Repurposing of drug in cancer treatment

Introduction
Cancer is defined as the uncontrolled division of cells due to mutation in DNA and having
potential to spread to different parts of the body. Cancerous cells leads to metastasis by
lymphatic system. During cancer progression, tumors become heterogeneous in nature which is
characterized by different molecular features and wide response to treatment. The survival rate,
complications, poor prognosis, recurrence are the major challenges in cancer treatment. More
than 200 different types of cancer are identified which are named according to the tissue where it
persists i.e. breast, lung, cervical, colon, and pancreatic cancer. According to the Global Cancer
Data 2022, 18.1 million cancer cases reported with 9.6 million cancer death worldwide.

According to American Cancer Society Journal, 2022:

Type of cancer Estimated new cases Estimated deaths

Breast cancer 287,850 43,250
Pancreatic cancer 32,790 23,860
Lung cancer 117,910 68,820
Ovarian cancer 65,950 12,181
Prostate cancer 268,490 34,500

Treatment of cancer available till date includes chemotherapy, radiation therapy, bone marrow
transplant, immunotherapy, hormone therapy, targeted drug therapy, and cry ablation. There are
some drawbacks of cancer treatment which includes complications in targeting cancer stem cells,
lack of specificity, potential of recurrence of tumor, lack of epigenetic profiling of cancer and
specificity of epi-drugs, cost ineffective, and development of drug resistance of tumor cells that
decreases the antitumor efficiency of therapeutic agents. To overcome these difficulties, there is
a need of development of novel therapies and new anti-cancer drugs. That’s why drug
repurposing came as a recent advancement in cancer world with the advancement in genomics,
proteomics, and computational world.
Drug repurposing is a strategy of identifying new therapeutic uses of existing FDA approved
drugs. It is also known as drug repositioning, therapeutic switching, drug re-profiling and re -
tasking. Reasons of repurposing of drug: reduces risk of disintegration, no human trails are
needed, lower risk of failure, shortens time cycle of drug development process, higher success
rate, lesser investment, understanding of mechanisms of action and molecular targets, knowledge
about toxicity and safety, availability of clinical experience and data. Napolitano.et.al.
demonstrated the cost of drug repurposing process is less than 60% expenditure in traditional
drug development.

The repurposing of drug process involves the selection of drug which has to repurpose on the
basis of availability of drug as a generic or off -patent, availability of clinical experience data,
availability of knowledge of safety and toxicity of effect, anti-cancer activity and its interactions
with target, widespread availability of drug in WHO Essentials Medicines List. After selection of
drug, computational testing is performed for its effectiveness, novel activity, potent targets i.e.
protein or pathway. Recently, Insilco screening or experimental approach is used for structural
and ligand based drug design. Clinical development is also known as drug development which
involves product development, pre-clinical or clinical trials for testing the safety of drug in
humans and lastly marketing of drug is done. The repurposed drugs can be used as a
monotherapy, chemoprotective agents or to enhance the efficiency and roles of chemotherapeutic
agents. Anticancerous drug or antineoplastic drug are basically anti-metabolite, tyrosine protein
kinease inhibitors, alkylating agents, hormones or hormones antagonists, proteosome,
angiogenesis and EGF receptors inhibitors. There are different repurposed drug used in the
cancer treatment reported: metformin, cyclophoshamide, thalidomidine, disulfiram, nelfinivir,
dexrazoxane, arteminisinin, mibefradil, doxorubicin, everolimus.

Libby, G. et al. reported that repurposing of drug for cancer treatment resulted in 37% reduction
in cancer incidence. Bonovas S. et al. reported in a meta- analysis of postoperative mortality in
cancer patients having preexisting diabetes that the presence of diabetes in cancer patients is 8%
to 18% shows bidirectional relationship between both diseases. Cyclophoshamide [cytoxan] is
alkylating agents used as anti-rheumatic drug which is repurposed to treat breast, blood cancer. It
has cytotoxic effect due to its cross linking ability to DNA and inhibits protein synthesis.
Hydralazine which is a hypersensitivity drug is used in cervical and ovarian cancer is in phase 3
trials. Thalidomide is a drug used in treatment of morning sickness in women that has anti-
angiogenesis activity used in myeloma treatment. Disulfiram [antabuse] used treat alcoholism is
in progress of testing with copper in treatment of breast cancer. Nelfinivir is a protease inhibitor
used to treat HIV which is in 1 phase trails for treating lung cancer. Artemisinin is an anti
malarial drug used in breast cancer treatment as it arrests cell cycle.

