Journal of Advanced Research (2015) 6, 45–62

Cairo University

Journal of Advanced Research

REVIEW

P-glycoprotein inhibitors of natural origin

as potential tumor chemo-sensitizers: A review
Hossam M. Abdallah a,b, Ahmed M. Al-Abd c,d
, Riham Salah El-Dine b,
Ali M. El-Halawany a,b,*

a
Department of Natural Products, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
b
Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
c
Pharmacology Department, Medical Division, National Research Center, Giza, Egypt
d
Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia

A R T I C L E I N F O A B S T R A C T

Article history: Resistance of solid tumors to treatment is significantly attributed to pharmacokinetic reasons at
Received 21 August 2014 both cellular and multi-cellular levels. Anticancer agent must be bio-available at the site of
Received in revised form 15 action in a cytotoxic concentration to exert its proposed activity. P-glycoprotein (P-gp) is a
November 2014 member of the ATP-dependent membrane transport proteins; it is known to pump substrates
Accepted 18 November 2014 out of cells in ATP-dependent mechanism. The over-expression of P-gp in tumor cells reduces
Available online 1 December 2014 the intracellular drug concentrations, which decreases the cytotoxicity of a broad spectrum of
antitumor drugs. Accordingly, P-gp inhibitors/blockers are potential enhancer for the cellular
Keywords: bioavailability of several clinically important anticancer drugs such as, anthracyclines, taxanes,
Multidrug resistance (MDR) vinca alkaloids, and podophyllotoxins. Besides several chemically synthesized P-gp inhibitors/
Multidrug resistance-associated blockers, some naturally occurring compounds and plant extracts were reported for their mod-
protein 1 (MRP1) ulation of multidrug resistance; however, this review will focus only on major classes of natu-
Natural products rally occurring inhibitors viz., flavonoids, coumarins, terpenoids, alkaloids and saponins.
P-gp (P-glycoprotein) ª 2014 Production and hosting by Elsevier B.V. on behalf of Cairo University.

Hossam M. Abdallah, PhD, received his M. S.

degree in Pharmacognosy and PhD in Chem-
istry of Natural Products from Faculty of
Pharmacy, Cairo University. In 2013, he was
promoted to Associate Professor of Pharma-
cognosy, Faculty of Pharmacy, Cairo Uni-
* Corresponding author. Tel.: +966 (0)2 640 0000x22155; fax: +966
versity. Currently, he is working at Natural
(0)2 695 1696. Products and alternative medicine Depart-
E-mail address: ali.elhalawany@pharma.cu.edu.eg (A.M. El-Halawany). ment, Faculty of Pharmacy, King Abdulaziz
Peer review under responsibility of Cairo University. University. He has 29 peer-reviewed publica-
tions, a reviewer in several peer-reviewed journals in the field of natural
products, a PI and CO-I in more than ten projects. He has a scientific
communication with two international institutes.
Production and hosting by Elsevier

http://dx.doi.org/10.1016/j.jare.2014.11.008
2090-1232 ª 2014 Production and hosting by Elsevier B.V. on behalf of Cairo University.
46 H.M. Abdallah et al.

intracellular drug concentrations with consequent decrease in

the cytotoxicity of a broad spectrum of antitumor drugs
Ahmed M. Al-Abd has graduated (2000) from including anthracyclines (e.g. doxorubicin; DOX), vinca alka-
Faculty of Pharmacy, Ain Shams University. loids (e.g. vincristine), podophyllotoxins (e.g. etoposide) and
He obtained his PhD degree (Pharmacology taxanes (e.g. taxol). Gene sequence analysis in different species
and Toxicology) from Beni-Suif University, revealed two human P-gp genes, three mouse P-gp genes and
Egypt in 2011. Currently, he is an Assistant
one P-gp gene in hamster cells [2]. Structure of human P-gp
Professor at King Abdulaziz University and
visiting scholar in Bouvé College of Health
protein comprises 1280 amino acid in 12 transmembrane seg-
Sciences, Northeastern University, USA. He is ments and one ATP-binding motif with three characteristic
an author and co-author for more than 25 glycosylation sites [3].
peer-reviewed publications; Co-inventor in 2 Three different P-gp isoforms were identified (P-gp class I,
patents. Ahmed Al-Abd has a broad international scientific commu- II and III); only P-gp class I and III were characterized in var-
nication network (collaborator with more than 15 research institutes in ious normal human tissues with potential role in the normal
more than 5 different countries worldwide). physiology of these tissues [4]. P-gp class III is expressed in
liver hepatocytes; and mice lacking its expression fail biliary
phopholipid secretion. P-gp is expressed as well in a wide range
Dr. Riham Salah El Dine was graduated at
of epithelia with potential transport function, such as colon,
1998 from Faculty of Pharmacy, Cairo Uni-
versity. Afterward, she worked as teaching small intestine, liver, pancreas, kidney, uterus and placenta.
assistant in Department of Pharmacognosy, In addition, P-gp was found expressed in highly specialized
Cairo University from 1998 to 2003. In 2004, capillary transport endothelia such as brain and testis [5–8].
she was enrolled as a PhD candidate in Insti- Other MDR-related proteins were discovered within differ-
tute of Natural Medicine, Toyama, Japan. She ent types of malignancies [9] such as multidrug resistance
got her PhD under the supervision of Dr. related proteins (MRP’s) [10,11] and breast cancer resistance
Masao Hattori. After PhD, she was awarded a protein (BCRP-1) [12–14]. Compounds inhibiting these P-gp
postdoctoral fellowship in the same labora- related efflux proteins are supposed to increase the intracellu-
tory for 6 months. From 2008 up to date, she is appointed as an
lar concentration of chemotherapeutic agents in similar way to
Assistant Professor, Faculty of Pharmacy, Cairo University. She is a
inhibiting P-gp molecule itself. [15–18].
co-author of more than 17 peer-reviewed publications; and a reviewer
for several peer-reviewed journals in the field of natural products. Despite the role of P-gp transporter in normal physiology;
the overexpression of P-gp (and related proteins) on tumor
cells results in significant decrease in the intracellular concen-
Ali El Halawany, PhD, was graduated from tration of a wide range of anticancer drugs nonetheless of nat-
Faculty of Pharmacy, Cairo University in ural origin. Early evidence for the role of P-gp in the efflux of
1996. He obtained his master degree in Phar- anticancer drugs outward and abolishing their cytotoxicity was
macognosy in 2002. In 2004, he was selected observed before more than two decades. Purified membrane
for MEXT scholarship by the Japanese gov- vesicles from resistant tumor cells significantly bind more radi-
ernment to be enrolled as PhD Candidate in
olabeled vincristine [19,20]. P-gp showed significant role in the
Institute of Natural Medicine, Toyama,
Japan. After finishing the PhD in 2007, he was
transport of anthracyclines in Madin–Darby canine cells as
awarded a COE scholarship in the same lab- well [20]. In addition, radiolabeled colchicines transport was
oratory for 6 months followed by another found to be mediated by purified P-gp particles [21].
6 months as a visiting researcher. In 2009, he worked at Institute of Several molecular mechanisms have been postulated for P-
Natural Medicine as a foreign researcher for 1 year till 2010. From gp mode of action such as increasing the intracellular pH,
April 2014 up to date, he is working as an Associate Professor, depolarizing plasma membrane electric potential, proton and
Department of Pharmacognosy, Cairo University. He is an author/co- chloride ion pumps [22,23]. The leaflet flip model of Higgins
author for more than 28 peer-reviewed publications; Co-inventor in 1 and Gottesman appears to be the most descriptive molecular
US patent, a member in the editorial board of BFOPCU journal and a explanation to the mode of P-gp action [24].
reviewer for several peer-reviewed journals in the field of natural
products.
P-gp receptor modulation

