Cancer and

Starvation

My name : Hadeel Heisham Braika

Course : pharmacotherapy
Supervised by : Dr Mahmoud Taleb
Pharmacy college at Al-Azhar University

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 Abstract
Conventional therapies for malignant tumors have limitations and
disadvantages. In recent years, the cancer starvation therapy has emerged
which intends to deprive cancer cells of nutritional supply. There are several
approaches to“starve” cancer cells: to intervene tumor angiogenesis by
targeted inhibition of angiogenic factors or their receptors and integrins; to
block the blood supply of cancer cells by embolizing or compressing blood
vessels; to intervene metabolic process of cancer cells by inhibition of the
signal pathways of mitochondrial serine-glycine-one earbon metabolism,
glycolysis and amino acid metabolism. Cancer starvation therapy can be
employed with oxidation therapy, chemotherapy, sonodynamic therapy, anti-
autophagy therapy or other therapies to achieve synergistic effects.

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 Contents

1、Introduction
2、Anti-angiogenesis therapy
3、Vascularization blocked therapy
4、Therapy by Glycolysis inhibition
5、Amino acids depletion therapy
6、Fasting and nutrition
7、Synergistic treatment strategy
8、Conclusion
9、References

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01
Introduction

According to International Agency for Research on Cancer (IARC)

GLOBOCAN cancer statistics estimated 19.3 million new cases of
cancer, and almost 10.0 million deaths from cancer worldwide in 2020 .
Therefore, it is urgent to further improve the level of diagnosis and
treatment of malignant tumors. At present, the main treatment of
malignant tumors includes surgery, chemotherapy and radiotherapy.
Surgical treatment is the first choice for many patients with malignant
tumors . Chemotherapy mainly uses cytotoxic drugs . Radiotherapy plays
a very important role in the treatment of facial skin cancer,
nasopharyngeal carcinoma, head and neck malignant tumors . The three
treatments have their own limitations, and the effect is often not good
when used alone. Combination therapy is often used in clinic, but the
effect is still not good for highly malignant tumors, so it is necessary to
develop new treatment methods . Starvation therapy provides a new idea
for the treatment of malignant tumors by blocking the nutritional supply
of tumors and "starving" cancer cells by various means, rather than
directly removing or killing cancer cells .

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02 Anti-angiogenesis lead to starve cancer

The unlimited passage and rapid proliferation of tumor cells require the
blood to transport a large amount of nutrients and oxygen, so tumor
growth is very dependent on the rapid formation of tumor blood vessels.
Angiogenesis is tightly regulated by pro-angiogenic and anti-angiogenic
factors. The signaling pathways of tumor angiogenesis include growth
factors and their receptors, which are released by tumour or stromal
cells, such as VEGF, angiopoietin, hepatocyte growth factor (HGF),
platelet derived growth factor (PDGF), VEGFR, placental growth factor
and its receptor (PIGF/PIGFR), fibroblast growth factor and its receptor
(FGF/FGFR), Tei receptors and PDGF receptors. In addition, tyrosine
kinase receptor activity and the hypoxia-inducible factor-1α (HIF-1α)
system, are effector of the angiogenic response in cancers. So Anti-
angiogenic agents targeting the VEGF and HIF-α pathways include
monoclonal antibodies to VEGF (e.g. bevacizumab), small-molecule
tyrosine kinase inhibitors (TKIs) e.g. sorafenib, decoy receptor or VEGF
trap e.g. aflibercept and VEGFR2 inhibitors (e.g. ramucirumab). These
classes of drugs are vascular targeting which in many ways are
advantageous over tumour cell targeting drugs. Their use leads to a
reduction in the tumour blood supply and growth of the tumour blood
vessels.
Tumour resistance and cardiovascular toxicity limit the efficacy and long-
term use of anti-angiogenic agents in cancer therapeutics. Then tumour
resistance can be overcome by dual anti-angiogenic therapy or
combination with conventional chemotherapy and immunotherapy.

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 Vascularization blocked to starve cancer

Another promising strategy for cancer starvation therapy was proposed

by shutting off the blood supply with nanothereapeutics that could
selectively blockade tumor vascular and then inducing tumor necrosis.

