antibodies are indicators of new mediated signaling pathways
methods to avoid or cure cancers [202–204]. • Inhibits mammalian target of
rapamycin
Combination therapy, a method of care that incorporates two or
• Inhibits VEGF signaling
more medicinal drugs, is the foundation of cancer therapies. Anti-cancer • Induces apoptotic cell-death by
medications’ amalgamation increases effectiveness relative to the activating intrinsic pathway
monotherapy method, since it addresses primary receptors in a char (mitochondrial membrane de
acteristically synergic or additive fashion. This strategy theoretically polarization, caspase-3 depen
dent, increased pro-apoptotic
declines drug resistance while, at the same time, offering therapeutic Bax expression, decreased anti-
anti-cancer advantages, such as reducing tumor development and met apoptotic Bcl-xl expression,
astatic capacity, halting mitotic cells, decreasing stem-cell populations increased Hsp90 expression,
of cancer, and triggering apoptosis. Conventional mono-therapeutic decreased Hsp70 expression)
and increases production of ROS
strategies are not selectively aimed at actively proliferating cells,
• Inhibits mammalian target of
eventually contributing to both healthy and cancer cells’ death. rapamycin (mTOR)
Chemotherapy can be harmful to patients with several side-effects and 3. Lobaric acid • Arrests G2/M phase of cell-cycle [80,133,135]
dangers. It can also dramatically decrease their immune response by • Disabling replicative
impacting bone marrow cells and escalating vulnerability to host dis immortality by inhibiting
telomerase activity and
eases [205,206]. The use of methanolic extract of Ramalina farinacea inhibition of 5-lipoxygenase
with ampicilin results in increase of antibiotic effect of ampicilin. This activity
combination is sometimes recommended to evade drug resistance and to • Induces apoptotic cell death by
achieve better efficacy for the treatment of the diseases [207]. The use of activating intrinsic pathway
(increased PARP cleavage,
lichen acid and extracts in the combintional therapy is of novel
decreased Bcl-2 expression);
approach. It should be kept in mind that out of huge number of com cytoplasmic vacuolization and
pounds only a small amount, having good potential, reaches preclinical blebbing; nuclear fragmentation
stage during drug discovery. and inhibition of thioredoxin
In contrast, combination therapy may be toxic if one of the agents reductase
4. Lobarstin • Arrests G2/M phase of cell-cycle [93,133]
used is chemotherapeutic. It is reported that toxicity is considerably and inhibition of growth factor
lower due to targeting various cancer-related pathways. Emil et al. and DNA repair
(1965) postulated the first combination chemotherapy for acute leuke • Induces apoptotic cell-death by
mia [208]. This idea of combination therapy is also being used for lichen activating intrinsic pathway
(increased PARP cleavage,
compounds and their extracts. In addition to the combination of isolated
decreased Bcl-2 expression)
lichen compounds (secondary metabolites), various authors have 5. Lecanoric acid • Disabling replicative [49,80]
investigated lichen extracts’ anticancer effects. Acetone or methanol immortality by inhibiting
extracts are made from multiple lichen species for further investigation telomerase activity and inhibit
on different cell-lines. Among lichens, usnic acid, atranorin, and pro the expression of β-catenin-
dependent gene transcription
tolichesterinic acid are efficient towards certain types of cancers, in (Wnt signaling pathway)
conjunction with other anti-cancer drugs and are, therefore, possible • Induces apoptotic cell-death by
candidates for evolution of cancer therapies. Studies have shown that inhibiting thioredoxin reductase
acetone extract, with a lethal concentration of Flavocetraria cucullata, enzyme
6. Lichenin • Disabling replicative [89]
from which Usnic acid is isolated, exerts cytotoxicity on cancer cells by
immortality by inhibiting
inducing apoptosis [189]. Extracts of Usnea barbata, Toninia candida and telomerase activity
their secondary metabolites usnic acid and nortictic acid were used (continued on next page)
against LS174 and FemX cells. The combined mixture of extracts derived
12
Table 3 (continued ) diffractaic acid and lobaric acid, was evaluated. Lobaric acid induced
S. Bioactive Molecular mechanism Reference(s) highly toxic effects, shown by a decrease in cell viability to 35.09 % in
No. compound PRCC and 30.47 % in GBM cells, whereas diffractaic acid and usnic acid
• Induces apoptotic cell-death by
exerted greater total antioxidant potential in PRCC cells in comparison
activating intrinsic pathway with other compounds [211]. The inhibitory effect of usnic acid and
(increased Bax expression); atranorin on cancer have also been tested in the cell-lines of human
Extrinsic pathway (increased prostate cancer (DU-145, PC-3) and human melanoma (HTB-140).