Introduction
The P-gp inhibitor may act as a competitive blocker via occu-
pying the drug binding sites or as a non-competitive antagonist
Definition and molecular background by binding chemosensetizer sites [25]. Example for competitive
binding of two drugs on the same binding site of P-gp molecule
Multidrug resistance (MDR) is the ability of drug resistant was found for competition between radiolabeled vinblasine
tumors to exhibit simultaneous resistance to a number of struc- and azidopine on purified P-gp molecules [26]. Similarly, bind-
turally and functionally unrelated chemotherapeutic agents. ing of radiolabeled vinblasine was inhibited by co-incubation
P-glycoprotein (P-gp), the very famous MDR family mem- with vincristine and daunorubicin [27]. On the other hand, col-
ber protein, was first characterized in multidrug resistant Chi- chicines, actinomycin-D and calcium channel blockers do not
nese hamster ovary (CHO) cells by Ling and co-workers [1]. P- compete for vinblastine-binding site within P-gp molecules;
gp transports in a unidirectional fashion any xenobiotic as a yet inhibiting the binding of radiolabeled vinblasine or azido-
substrate outward via an ATP-dependent mechanism. In pine would suggest multiple binding domains on P-gp mole-
tumor cells, expression of P-gp results in reduction of cules [28]. ATPase activity of P-gp molecule was first
P-glycoprotein inhibitors of natural origin 47

identified since the very early discovery of the P-gp molecule cardiovascular effects. Among these analogues, dexverapamil
itself [29]. Yet several agents are designed and tested to inhibit (R-enantiomer of VRP), emopamil, gallopamil, and Ro11-
particularly the ATPase function of P-gp molecules and related 2933 inhibit the P-gp activity in vitro equipotent to more
proteins [30,31]. That might explain the discrepancies in bind- potent than VRP, but with marginal toxicity in many animal
ing sites within P-gp molecules for different P-gp blockers. models [47–50]. PSC 833 is a non-immunosuppressive analog
of cyclosporine-A and more potent P-gp inhibitor in vitro
Modulation of P-gp and chemosensetization [51,52].