Recently, a nucleolin-targeting multifunctional DNA nanorobotic system

was constructed for smart drug delivery. The presence of the nucleolin
subsequently triggered the opening of these DNA nanotubes and
released the loaded therapeutic thrombin, which then led to specific
intravascular thrombosis and tumor vessel blockade at the tumor site
Thrombin is a serine protease that catalyzes series of coagulation-
related reactions and leads to rapid thrombus formation during the
clotting process. If thrombin can be precisely delivered to the tumor site
and lead to selective occlusion of tumor-associated vessels by inducing
the local blood coagulation, it might be a promising way for inhibiting the
growth and metastasis of tumors.

Zhang et al. Made an injectable polyvinylpyrrolidone-modified

magnesium silicide nanoparticle, which can be used as an oxygen
consumer and activated under weak acidic conditions in the tumor
microenvironment, in which the intermediate silane can consume oxygen
in tumor cells and blood vessels to achieve the effect of cutting off
oxygen supply; Silica, the end product, can self-aggregate to form
micronsized flocs, which can effectively block blood vessels.

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 03
Glucose is the major energy supplier for tumor growth and proliferation. Cancer cells
display increased uptake of glucose and glycolysis.
2-deoxyglucose has long been known to abolish ATP generation through the glycolytic
pathway. 2-deoxyglucose is an analogue of glucose and is able to bind and suppress
hexokinase II, an enzyme that catalyzes the initial metabolic step in the conversion of
glucose to glucose-6-phosphate during glycolysis. Inhibition of this rate-limiting step
causes a depletion of cellular ATP, leading to blockage of cell cycle progression and anti
tumor effect in cancer cells. Also 3-bromopyruvate (3-BrPA) is a potent inhibitor of
hexokinase II and effectively inhibits glycolysiscauses ATP depletion and this suppresses
ATP-binding cassette (ABC)transporter activity and drug efflux leading to more drug
retention.This results in the ability of 3-BrPA in overcoming chemoresistance and improving
cancer therapeutics, 3BrP is selective to cancer cells and therefore it is less toxic to healthy
surrounding tissues .
Glucose transporters (GLUTs) are a wide group of membrane proteins that facilitate the
transport of glucose and other substrates over a plasma membrane and entering into cells
as nutrients. Overexpression of GLUT-1 and/or GLUT-3 is associated with poor prognosis of
several types of human tumours. GLUT-1 transporter is a potential target for anticancer
therapy as inhibition of its expression is associated with reduction in tumour growth .

Lactate dehydrogenase (LDH) has two subtypes: LDH-A and LDH-B. In hypoxic cells,
conversion of pyruvate into lactate (final step in the glycolytic pathway) is catalyzed by LDH-
A. Lactate accumulation substantially reduces intracellular pH and this is detrimental to the
cell. Production of NAD+ from oxidation of the cofactor NADH is necessary from the
reduction step of pyruvate into lactate to continue glycolysis. Evidence suggests that LDH-
A, which is upregulated in invasive glycolytic cancers, plays a critical role in cell
proliferation. This allows the tumours to survive even in low oxygen levels.Several studies
have already found that the inhibition of LDH-A in cancer cells could stimulate
mitochondrial pyruvate metabolism, decrease mitochondrial membrane potentials and
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finally leading to cancer cell death
04
Glycolysis inhibition

amino acids provide many of the structural elements of a cell and are an
important source of energy. It is therefore not surprising that cancer
cells, although striving to maintain amino acid homeostasis by
promoting amino acid synthesis or salvage, become more dependent on
exogenous supply of amino acids. proline-glutamine and asparagine-
arginine metabolic loops in tumor cells, which means that the
metabolism of these four amino acids is interrelated. These four amino
acids are often undersynthesized in tumor cells and are of great
significance, so anti-tumor research based on targeting proline,
glutamine, asparagine and arginine has made some progress.

Asparagine (Asn) is the most successful and best documented target for
amino acid depletion therapy in the treatment of cancer, Two
independent studies show that Asn can stimulate de novo glutamine
(Gln) biogenesis and high levels even promote epithelial to mesenchymal
transition(EMT), a crucial event in the cascade of events that drive
metastasis. Accordingly, ASNase mediated limitation of Asn repressed
both primary tumor growth as well as the development of metastasis,
not only by depriving the tumor of Asn, but by proxy depleting Gln .

Glutamine is an important nutrient for tumor cells and can promote

tumor cell growth by activating signaling pathways. Gln is considered as
rate limiting to tumor growth.Gln metabolism is highly regulated. Both de
novo biosynthesis of Gln and glutaminolysis are upregulated in several
cancers, via common oncogenes/tumor suppressors including c-Myc
and p53, glutamine-deficient environment can achieve the starvation
therapy of tumor cells .