Fas and FasL expression); DNA
Interestingly, both atranorin and usnic acid inhibited the organization of
fragmentation
7. Diffractaic acid • Induces apoptotic cell death by [80] actins, migration and proliferation of cancer cells, while their effects on
inhibiting thioredoxin reductase apoptosis were less imperative [212].
8. Salazinic acid • Inhibits G0/G1 phase of cell- [95] Treatment with a combination of usnic acid and rapamycin to
cycle various breast cancer cell-lines causes major migration and invasive
9. Physodic acid • Arrests G0/G1 phase of cell- [47,49,71]
cycle and M-phase phosphopro
inhibition [213]. Besides, a combination of the chemotherapy drug
tein 1 (MPP1) bleomycin and usnic acid increases caspase-3 and 8 activities, toxicity,
• Inhibits expression of catenin p53/21 pathways, and apoptosis [51]. Treatment of HCT116 cells with
dependent gene transcription lobaric acid and lobastin led to significant changes in morphology of
(Wnt signaling pathway) and
cells from polygonal to circular, due to apoptosis along with fragmen
Matrix Metalloproteinase-7
• Induces apoptotic cell-death by tation and breakage of cells [133]. Combination of protolichesterinic
activating intrinsic pathway acid with doxorubicin, a chemotherapy agent, also shows cytotoxicity in
(increased pro-apoptotic Bax breast cancer cell-line (HeLa) and not in leukaemia cell-line (K562) and
expression, decreased anti- neuroblastoma cell-line (SH-SY5Y). Synergistic cytotoxicicity in HeLa
apoptotic Bcl-xl, decreased
expression of Hsp70) and
cells, but not on SH-SY5Y and K562 cells, were reported when proto
• Increases production of ROS lichesterinic acid was used in combination with doxorubicin. The reason
10. Parietin • Arrests S-phase of cell-cycle [66] of synergistic cytotoxicity might be due to apoptosis induced by both
11. Pannarin • Induces apoptotic cell-death by [151,195] protolichesterinic acid as well as doxorubicin which, in turn, can induce
activating intrinsic pathway
caspases -3, -8, and -9 activities [214–216]. SFE extract isolated from
(caspase-3-dependent); DNA
fragmentation and necrosis Usnea barbata and usnic acid affect autophagy and apoptosis in mela
12. Protolichesterinic • Arrests G0/G1 phase of cell- [78,103,105, noma B16 cancer cell-line, resulting in morphological changes in acidic
acid cycle 135] cytoplasmic vesicles that promote vesicular transport in organelles and
• Disabling replicative endocytic systems [217]. Usnic acid and atranorin are suggested to
immortality by inhibiting
cause programmed cell-death via the mitochondrial pathway in ovarian
telomerase activity and 5-lipox
ygenase enzyme activity carcinoma cell-line A2780 [20].
• Induces apoptotic cell-death by
activating intrinsic pathway 7. Computer aided drug-designing of anticancer compounds
(caspase-3 dependent, increased
pro-apoptotic Bax expression,
decreased anti-apoptotic Bcl-xl, As a global health issue with 200 different types and one among the
decreased Hsp70 expression); leading causes of death worldwide, the drug preparation for cancer is
Extrinsic pathway (increased complicated, challenging, expensive and time consuming. The devel
expression of TNF-related opment of computer aided drug-designing (CADD) has helped to over
apoptosis-inducing ligand
TRAIL); cytoplasmic vacuoliza
come these complications to a vast extent and is now an emerging
tion and blebbing and nuclear promising technology. CADD is an effective drug designing technique,
fragmentation cheaper and powerful, showing magnificient possibility in the field of
• Inhibits FASN activity anticancerous drug designing [218]. CADD helps to discover, create, and
13. Protocetraric acid • Arrests G0/G1 phase of cell- [70]
analyse drugs and other biologically active molecules agaist cancer. The
cycle
14. Vulpinic acid • Induces cell-death by activating [80,124] ligand-based computer-aided drug discovery (LBCADD) method entails
intrinsic pathway (increased looking at ligands that have been shown to interact with a target of
Bax expression, decreased Bcl-2 interest. These techniques make use of a series of reference structures
expression, Increased p53 gene derived from compounds that are known to interact with the target and
expression);
• Inhibits thioredoxin reductase
then analyse their two and three dimentional structures. The basic goal
of these methods is to predict the existence and intensity of a given
molecule’s binding to the target. CADD methods will increase the
from Pseudoevernia furfuraceae and Evernia prunastri, and their secondary chances of identifying compounds with desirable properties, speed up
metabolite physodic acid, are used on FemX and LS174 cells for their hit-to-lead growth, and increase the chances of getting a compound pass
anticancer activities. Researchers have documented that methanol ex the several hurdles of preclinical testing [219].