The process of chemosensetization involves the co-administra- Third generation P-gp blockers
tion of a P-gp inhibitor with an anticancer drug in order to Combinatorial chemistry and structure–activity relationships
enhance intracellular anticancer drug accumulation via impair- approaches were used to bring up the third generation P-gp
ing the P-gp efflux function. Numerous compounds have been blockers with antagonism function at nanomolar range (20–
shown to inhibit the drug efflux function of P-gp and therefore, 100 nM). Several of these compounds possess only P-gp block-
increase the intracellular concentration of chemotherapies with ing effect such as zosuquidar (LY335979) [53], elacridar
ultimate decrease in cellular resistance. Several chemical clas- (GF120918) [54], XR9051 [55], OC144-093 [44]. Others have
ses are known as P-gp inhibitors such as, cyclosporines, cal- dual P-gp and MRP blocking activity such as biricodar (VX-
modulin inhibitors, indole alkaloids, coronary vasodilators, 710), and timcodar (VX-853) [56] or dual P-gp and BCRP tari-
quinolines, hormones, calcium channel blockers, and several quidar (XR9576) [57]. These agents appear to possess accept-
surfactants [32]. Considerable number of cancers exhibit either able toxicity profile; however their success in combination
intrinsic or treatment induced acquired resistance. Over- with anticancer agents is yet to be determined in clinical
expression of P-gp molecules correlates positively with poor settings.
response of tumor cells to chemotherapy [33] at both stages
of first diagnosis (intrinsic resistance) and during disease P-gp blockers of natural origin
relapse (acquired resistance) of several neoplastic disorders
such as leukemias [34]; lymphomas [35]; adult and childhood Several naturally occurring compounds and plant extracts
sarcomas, and neuroblastomas [36]. were reported for their modulation of multidrug resistance;
The two major limitations for P-gp inhibitors to be used however, this review will focus only on major classes viz.,
clinically are their unwanted immunosuppressive and cardio- flavonoids, stilbenes, coumarins, terpenoids, alkaloids and sap-
vascular effects. According to these two major hurdles, P-gp onins. In addition the review will cover the literature regarding
blockers are classified into first, second or third generation. natural P-gp inhibitors in the period between 1989 and 2015.
Search was conducted on common databases such as ISI
First generation P-gp blockers web of Knowledge, Scopus and using the Saudi digital library
Verapamil (VRP) is the prototype P-gp blocker [37] and was (SDL) for getting the full text.
found to enhance intracellular accumulation of many antican-
cer drugs, including DOX in numerous cancer cell lines Flavonoids and stilbenes
[22,38,39]. Further studies found that the P-gp inhibiting activ-
ity is shared by many other calcium channel blockers such as, It was reported that plant derived polyphenolic compounds,
diltiazem [38], bepridil [40], nicardipine, nifedipine [38], felo- mainly flavonoids and stilbenes or their synthetic derivatives,
dipine, and isradipine [41]. In addition, non-calcium channel can modulate the main ABC transporters responsible for can-
blockers such as calmodulin antagonists (trifluorperazine, clo- cer drug resistance, including P-glycoprotein, multidrug resis-
penthixol, trifluopromazine, and flupenthixol)[38], chlorprom- tance-associated protein 1 (MRP1) and breast cancer
azine and prochlorperazine, indole alkaloids, the anti-malarial resistance protein (BCRP) [58]. Flavonoids and stilbenes repre-
quinine and the anti-arrhythmic quinidine [42] demonstrated sent the third generation of P-gp inhibitors and they produced
P-gp inhibiting activity. P-gp inhibiting agents are pharmaco- a comparable effect to those of the well-known P-gp inhibitors
logically active in vitro in concentration range from (1 to verapamil and cyclosporine [59].
50 lM). Similar serum-concentration range of these P-gp Several flavonoids and stilbenes (Fig. 1) have been reported
inhibiting agents is known to cause serious and devastating to inhibit BCRP encoded by the ABCG2 gene. Thus, the con-
immunosuppressive and cardiovascular effects [25,43]. Cyclo- sumption of flavonoids with high inhibitory activity could
sporin-A (the commonly used immunosuppressive agent) change pharmacokinetics and drug levels of drugs that are eff-
remained one of the golden first generation P-gp inhibitors luxed by BCRP. The following flavonoid structural features
for several years [44–46]. were found to contribute positively to BCRP inhibition; (A)
A hydroxyl group in position 5, double bond between position
Second generation P-gp blockers 2 and 3, and a methoxyl group in position 3. (B) The exchange
The vast majority of all first generation P-gp inhibitors is ther- of a 3-methoxy group by an OH-group resulted in decrease in
apeutic agents and reverses P-gp efflux activity in vitro at con- activity [60]. The following compounds are some examples of
centrations range higher than their individual clinical flavonoids reported as P-gp inhibitors; ()-Epigallocatechin-
therapeutic windows. The search for non-toxic second genera- 3-gallate (EGCG) downregulates P-gp and BCRP but did
tion P-gp blockers resulted in newer analogs of the first gener- not affect MRP1 in a tamoxifen resistant MCF-7 (breast can-
ation agents with more potent P-gp inhibition and cer) cell line [61]. Flavonoids with hydrophobic group such as
considerably less toxicity. Several structural analogs for VRP prenyl substituents might constitute the promising candidates
were synthesized for better P-gp intrinsic activity and less for MDR reversal agents. 8-prenylnaringenin (8-iso-
48 H.M. Abdallah et al.

Fig. 1 Structures of some flavonoids and stilbenes reported as P-gp inhibitors.

pentenylnaringenin) (Fig. 1), a potent phytoestrogen isolated which might be mainly due to inhibition of the CYP3A (Cyto-
from common hops (Humulus lupulus), strongly inhibited chrome P450, family 3, subfamily A) – mediated metabolism of
MRP1 transport activity in human erythrocytes. It was not tamoxifen in the small intestine and/or in the liver and inhibi-
able to modulate MDR in human adenocarcinoma cell line tion of the P-gp efflux pump in the small intestine [64]. Silym-
in spite of its ability to inhibit both P-glycoprotein and arin can inhibit P-gp mediated efflux in Caco-2 cells (colon
MRP1 activities [62]. cancer cell line), suggesting they could potentially increase
Icaritin (Fig. 1), isolated from Herba Epimedium, signifi- the absorption/bioavailability of co-administered drugs that
cantly increased the intracellular accumulation of ADR and are effluxed P-gp [65].
decreased the expression of the MDR1 gene in a multiple Biochanin A (Fig. 1) and silymarin were reported to poten-
drug-resistant HepG2 (liver cancer cell line)/adriamycin tiate DOX cytotoxicity in P-gp positive cells. The underlying
(HepG2/ADR) cell line compared with drug-sensitive HepG2 mechanism(s) may involve direct interaction with P-gp as evi-
cells. In addition, icaritin significantly downregulates the denced by flavonoid modulation of P-gp ATPase activity [66].
expression of P-gp [63]. Nguyen et al. studied the effect of large number of flavo-
Baicalein (Fig. 1), the major flavonoid in Scutellariae radix, noids on P-gp inhibition. Biochanin-A, genistein, quercetin,
significantly enhanced the oral bioavailability of tamoxifen, chalcone, silymarin, phloretin, morin, and kaempferol
P-glycoprotein inhibitors of natural origin 49