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05
Amino acid depletion
Several epidemiological studies have demonstrated that diet plays an
important role in the initiation, promotion, and progression of many
common cancers, The chronic metabolic imbalance generated by
excessive consumption of food is associated with increased oxidative
stress, insulin resistance, inflammation, and changes in hormone and
growth factor concentrations that play key roles in the pathogenesis of
many cancers .
Fasting and fasting-mimicking diets (FMDs) provide a particularly
promising intervention to promote differential effects in normal and
malignant cells. These effects are caused in part by the reduction in IGF-
1, insulin, and glucose and the increase in IGFBP1 and ketone bodies,
which generate conditions that force cancer cells to rely more on
metabolites and factors that are limited in the blood, thus resulting in cell
death.
Other dietary interventions (e.g., ketogenic and protein-restricted diets)
that promote some of the metabolic responses caused by fasting have
also been tested in cancer treatments, KDs, which are rich in fats and
poor in simple and complex carbohydrates, increase blood ketones and
can decrease blood glucose. protein-restricted diets that could inhibit
tumor growth by reducing the amino acid supply to tumor cells and
consequently affect protein synthesis, mTOR activation, and other
metabolic processes .

Starvation
a chronic nutritional insufficiency that is commonly used as a substitute
for the word fasting, particularly in lower eukaryotes, but is also used to
define extreme forms of fasting.

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06
07 Synergistic starvation therapy with others
Fasting and cancer
other methods
Because of the strong variability and adaptability of tumors, single drug
treatment is often prone to drug resistance and poor efficacy; And each
treatment strategy has its own limitations, so how to combine the
characteristics of various treatment methods, complement each other's
advantages, and construct a new "cocktail therapy" has become a new
idea for cancer treatment.
GOx could be used as an antitumor agent alone through consuming the
intratumoral glucose and making the tumor “starving”. The continuously
generated H2O2 could further lead to DNA damage and tumor cell
apoptosis, thus realizing the synergistic treatment of starvation therapy
mediated by glucose oxidase with sonodynamic therapy, hypoxic
activation therapy, photodynamic therapy .

Autophagy is a conserved metabolic pathway, through which cells can

decompose and recycle some intracellular components. Normal
autophagy is a cellular stress response, such as stress protection under
starvation. Therefore, autophagy becomes a mechanism of tumor cell
resistance to treatment when starvation therapy is applied to tumor cells

chemotherapeutic agents and natural compounds are used in

combination.The objectives and rationale behind combining
conventional therapies with natural treatments are as follows:
1. To give a safer and more effective dose to reduce the negative side
effects.
2. To help build healthy cells’ resistance to chemotherapy and
radiotherapy and increase drug accumulation in cancer cells.
3. To increase additive or synergistic cytotoxic effect with chemotherapy
and radiotherapy.
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08
Conclusion

Preclinical and clinical studies have demonstrated the important role of

dysregulated metabolism in tumor initiation and progression, some of
the most common alterations in cancer cells are mutations leading to the
activation of signal transduction proteins and alterations of metabolic
pathways. As a consequence, tumor cells require an abnormally high
level of glucose to produce the glycolytic ATP and other metabolites
needed to proliferate and survive.

Attractive strategy for cancer treatment, nanomedicine-mediated cancer

starvation therapy could selectively deprive the nutrients and oxygen
supply through antiangiogenesis treatment, tumor vascular disrupting or
blockade, direct depletion of the intratumoral glucose and oxygen, and
other processes.

In starvation therapy, The emergence and development of starvation

therapy has greatly promoted cancer treatment and brought good news
to many cancer patients, so starvation therapy will play an important role
in the treatment of malignant tumors in the future.

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09
References

References
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HTTPS ://DOI .ORG /10.3390/ BIOMEDICINES 5020034
HTTPS ://DOI .ORG /10.1016/ J .TEM .2018.01.008
HTTPS ://DOI .ORG /10.1016/ J .TEM .2021.03.003
2019; 9(26): 8026-8047. DOI: 10.7150/ THNO .38261
HTTP ://DX. DOI. ORG /10.1016/ J. BBCAN .2016.06.005
HTTPS ://DOI .ORG /10.1158/0008-5472.613.65.2
HTTPS ://DOI .ORG /10.1186/ S43046-021-00072-6

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