tracts of Lasallia pustulata, Parmelia sulcata, Parmelia caperata, and
P. saxatilis extracts show high cytotoxicity against LS174 and FemX cells 8. Conclusions and future prospects
[209,210]. Xanthoria parietina acetone extract, used on the
MDA-MB-231 and MCF-7 cells, inhibits the proliferation of these cells. Lichens are a promising source of active compounds, having the
Researchers in combinational therapy used parietin and acetone extract potential to act as anti-cancer medications. Validation of their anti-
at various concentrations on various cancer-lines such as MDA-MB231, cancer properties, however, requires further experiments to clarify
MCF-7 breast cancer cells, and 3T3L1 cells. Protocetraric acid, and their role in targeting the molecular pathways and metabolic networks
depsidones - norstictic acids, collectively with perlatolic and depsides - against cell proliferation. Despite the vast number of lichen species
divaricatic acids, show potentcy to toxicity on UACC-62 cells and have available worldwide, the number of species examined and lichen-
improved selectivity in melanoma cells relative to standard 3T3 cells. derived products is minimal. Given the growing interest in natural
In human glioblastoma multiforme (U87MG-GBM) and rat cerebral sources of anti-cancer agents, and the propensity for an increasing body
cortex cells (PRCC), the anti-cancer efficacy of usnic acid, together with of studies based on lichen bioactivity, new compounds would be
13
Fig. 3. Overview of the molecular mechanism of lichen-derived bioactive compounds.
identified from poorly-studied species and unexplored geographical re levels. With recent technological interventions, the development of cost-
gions. Developments in analytical methods have resulted in new effective options for growing and harvesting lichen metabolites
chemical materials being described from lichens widely and chemically commercially as a source of influential anticancer therapeutics show
well known. However, we are still under the deep quest to report single real promise.
lichen-derived anti-cancer medications in general use or for clinical
trials. Among lichens, usnic acid, atranorin and protolichesterinic acid Authors contribution
are efficient against some forms of cancer, either in isolation or in
conjunction with other anticancer drugs, and are possible candidates for THD, SAD and SH planned, designed and initiated the work. SUI,
novel cancer therapy. The future preclinical and clinical studies, ZAM and RD wrote the manuscript and prepared the figures and tables.
concentrated on carcinogenesis-influencing extracts or isolated lichen BPS and PV contributed in manuscript writing. THD, SAD, SH, BPS and
metabolites, should focus on several important issues, such as clarifi PV revised the manuscript, and BPS and PV arranged the references. The
cation of molecular targets and signalling pathways for the action of final version of the manuscript was read and approved by all the authors
anti-cancer drugs, and the identification of appropriate and non-toxic for submission.
human doses. It is also important to identify the epigenetic changes,
such as methylation in gene promoters, post-translational modifications Funding
in histones and the regulation of miRNA. Lichen-based compounds have
also been used to evaluate the cancer stem cells, multidrug resistance, or None
for re-sensitization ofcancer cells to standard chemotherapy. The
chemical composition of most lichen molecules is elemental and easy to Declaration of Competing Interest
synthesize. In this respect, all of these synthetic compounds can be used
as precursors to confirm particular anti-cancer pathways, enhance sta The authors declare no conflict of interest.
bility and mitigate adverse side-effects in the body that may contribute
to better anti-cancer practices and have useful therapeutic applications. Acknowledgements
The combinatorial therapies against the wide range of cancers,
particularly in triple negative breast cancer, have largely contributed as We sincerely thank Prof. G. H. Dar for critically going through the
potential strategies to trigger the apoptosis and anti-proliferaive activity manuscript. We are thankful to Dr. Shusheel Verma and Dr. Raja Amir,
to decrease the stem cell proliferation and inhibit cancer development. School of Biosciences & Biotechnology, BGSB University, Rajouri, for
These combined approaches have led to the development of new drugs their inputs and valuable suggestions. The authors also acknowledge the
for targeting cancers more efficiently and accuratrely. The in anonymous reviewers for their helpful comments.
vestigations may further pave ways and strategies to understand the
mechanism to specific target pathways associated with the human traits,
create customized lichen medications, and evolve therapies at various
14
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Lichens Anti Cancer 2