(Fig. 1), significantly increased the accumulation of both dau- confirmed that this conjugate inhibits drug efflux by P-gp, in
nomycin (DNM) and vinblastine (VBL) in human pancreatic addition, P-gp ATPase assay showed that this compound
adenocarcinoma Panc-1 cells. The study concluded that; the interacts with the drug-binding site of P-gp to stimulate its
aforementioned compounds can inhibit MRP1-mediated drug ATPase activity.[76]
transport through binding interactions with MRP1, as well as
modulation of GSH (glutathione) concentrations [67]. Coumarins
Flavonoids from grape fruit juice such as kaempferol and
naringenin caused a decrease in P-gp levels and MDR-1 tran- Several naturally occurring and synthetic coumarins, furano-
script levels as well in the human immortalized tubular cell line coumarin, pyranocoumarin and sesquiterpenoid coumarins
(HK-2) [68]. were investigated for their ability to reverse multi drug resis-
In EPG85-257RDB cells (P-gp-positive gastric carcinoma tance by inhibiting P-gp activity.
cell line) quercetin (Fig. 1) acted as a chemosensitizer through In a study carried out by Raad et al. [77], a set of 32 natural
decreasing of P-gp expression, inhibition of drug transport and and synthetic coumarins were tested in order to evaluate their
downregulation of ABCB1 (ATP-binding cassette sub-family activity on human leukemic cells (K562/R7) overexpressing P-
B member 1 ) gene expression [69]. Therefore, concurrent use gp. They proved that coumarins substituted by a common a-
of quercetin provides a therapeutic benefit by increasing the (hydroxyisopropyl) dihydrofuran moiety, exhibited a signifi-
bioavailability of doxorubicin administered orally [70]. cant inhibitory effect on P-gp when compared to the positive
Procyanidine isolated from bark of Pinus massoniana control cyclosporin A. The presence of phenyl group at posi-
(Fig. 1) markedly increased the accumulation of Rh123 (rho- tion C4 in coumarin was found to be essential for activity.
damine 123) within cells by inhibiting its efflux in a dose- In addition, the [a-(hydroxyisopropyl-dihydrofuran) group,
dependent manner. Procyanidine was a potent inhibitor of P- especially at positions C7–C8, also showed some interest for
gp on BBB (blood brain barrier) and could improve the ther- activity compared to other additional groups [77].
apeutic effects on cerebral tumors of some drugs which are dif- GUT-70 (Fig. 2), a tricyclic coumarin, isolated from the
ficult to accumulate in the brain [71]. stem bark of Calophyllum brasiliense collected in Brazil, inhib-
3,5,7,30 ,40 -pentamethoxyflavone (Fig. 1) from Kaempferia ited human leukemic cell lines, including the P-glycoprotein
parviflora rhizome increased the accumulation of Rh123 and overexpressing cell lines, in a concentration and time-depen-
daunorubicin in LLC-GA5-COL150 cells (a transfectant cell dent manner with IC50 values from 2–5 lM [78].
line of a porcine kidney epithelial cell line (LLC-PK1) with (±)-Praeruptorin A (PA) (Fig. 2), a naturally existing pyr-
human MDR1 cDNA) in a concentration dependent manner. anocumarin isolated from the dried root of Peucedanum praer-
In addition, 5,7-dimethoxyflavone (Fig. 1) to a lesser degree uptorum Dunn., re-sensitizes P-gp mediated MDR (P-gp-
increased Rh 123 accumulation in LLC-GA5-COL150 cells MDR) cancer cells to anticancer drugs. The PA derivative
[72], and exhibited a stimulatory effect on the accumulation (±)-30 -O,40 -O-dicynnamoyl-cis-khellactone (DCK), was more
of doxorubicin in A549 cells (adenocarcinoma human alveolar potent than PA or verapamil in the reversal of P-gp-MDR.
basal epithelial cells) [73]. In P-gp-MDR cells DCK increased cellular accumulation of
Myricetin (Fig. 1) significantly enhanced the cellular accu- DOX without affecting the expression level of P-gp. DCK
mulation of Rh123 in MCF-7/ADR cells overexpressing P- could bind simultaneously with substrates to P-gp through
gp. It increases the oral bioavailability of DOX due to the an allosteric site and thus affecting P-gp–substrate interactions
enhancement of its absorption in the gastro-intestinal tract [79].
via the inhibition of P-gp and reduction of first-pass metabo- Decursinol (Fig. 2), a major coumarin derived from the
lism of DOX due to inhibition of CYP3A in the small intestine roots of Angelica gigas, showed high permeability in Caco-2
and/or in the liver [70]. cell monolayers in the absorptive direction. Secretion increased
Wogonin (Fig. 1), a flavone, significantly potentiated eto- in a concentration-dependent manner, with an efflux ratio of
poside-induced apoptosis in HL-60 (Human promyelocytic more than 2 at 50 lM, indicating that it could be transported
leukemia) cells. It impaired the function of P-gp and thus through an active efflux transporter such as P-gp, multidrug
increased cellular content of etoposide in the cells. Moreover, resistance protein 2 or BCRP [80].
wogonin is likely to act as an inhibitor of P-gp and potentiate
the apoptotic action of etoposide. On the other hand, wogonin
Sesquiterpene coumarins
inhibited etoposide-induced apoptosis in thymocytes, one of
the normal cells. The potentiation by wogonin is likely to be
a specific action for cancer cells but not normal cells. There- Farnesiferol A (Fig. 2) (from the roots of Ferula persica) and
fore, this flavone may be used to reduce the excretion of the galbanic acid (Fig. 2) (from the roots of Ferula szowitsiana)
anticancer agents via P-glycoprotein and increase the pharma- significantly inhibited the P-gp activity compared to verapamil
cological action of it in cancer cells [74]. in a doxorubicin resistant breast cancer cell line (MCF7/ADR)
Resveratrol, a well-known stilbene, was reported to enhance [81]. Similarly, driportlandin (Fig. 2), isolated from Euphorbia
the cytotoxic profile of both docetaxel and doxorubicin in solid portlandica, was more active on the reversal of multidrug resis-
tumors through inhibition of P-gp efflux and downregulation of tance (MDR) of mouse lymphoma cells than verapamil [82].
MDR1 gene [75].
The effect of amino acid conjugation with flavonoid was Furanocoumarin
studied on MDR. Conjugation of quercetin with glutamic acid
moiety attached at 7-O position was potent as verapamil in Dihydroxybergamotin and other furanocoumarins contained
reversing MDR and sensitized MDR MES-SA/Dx5 cells to in grapefruit juice, such as bergamotin, FC726, bergaptol
various anticancer drugs. Analysis on Rh-123 accumulation
50 H.M. Abdallah et al.