Mechanism of action of repurposed drug during cancer treatment: activation of protein kinease
[AMPK] that inactivates mammalian target of rapamycin [Mtor], Cyclooxygenase-2[COX2] and
phosphatidylinositol-3-kinease [PI3K] which leads to change in level of reactive oxygen level
[ROS] and mitochondrial functions inhibits. It also induces ferroptosis of SLC7A11 by inhibiting
UFMylation leads to cell death regulation. The recent focus is to detect the effect of drug on
vascular functionality, maturity and angiogenesis which is a hallmark for cancer. The expression
of p53 and NRF2 are the upstream regulators of SLC7A11 and their roles in the regulation of
ferroptosis can be a direction for further research in future.

1. BREAST CANCER:
It is the second most leading cancer in the world leading to the 2.3 million
women death globally. It is characterized by its 4 types on the basis of presence
of estrogen, progesterone receptors and human epidermal receptors 2[HER2]:
[i] ER/PR+, HER2+[ luminal B subgroup] [ii] ER/PR-, HER2+ [ iii] ER/PR+,
HER2-[Luminal A subgroup] [iv] ER/PR-, HER2-. Out of these, ER/PR- ,
HER2- [known as triple negative breast cancer, TNBC] is the most aggressive
breast cancer because there is no receptors present on these tumors. ER positive
BC reported 80% of all types of cancer and PR positive accounts 65% of the
total. 20% of the BC overexpressed HRR2. It is reported that 70 % of the breast
cancer are hormone receptor positive known as luminal breast cancer. Luminal
B subgroup is characterized by high expression of Ki67 or HER2 and have poor
prognosis than luminal A. HER2+ BC leads to the overexpression of
HER21ERBB2 oncogenes. Pathological and molecular characteristics of breast
cancer are p53, Ki67, CA153, CEA, BRCA1/ BRCA2.
 Category of drug Name of repurposed drug Mechanism
Alkylating agent cyclophoshamide Inhibits the DNA replication
Anthracyclins Doxorubicin DNA intercalation
Antimetabolite Fluorouracil, methotrexate, Incorporate false building
gemcitabine block during cell growth
CDK 4/6 inhibitors Palbociclib, palbonix Cell cycle interference
HT-SERM Tamoxifen, raloxifene Binds to ER

TNBC is divided into 4 subtypes on the basis of gene expression profile: basal- like1 [BL1],
basal-like2 [BL2], luminal androgen receptors [LAR], and mesenchymal [M]. Patho- physiology
of BC: BC is characterized either as invasive and non-invasive types. The non-invasive subtype
includes lobular and ductal carcinoma insitu while an invasive subtype includes lobular and
ductal carcinoma. Roshan.et.al reported the infiltration of T cell in invasive BC and mostly the
activated CD4+Th1 polarized cells that secrets inflammatory cytokines which leads to
upregulation of the MHC1 and MHC2 class molecules which is an essential part of immune
mediated anti-tumor effects. Activation of Th2-polarised CD 4+ T-helper cells results in
expression of inflamatory cytokines [IL4, IL5, IL6, IL10, and IL13] that enhanced the humoral
immunity responses and down regulates the cell mediated anti-tumor immunity which promotes
pro- tumor humoral responses. Bicalutamide is the first drug which is repurposed for treatment
of AR-positive TNBC induces cell apoptosis in MDA-MB-453 and MDA-MB 231 breast cancer
cells. Recently, Metformin [MET] is an antidiabetic drug used in treatment of diabetes milletus
type 2 patients which are repurposed as potential anticancer agent that decreases the stimulatory
effects of insulin in breast cancer cells. Breast cancer express high levels of insulin receptor that
increases insulin circulation which is associated with breast cancer recurrence and death. The
mechanism involves in the anti tumor action of metformin involves both direct [insulin
dependent] and indirect [insulin independent]. Luengo.et.al suggested that hepatic expression of
AMPK and upstream kinases LKB1 may be not required for suppression of gluconeogensis
performed by metformin in mice models. An AMPK independent mechanism involves glucagon
activates adenylyl cyclase lead to the production of cAMP and stimulates cAMP-dependent
protein kinease [PKA] signaling. Activation of PKA decreases the level of fructose-2, 6,-
bisphosphate which favors gluconeogensis in the liver and increases level of glucose in blood.
Metformin opposes action of glucagon due to inhibition of mitochondrial electron transport chain
that elevates cytotoxic ratio of AMP: ATP ratio which stops cAMP production. Madiraju.et.al.
suggested that metformin also inhibits mitochondrial glycerol-phosphate dehydrogenase [m
GPD]. MGPD transports cytosolic reducing unit from NADH into mitochondria by glycerol-
phosphate shuttle pathway. Inhibition of m GPD and mitochondrial complex1 reduces the ability
of mitochondria to oxidize NADPH of cytosolic which decreases the entry of reducing units into
electron transport chain. It inhibits proliferation of cancer cells by inducing cell cycle arrest and
apoptosis by regulating the expression of proteins that regulate G1-S cell cycle transition i.e.
cyclin E1, cyclin D1, and E2F transcription factor1. Cyclooxygenase [cox2] increases the
production of prostaglandin E2 [PGE2] that stimulates breast cancer progression .It also shows
chemoprotective effect by regulating cytochrome P4501A1 [CYP1A1]/aryl hydrocarbons
receptor [AhR] pathways. Wheaton WW.et.al suggested that metformin reduces the stabilization
of hypoxia-inducible factor alpha [HIFs α] and reduces the expression level of target genes in
tumors. Metformin also inhibits m TOR signaling pathway. Rapamycin is a specific inhibitor of
m TOR which inhibits cap-dependent translation. mTOR regulates m RNA translation by
phosphorylation of its 2 main targets: 4E-BPs and ribosomal protein kinases S6 [rpS6] kinases
[S6K1/S6K2].