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Lichens Anti Cancer 2

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Seminars in Cancer Biology xxx (xxxx) xxx

Contents lists available at ScienceDirect

Seminars in Cancer Biology

Lichens as a repository of bioactive compounds: an open window for green

3.1. Atranorin adenocarcinoma HT-29, Human cervix adenocarcinoma HeLa, Human

Sk-Hep1 [12]. such as Parmelia sulcata, P. saxatilis, P. caperata, Parmotrema lichex

1. Extracts of Umbilicaria crustulosa, FemX, LS174 Increased Cytotoxicity in vitro [157]

Increased anticancer activity on both

effect on animals is visualized as apoptosis of cancer cells via caspase Table 3

Fig. 3. Overview of the molecular mechanism of lichen-derived bioactive compounds.

You might also like

Lichens Anti Cancer 2

Uploaded by

Copyright:

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Lichens Anti Cancer 2

Uploaded by

Document Information

Copyright

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Lichens Anti Cancer 2

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Copyright:

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Seminars in Cancer Biology xxx (xxxx) xxx

Contents lists available at ScienceDirect

Seminars in Cancer Biology

Lichens as a repository of bioactive compounds: an open window for green

3.1. Atranorin adenocarcinoma HT-29, Human cervix adenocarcinoma HeLa, Human

Sk-Hep1 [12]. such as Parmelia sulcata, P. saxatilis, P. caperata, Parmotrema lichex­

1. Extracts of Umbilicaria crustulosa, FemX, LS174 Increased Cytotoxicity in vitro [157]

Increased anticancer activity on both

effect on animals is visualized as apoptosis of cancer cells via caspase Table 3

Fig. 3. Overview of the molecular mechanism of lichen-derived bioactive compounds.

You might also like

Sk-Hep1 [12]. such as Parmelia sulcata, P. saxatilis, P. caperata, Parmotrema lichex