Fig. 2 Structures of coumarins reported as P-gp inhibitors.

and bergapten (Fig. 3), increased the steady-state uptake of was tested on NIH-3T3 (mouse embryo tissue fibroblast) cells
[3H]-vinblastine by Caco-2 cells due to inhibition of drug efflux expressing the human P-gp multidrug transporter, to establish
transporters, such as P-gp [83]. quantitative comparisons of their respective abilities to block
Moreover, cnidiadin isolated from Tordylium apulum (Api- the drug efflux from target cells. The most important pharma-
aceae) (Fig. 3) is a cytotoxic agent found to be capable of com- cophoric features of these compounds were in the region of the
petitively inhibiting the binding and efflux of drug by P-gp and substituents at the C-2, C-3 and C-8 positions, which seem to
of enhancing the cell toxicity of vinca alkaloids in Madin– be critical for determination of the overall effectiveness of ses-
Darby canine kidney (MDCK-MDR1) cells and mutant quiterpenes as P-gp inhibitors [86]. A 3D QSAR (Quantitative
human carcinoma (KB/VCR) overexpressing P-gp [84]. structure–activity relationship) study concluded that, the ester-
ification level of the compounds, the presence of two aromatic
Terpenoids ester moieties and the size of the molecule are important fac-
tors for the reversal activity. Most of the analyzed compounds
Sesquiterpenes showed low intrinsic toxicity and many of them were able to
efficiently overcome the MDR phenotype in the resistant line
by modulating drug accumulation. Compounds MAMA 7,
Celastraceae plants represent highly effective and specific mod-
MAMA10, MACHU 4, MACU 5, MACU 7 and MACU 8
ulators of the MDR phenotype in Leishmania, due to their
(Fig. 4) were the most active compounds.
dihydro-b-agarofuran sesquiterpenes (Fig. 4). Some of them
Two derivatives of the anti-malarial artemisinin, SM616
could be considered as lead compounds for further develop-
and GHP-AJM-3/23 (Fig. 4) inhibited P-gp activity in sensitive
ment [85]. In a study by Cortes et al. (2005), the inhibitory
CCRF-CEM leukemia cells and P-gp over-expressing multi-
activity of a series of 76 dihydro-b-agarofuran sesquiterpenes
P-glycoprotein inhibitors of natural origin 51

Fig. 3 Furanocoumarins with P-gp inhibitory effect.

drug-resistant CEM/ADR5000 leukemia cells as well as in por- jatrophanes, lathyranes and also among the tetracyclic diter-
cine brain capillary endothelial cells (PBCEC) [87]. penes [90].
A non-cytotoxic concentration of b-caryophyllene signifi- Macrocyclic lathyrane, and jatrophane diterpenes may be
cantly increased the anticancer activity of a-humulene and iso- valuable as lead compounds for the development of P-gp mod-
caryophyllene on MCF-7 cells. Moreover, b-caryophyllene ulators in different multidrug-resistant cancer cells. The mac-
potentiated the anticancer activity of paclitaxel on MCF-7, rocyclic lathyrane diterpene latilagascene B (lat. b, Fig. 5),
DLD-1 (colon adenocarcinoma) and L-929 (murine fibroblast) previously isolated from Euphorbia lagascae, its acylated deriv-
cell lines [88]. atives, latilagascenes G, H, and I and the macrocyclic diter-
penes of the jatrophane-type, tuckeyanols A and B, and
Limonoid euphotuckeyanol (Fig. 5), isolated from Euphorbia tuckeyana,
displayed very strong modulating activity against P-gp on
Obacunone, a limonoids isolated from Phellodendron amurense human MDR1 gene-transfected and parental L5178 mouse
(Rutaceae), showed significant P-gp MDR inhibition activity lymphoma cell lines [91].
in MES-SA/DX5 (human MDR uterine sarcoma cell line) The macrocyclic lathyrane diterpenes, latilagascenes D–F
and HCT15 cells (human colorectal cancer cell line) with an and jolkinol B (Fig. 5), isolated from the methanol extract of
ED50 value of 0.028 pg/mL and 0.0011 pg/mL, respectively Euphorbia lagascae, displayed potent activity on mouse lym-
[89]. phoma cells compared with that of the positive control, verap-
amil [92].
Diterpenes The macrocyclic lathyrane polyester Euphorbia factor L10
(Fig. 5) has been obtained from the seeds of the caper spurge
(E. lathyris) as a novel chemotype for P-gp inhibitors [93].
Different skeletones of diterpenes including jatrophanes,
Euphodendroidin D and pepluanin A were the most powerful
lathyranes, uphoractine, pepluane and paraliane that were iso-
inhibitors of daunomycin-efflux activity within the class of
lated from Euphorbia species were assayed for P-gp inhibitory
jatrophane diterpenes. Their efficiency was found to be at least
activity in mouse lymphoma cells by using the Rh 123 exclu-
twofold higher than the conventional modulator cyclosporin
sion test (Fig. 5). The effect on drug accumulation in drug-
A. The analysis of euphodendroidin’s activities has evidenced
resistant cells is proportional to the hydrophobicity of diter-
the involvement of ring A in P-gp binding, highlighting the rel-
penes. Highly active compounds can be found among the
evance of a free hydroxyl group at position 3, together with the
52 H.M. Abdallah et al.