Hyperphosphorylated 4E-BP1 binds to e1F4E that prevents the formation of e1F4F which
inhibits cap-dependent translation. Phosphorylation of S6K1 by m TOR enhances the kinases
activity of their downstream targets i.e. 40SrpS6, e IF4B, and S6K1Aly/REF-like target. AMPK
[heterotrimer serine/threonine protein kinease] effects m RNA translation by inhibiting m TOR
by phosphorylation and activation of tuberous sclerosis complex 2[TCS2] and subunit of
TCS1/TCS2 complex [hamartin, tuberin] which regulates m TOR signaling negatively. Hence,
inhibition of m TOR by activation of AMPK can be a new approach for treatment for breast
cancer.
2. OVARIAN CANCER:

It is fifth most common cancer in the women. OC results in 239,000 new cases and 152,000
worldwide deaths annually. Almost all benign and malignant tumors derived from three cell
types: epithelial cells, stoma cells, and germ cells. More than 90% of OC are epithelial- derived,
5%-6% are sex cord-stromal tumors [i.e. granulose cell, thecomas], and 2%-3% are germ cell
derived tumors. Malignant OC is also known as carcinomas which consists of five main
histotypes: high grade-serous[HGSOC,70%], endometrioid[ENOC,10%], clear
cell[CGCOC,10%], mucinous[MOC,3%], and low-grade serous[LGSOC,<5%]. High and low
grade serous tumors originate from epithelium of fallopian tube, CCOC and ENOC derived from
cysts of endometriosis, and MOC derived from transitional cell nests of mesothelial tubal
junction. HGSOC and LGSOC are derived from tubal epithelium. All these 5 histotypes are
thought to be progressed in a stepwise manner from borderline tumors are characterized as Type
I. Type II tumors showed an aggressive phenotype and lacking a clear precursor. Type I tumors
are linked with mutations in genes BRAF and KRAS. PTEN gene mutations in endometroid
tumors and HGSOC tumors have p53 mutations predominantly. The different drugs which are
used to treat OC are as: statins, metformin, bisphosphonates, ivermectin, itraconazole, ritonavir.