Fig. 4 Structures of the most active sesquiterpenes as reversal agents of MDR phenotype of Leishmania.

negative effect of this group at position 2 (Fig. 6). In addition, common gross pharmacophore, which is dramatically affected
substitution at the proximal C-5 with a large group also by changes of the oxygenation pattern, but surprisingly toler-
decreased the activity. The biological evaluation of modified ant in terms of modifications of connectivity as summarized
jatrophanes has shown effect of substitution at positions 3, 6 in Fig. 6 [94].
and 15 and the importance of relative configuration of hydro- In addition, macrocyclic jatrophane diterpenes, named
xyl groups. In addition, substitution at position 6 affects the euphomelliferine and euphomelliferine A (Fig. 5) isolated from
inhibitory ability in a way that dramatically depends on the the methanolic extract of E. mellifera displayed a significant
location of the free hydroxyl group. Euphocharacin’s activities MDR reversing activity, in a dose-dependent manner, on
highlighted the positive roles of benzoyl and propyl at C-9 and human MDR1-gene-transferred mouse cells (L5178Y MDR)
C-3, respectively, and confirmed the negative role of hydroxyl and on human colon adenocarcinoma cells (COLO 320). They
at C-2 and the positive effect of the same group at C-15. The did not induce apoptosis in the COLO 320 cells [95].
results of biological assays on pepluanins have been used to The ent-abietane lactones, helioscopinolides A, B, E and F
extend the structure activity relationships to the other oxygen- (Fig. 7), isolated from Euphorbia species were able to reverse
ated carbon atoms of the medium-sized ring (C-7/C-15). the MDR of the tested human MDR1 gene-transfected mouse
Within the set of compounds investigated, pepluanin A with lymphoma cells, in a concentration-dependent manner in sub-
acetoyl at C-8 and nicotinyl (Nic) at C-9 has been reported cytotoxic concentration [96].
as the most powerful inhibitor, outperforming cyclosporine The tetracyclic diterpene polyesters, euphoportlandols A
A by a factor of at least two in the inhibition of P-gp-mediated and B (Fig. 7), isolated from Euphorbia portlandica, revealed
daunomycin transport. Taken together, these observations significant inhibition of P-gp activity [97].
suggest that jatrophanes and modified jatrophanes share a
P-glycoprotein inhibitors of natural origin 53

Fig. 5 Macrocyclic lathyrane and jatrophanene diterpenes with P-gp inhibitory effects.

Alkaloids Chinese herbal plant Yanhusuo (Corydalis yanhusuo W.T.

Wang, YHS) inhibits P-gp and MRP1-mediated efflux and
Alkaloids are basic nitrogenous compounds derived from activates ATPase activities of the transporters. Furthermore,
plant source and are classified into different groups based on glaucine suppresses expression of ABC transporter genes. It
the amino acid they are derived from. Many reports revealed reverses the resistance of MCF-7/ADR to adriamycin and
the ability of alkaloids to inhibit P-gp. There are two substruc- mitoxantrone effectively [98].
tural features present in compounds that modulate P-gp-asso- Lobeline, a piperidine alkaloid from Lobelia inflata and sev-
ciated MDR: (A) a basic nitrogen atom and (B) two planar eral other Lobelia species, inhibited P-gp activity. MDR rever-
aromatic rings. Glaucine (Fig. 8), an alkaloid component of sal potential of lobeline could be demonstrated in cells treated
54 H.M. Abdallah et al.

Fig. 6 Pharmacophoric elements for the anti-MDR activity of P-gp within the class of jatrophane diterpenes.

Fig. 7 Ent-abietane lactones from Euphorbia pubescens, E.tuckeyana and E. porlandica with P-gp inhibitory effects.

with DOX in that lobeline can sensitize resistant tumor cells at potent activities to restore sensitivity of resistant tumor cells,
non-toxic concentrations. However, lobeline cannot block such as MCF-7/ADR and (MDR nasopharyngeal carcinoma)
BCRP (Breast Cancer Resistance Protein) dependent mitoxan- KBv200 cells, to many antitumor drugs including doxorubicin
trone efflux [99]. and vincristine [101].
Reserpine is an effective ‘‘modulator’’ of P-gp-associated Cepharanthine, a bisbenzylisoquinoline (biscoclaurine)
multidrug resistance (MDR) in multidrug-resistant human leu- alkaloid, completely overcomes resistance of a multidrug-resis-
kemia cell line, CEM/VLB100. Reserpine derivatives with pen- tant subline, ChR-24, derived from human KB carcinoma
dant benzoyl function in an appropriate spatial orientation can cells, to vincristine, actinomycin D, and daunomycin, and par-
modulate MDR. It was found that the relative disposition of tially overcomes resistance to adriamycin. Moreover, this com-
aromatic rings and basic nitrogen atom is important for mod- pound enhanced sensitivity to (ADM) and vincristine (VCR),
ulators of P-gp-associated MDR, and they suggest a ligand- and enhanced apoptosis induced by ADM and VCR of P-gp
receptor relationship for these agents [100]. negative K562 cells (human chronic myelogenous leukemia).
Benzylisoquinoline alkaloids (Fig. 8) have a strong history Cepharanthine changed the distribution of ADM from cyto-
in modulation of MDR. Naturally occurring bisbenzylisoquin- plasmic vesicles to nucleoplasm in K562 cells by inhibiting
oline alkaloids that were isolated from natural plants were the acidification of cytoplasm organelles [102].
tested in vitro as MDR modifiers. Six of these natural com- Another class of bioactive alkaloids is tropane esters
pounds (FF19, FF18, FF15, FF14, FF11 and FF12) showed (Fig. 8). Some of these compounds were isolated from Erythr-
P-glycoprotein inhibitors of natural origin 55

Fig. 8 Examples of alkaloids reported as P-gp inhibitors.