1. Statins: These are the inhibitors of 3-hydroxy-3-methylglutaryl-coenzymeA reductase

[HMGCR] which is located upstream in the mevalonate pathway that are involved in
biosynthesis of cholesterol. It is used to reduce cholesterol levels in plasma that is used in
treatment of cardiovascular diseases. It can also influence vascular expansion and
remodeling, inhibits fibrinolysis and coagulation, reduce inflammation. Li, X.et.al
suggested that overall survival rate in OC patients is higher in statins users with hazard
ratio =0.63. Matiryosyan.et.al suggested that lovastatin triggers apoptosis of OC cells by
blocking the activity of HMGCR and blocks the drug efflux pumps which sensitizing
chemoresistant cells to doxorubicin [mevalonate-dependent mechanism]. Dr.
Richardson’s.et.al demonstrated that pitavastatin which is a lipophilic statin have great
potential in treatment of chemoresistant tumors.
2. Metformin: It is used in the treatment of type 2 diabetes patients that inhibits the
respiratory-chain complex1 that mediates the activation of liver kinases B1and AMPK
 that increases ADP/ATP and AMP/ATP ratio which leads to the reduction in hepatic
glucose output. Hijaz.et.al suggested that metformin in combination with cisplatin
inhibits angiogenesis and cell viability, induces apoptosis in OC tumor cell. Effect of
metformin in combination with carboplatin- paclitaxel chemotherapy in OC treatment is
currently in phase 1 trial.
3. Bisphosphonates [alendronate, and zoledronic acid]: These are widely used in the
treatment of osteoporosis by bone resorption inhibition that decreases the osteoclast
activity. It blocks fernery pyrophosphate synthase enzyme which is necessary for
maintaining the function of osteoclast. They blocks cell proliferation, angiogenesis and
promote apoptosis. Kobayashi.et.al suggested that alendronate reduces stromal invasion,
ascites, and tumor burden which is responsible for its anti-tumoral effect in OC. Muinelo-
Romay, L.et.al suggested that zoledronic acid have anti-invasive and anti-proliferative
activity that leads to delay recurrences in OC by disturbing the steps of tumor
dissemination.
4. Ivermectin: It is a polycyclic lactone pesticide produced by bacteria Streptomyces
avermitilis which is a broad-spectrum antiparasitic agent that binds to glutamic acid
operative chloride ion channel present in muscle and nerve cells. This binding increases
the permeability of cell membrane that promotes entry of chloride ions into cell which
results in hyper polarization of muscle and nerve cells causes paralysis of parasite. It is
widely used to treat onchocerciasis, lymphatic filariasis, and scabies. It is used as an anti-
neoplastic agent that targets yes-associated protein1 [YAP1] as high expression of YAP1
is a prognostic indicator of OC. It also exhibits karyopherin subunit beta1 [KPNB1]
dependent anti-tumor effect. Zhang, X.et.al represented that ivermectin suppress the
phosphorylation of molecules involved in Akt/m TOR signaling pathway.
5. Itraconazole: It is a broad-spectrum antifungal agent that inhibits the synthesis of
ergosterol by blocking lanosterol14a-demethylase enzyme lead to the destruction of cell
membrane of fungi. It targets different oncological mechanisms: inhibiting Hedgehog, m
TOR, and Wnt/β-catenin signaling pathways, reversing chemoresistance mediated by P-
glycoprotein, inhibits angiogenesis by inhibiting phosphorylation of ERK and vascular
endothelial growth factor receptor 2[VEGFR2].
6. Ritonavir: It is a protease inhibitors used to treat AIDS. It possesses anti-proliferating
activity in cells of OC by inhibiting AKT pathway and induces cell cycle arrest. Cheung,
T.W.et.al reported that highly active anti-retroviral therapy [HAART] is defined as the
combination therapy in which protease inhibitors i.e. ritonavir, and nelfinavir and reverse
transcriptase inhibitors i.e. zidovudine are used to decrease the risk of OC.

3. PROSTATE CANCER:
Prostate is a gland in males that is located between penis and the bladder. It
produces seminal fluid which nourishes or transport sperms. PCA is a type of
adenocarcinoma in which neoplasia of glandular cell is detected. It is the second
most leading cancer in men. According to, The American Cancer Society 2021
reported 248,530 new cases of prostate cancer and 34,130 deaths due to prostate
cancer. PTEN gene deletion is found in 16 -32% PCA cases. Ras mutations
facilitate epithelial-mesenchymal transition [EMT] that makes PCA more
aggressive. Tomlins S.A.et.al reported that 40-80% of PCA is seen due to gene
fusion of TMPRSS2-ERG transcription factors. HOXB-13 G84E is a gene
variant responsible for tumorigenesis of prostate cancer. The different
repurposed drug used for the treatment of PCA:
1. Lipid lowering agents:
A. STATINS: These are the lipid lowering agents that inhibits hydroxyl-3-
methyl-glutaryl-coenzymeA reductase [HMGCR] enzyme involved in the
mevalonate [MVA] pathway. Statins blocks MVA pathway that affect YAP
and tafazzin [TAZ]-dependent transcriptional responses reduces growth of
cancer cells. Lovastatin and simvastatin inactivates RhoA, arrest cell cycle
in G1phase, and induces apoptosis mediated by cytochrome C-dependent
and independent signaling pathways. They lower the expression of p-Rb,
Rb, CDK4, 6, cyclin D1, D3 but increases p27 and p21 in PCA cells.