oxylum rotundifolium and evaluated against a panel of human (Fig. 9) modify transport activity of MDR1 in multidrug-resis-
cancer cells. tant human MDR1-gene-transfected mouse lymphoma cells
6b-benzoyloxy-3R-(Z)-(3,4,5-trimethoxycinnamoyloxy)tro- (L5178Y). They enhanced the antiproliferative effects of doxo-
pane and 6b-benzoyloxy-3a-(3,4,5-trimethoxycinnamoyl- rubicin on MDR cells [108].
oxy)tropane, 6b-benzoyloxy-3a-(E)-(3,4,5-trimethoxycinnam A series of indole alkaloids of the aspidofractinine-type was
oyloxy)tropane-7b-ol, and 7b-acetoxy-6b-benzoyloxy-3a-(E)- assessed for their potential in reversing MDR in vincristine-
(3,4,5-trimethoxycinnamoyloxy)tropane, demonstrated great- resistant KB cells. Of the compounds tested, kopsiflorine,
est activity against MDR oral epidermoid carcinoma (KB- kopsamine, pleiocarpine, 11-methoxykopsilongine, lahadinine
V1) cells incubated in the presence of vinblastine. Thus tropane A and N-methoxycarbonyl-11,12-methylenedioxy-D16,17-kops-
esters of this type can reverse the MDR phenotype, presum- inine were found to show appreciable activity [109]. Kopsiflo-
ably by interacting with P-gp [103,104]. rine (Fig. 9) that was isolated from Kopsia dasyrachis,
Pervilleines B and C, obtained from a chloroform extract of enhanced cytotoxicity of vincristine in drug-resistant KB cells
the roots of Erythroxylum pervillei were found to restore the (VJ-300) in a concentration-dependent manner. It was found
vinblastine (VLB) sensitivity of cultured multidrug-resistant that, kopsiflorine interacts directly with P-glycoprotein and
KB-V1 cells PB through inhibiton of P-gp [105–107]. Veralos- inhibits the efflux of antitumor agents in drug-resistant cells
inine (Veratrum lobelianum) and veranigrine (V. nigrum) [110].
56 H.M. Abdallah et al.

Fig. 9 Examples of alkaloids reported as P-gp inhibitors.

Steroidal saponins cellular accumulation of drugs through direct interaction with

P-gp at the azidopine site. In addition, PTG may have a ben-
Saponins are a class of compounds present in some plant fam- eficial effect on cancer chemotherapy with respect to the possi-
ilies and classified into steroidal and triterpenoidal. Steroidal bility of long-term use without the concern of P-gp activation
saponins isolated from Paris polyphylla (Trilliaceae) [113]. Tenacissimoside A (Fig. 10) and 11R-O-benzoyl-12-O-
(Fig. 10), 3-O-Rha(1 fi 2)[Ara(1 fi 4)]Glc-pennogenine, gra- acetyltenacigenin B, two derivatives of tenacigenin B from
cillin and polyphyllin D, and ecdysteroids 20-hydroxyecdysone the plant Marsdenia tenacissima, reversed multidrug resistance
and pinnatasterone showed inhibition of P-gp-mediated dau- in P-gp-overexpressing multidrug-resistant cancer cells. They
norubicin efflux in K562/R7 (human leukemic) cell line [111]. increased sensitivity of HepG2/Dox cells to the antitumor
The cucurbitacins, balsaminagenin B, balsaminoside A, kar- drugs doxorubicin, vinblastine, puromycin, and paclitaxel
avelagenin C (Fig. 10), reversed multidrug resistance on [114].
human MDR1 gene transfected mouse lymphoma cells com- Astragaloside II (Fig. 10) is a saponin widely used in tradi-
pared with that of verapamil. Moreover, in the checkerboard tional Chinese medicine. It has been reported that astragalo-
model of combination chemotherapy, the interaction between side has antitumor effects on hepatocellular carcinoma Bel-
doxorubicin and compounds balsaminagenin B, balsaminoside 7402 cells in vitro and in vivo. Astragaloside II showed strong
A, karavelagenin C synergistically enhanced the effect of the potency to increase 5-fluorouracil cytotoxicity toward 5-fluo-
anticancer drug using daunorubicin and doxorubicin-resistant rouracil-resistant human hepatic cancer cells Bel-7402/FU.
acute myelogenous leukemia sublines (AML-2/D100 and The mechanism of astragaloside II on P-gp-mediated MDR
AML-2/DX100), which overexpress P-gp and MRP, respec- demonstrated that astragaloside II significantly increased the
tively [112]. intracellular accumulation of Rh 123 via inhibition of P-gp
Protopanaxatriol ginsenosides (PTG) has a chemosensitiz- transport function. Astragaloside II could down regulate the
ing effect on P-gp-mediated MDR cells by increasing the intra- expression of the P-gp and MDR-1 gene. In addition, astrag-
P-glycoprotein inhibitors of natural origin 57

Fig. 10 Steroidal saponins that reported as P-gp inhibitors.

aloside II suppressed phosphorylation of extracellular signal significant modulation of P-gp, CYPs (cytochrome P450s),
regulated kinase 1/2, p38 and c-Jun N-terminal kinase [115]. and PXR (Pregnane X receptor) suggesting a potential to alter
The taccalonolides (Fig. 10) are a class of structurally and the pharmacokinetic and pharmacodynamic properties of con-
mechanistically distinct microtubule-stabilizing agents isolated ventional drugs if used concomitantly [117].
from Tacca chantrieri. Taccalonolides A, E, B, and N were Finally, the literature found regarding the P-gp inhibition
effective in vitro against cell lines that overexpress P-gp and by natural products was too much to be covered in one review
MRP7. In addition, taccalonolides A and E were highly article, therefore the current review focused only on major
active in vivo against a doxorubicin and paclitaxel-resistant P- classes of naturally occurring compounds. However, several
gp-expressing tumor, Mam17/ADR. Taccalonolides have reports were found concerning the activity of various plant
advantages over the taxanes (microtubule stabilizers) in their extracts [118] and their constituents as P-gp inhibitors; viz.,
ability to circumvent multiple drug resistance mechanisms anthraquinones [119], phenylbutanoids [120], phytosterols
[116]. [121], cannabinoids [122], carotenoids [123], curcumenoids
Using in vitro assays saponins; primulanin and ardisima- [124], volatile oils [125], sulfur compounds [126], and polyacet-
milloside that were isolated from Labisia pumila showed ylenes. [127] In addition, some vitamins such as vitamin D
58 H.M. Abdallah et al.

revealed significant reversal of multi-drug resistance in many [3] Chen CJ, Chin JE, Ueda K, Clark DP, Pastan I, Gottesman
resistant cells [128]. Moreover, several marine and marine MM, et al. Internal duplication and homology with bacterial
derived endophytes, a major source of natural products, transport proteins in the mdr1 (P-glycoprotein) gene from
revealed significant P-gp inhibition such as lamellarine O and multidrug-resistant human cells. Cell 1986;47(3):381–9.
[4] Lee CH, Bradley G, Zhang JT, Ling V. Differential expression
shornephine A [129,130]. These previously mentioned classes,
of P-glycoprotein genes in primary rat hepatocyte culture.
among others, could be the focus of another separate review J Cell Physiol 1993;157(2):392–402.
article. [5] Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I,
Willingham MC. Cellular localization of the multidrug-
Conclusion and future prospectives resistance gene product P-glycoprotein in normal human
tissues. Proc Natl Acad Sci USA 1987;84(21):7735–8.
[6] Sugawara I, Nakahama M, Hamada H, Tsuruo T, Mori S.
Natural products are some of the major sources for drug dis-
Apparent stronger expression in the human adrenal cortex than
covery. There is a considerably growing body of evidence con- in the human adrenal medulla of Mr 170,000–180,000
cerning the reversal of multidrug resistance though p-gp P-glycoprotein. Cancer Res 1988;48(16):4611–4.
inhibition and other related proteins, using naturally occurring [7] Cordon-Cardo C, O’Brien JP, Casals D, Rittman-Grauer L,
compounds. A large number of compounds were found to be Biedler JL, Melamed MR, et al. Multidrug-resistance gene
P-gp blocking through the inhibition of the pumb ATPase (P-glycoprotein) is expressed by endothelial cells at blood-brain
activity. However, some classes of natural products, especially barrier sites. Proc Natl Acad Sci USA 1989;86(2):695–8.
polyphenols, were reported to be non-specific enzyme inhibi- [8] Arceci RJ, Croop JM, Horwitz SB, Housman D. The gene
tors which could affect other human enzymatic targets such encoding multidrug resistance is induced and expressed at high
as cytochrome system thus affecting the whole pharmacoki- levels during pregnancy in the secretory epithelium of the
uterus. Proc Natl Acad Sci USA 1988;85(12):4350–4.
netic and toxicity profile of anticancer drugs. Therefore, it is
[9] Kawai K, Kusano I, Ido M, Sakurai M, Shiraishi T, Yatani R.
necessary not only to investigate the P-gp blockade rather than Identification of a P-glycoprotein-related protein (mini-P-
studying the mechanism and selectivity of such blockade in glycoprotein) which is overexpressed in multidrug resistant
terms of ATPase inhibition. In addition, P-gp blockade might cells. Biochem Biophys Res Commun 1994;198(2):804–10.
possess significant role in affecting the cellular pharmacokinet- [10] Young LC, Campling BG, Cole SP, Deeley RG, Gerlach JH.
ics of anticancer drugs; however since its discovery (since more Multidrug resistance proteins MRP3, MRP1, and MRP2 in
than four decades), no significant clinical output for any P-gp lung cancer: correlation of protein levels with drug response
inhibitor could be declared. On the other hand, intratumoral and messenger RNA levels. Clin Cancer Res
distribution and tissue pharmacokinetics of anticancer drugs 2001;7(6):1798–804.
constitutes robust pharmacokinetic barrier that hinders their [11] Zeng H, Bain LJ, Belinsky MG, Kruh GD. Expression of
multidrug resistance protein-3 (multispecific organic anion
bioavailability within intratumoral micromillieu. The influence
transporter-D) in human embryonic kidney 293 cells confers
of P-gp inhibition on tissue pharmacokinetics and intratumor- resistance to anticancer agents. Cancer Res 1999;59(23):
al distribution of anticancer drugs is rarely studied. Yet, it is 5964–7.
pretty complicated to assess the avascular intratumoral distri- [12] Jonker JW, Smit JW, Brinkhuis RF, Maliepaard M, Beijnen
bution of P-gp substrates attributed to P-gp blockade. This JH, Schellens JH, et al. Role of breast cancer resistance protein
might be attributed to the heterogenous avascular distribution in the bioavailability and fetal penetration of topotecan. J Natl
of the P-gp blocker per se. Finally, it is strongly recommended Cancer Inst 2000;92(20):1651–6.
to study the influence of P-gp blockade in enhancing the avas- [13] Ross DD, Karp JE, Chen TT, Doyle LA. Expression of breast
cular distribution of P-gp substrates using suitable three cancer resistance protein in blast cells from patients with acute
dimensional avascular solid tumor model to facilitate clinical leukemia. Blood 2000;96(1):365–8.
[14] Maliepaard M, van Gastelen MA, de Jong LA, Pluim D, van
interpretation.
Waardenburg RC, Ruevekamp-Helmers MC, et al.
Overexpression of the BCRP/MXR/ABCP gene in a
Conflict of Interest topotecan-selected ovarian tumor cell line. Cancer Res
1999;59(18):4559–63.
The authors have declared no conflict of interest. [15] Gollapudi S, Thadepalli F, Kim CH, Gupta S. Difloxacin
reverses multidrug resistance in HL-60/AR cells that
overexpress the multidrug resistance-related protein (MRP)
Compliance with Ethics Requirements gene. Oncol Res 1995;7(5):213–25.
[16] Louisa M, Soediro TM, Suyatna FD. In vitro modulation of
This article does not contain any studies with human or animal P-glycoprotein, MRP-1 and BCRP expression by mangiferin in
subjects. doxorubicin-treated MCF-7 cells. Asian Pac J Cancer Prev
2014;15(4):1639–42.
[17] Kawabata S, Oka M, Shiozawa K, Tsukamoto K, Nakatomi
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