Name of statins Mechanism of action Dose

Fluvastatin Down regulating the 0-10 µM[in vitro]
phosphorylation of
FOXO1/AKT
Simvastatin Reduces PSA expression, 0-50µM[in vitro]
inhibits MCL-1 and Akt
Atrovastatin Lowers the expression of 0-10µM[In vitro]
hypoxia-inducible
factor[HIF-1α],Bcl-2,p-
Erk1/2, p-Akt and
activation of NF-κB
Mevastatin, Rosuvastatin Inhibits the synthesis of 0-10µM[In vitro]
GGPP, induction of
transcription of light chain
3[LC3]
Lovastatin Inactivation of RhoA 0-2µM[In vitro]
B. FIBRATES [FB]: It is a class of hypolipidemic medication which reduces
cholesterol [LDL] and TGs in bloodstream. These drugs are peroxisome
proliferative-activated receptor alpha [PPAR-α] which has anticancer
effects. FB arrests the cell cycle in G1 phase which downregulates E2F1 and
cyclins D1, decreased the level of Bcl-2 and increased the level of Bcl-2-
associated x protein [Bax] that leads to apoptosis.
2. Beta-Blockers: BBs are the cardioprotective medications showed
antagonist action by inhibition of β-adrenergic receptors. BBs are an
effective therapy for neuroendocrine prostate cancer [NEPCA].
Treatment by propranolol downregulates the expression of markers of
NE, inhibits angiogenesis, and develops NEPCA cell-derived xenografts
by disturbing the CREB1-EZH2-TSP1 pathway. Administration of
propranolol increases the level of autophagy markers i.e. p62 and LC3-
II.
3. Heparin: It is anticoagulant exhibits antiangiogenic properties due to
structural changes in fibrin, inhibiting binding of ligand to VEGF
receptors, inhibits endothelial factor pathway. It has antimetastatic
action by blocking P-and L- selectin, regulation of chemokines, and
suppressed the activity of heparinase. Hatziapostolou, M.et.al clinically
reported that FGF2 is related with growth of malignant prostate and high
level of serum FGF2 present in patients of PCA.
4. Cardiac glycosides [CGs]: These are steroid-like structures used to treat
congestive heart failure [CHF], atrial fibrillation and atrial flutter.
Ouabain [dose: 1-10µM] exhibits anticancer activity against androgen-
independent PCA that results in loss of activity of telomeric DNA. It
arrests the cell in M or G2 phase by halting the functioning of cyclins
and CDK inducing apoptosis in PC3 and C-42 cells. It also causes
endocytosis of Na+/K+-ATPase and increased expression level of cell
 cycle inhibitor p21 Cip. It downregulates marker STAT3 in cancerous
cell. Oleandrin [dose: 0.001-0.002µg/ ml] downregulates procaspase-3,
activates PARP and caspases, inhibits the activity of NF-κ B. Digitoxin
[dose: 1-10µM] inhibits synthesis of HIF-α and decreases the expression
level of HOXB-13 gene. Digoxin [dose: 1-10µM] induces differentiation
of CAF and inhibits the expression of TGFβ.
5. RAAS [rennin-angiotensin-aldosterone] inhibitors: Angiotensin2
[ANG2] is the main bioactive peptide out of all intermediates of RAAS
cascade. Captotril lowers the incidence of PCA by crossing the blood-
seminal plasma barrier and lowers the level of DNA damage marker 8-
hydroxydeoxyguanosine. Enalapril is an ACE-I which downregulates
transcriptional factor NF-κ B and VEGF m RNA.
4. LUNG CANCER:
Lungs are most typical organ for cancer to spread in the body. This is due to fact
that blood flows back to heart from different body parts and then enters into
lungs. Cancer cells that is present into bloodstream remains in the capillaries of
the lungs. Sigel, R.L. et.al suggested that lung cancer causes 1670 deaths per
day in 2023. It has second highest incidence of cancer with 238,430 new cases
and 81% mortality rate in 2023. According to National Institute of Health, U.S.
reported that the 5-year survival rate for lung cancer is 56% when the diseases is
still localized [intrapulmonary] and 16% of lung cases receive an early
diagnosis. The 5-year survival rate for distant tumors is 5% which suggested
that the survival rate of lung cancer is low as compare to other types of cancer.
Lung cancer is categorized into two types: small cell lung carcinoma [SCLC]
with 15-20% cases and non small cell lung carcinoma [NSCLC] with 80%
cases. NSCLC subtypes includes: adenocarcinoma, squamous, adenosquamous,
spindle cell, large cell, pleomorphic, and giant cell carcinomas.
Adenocarcinoma is most common subtype of NSCLC measures 60% of the lung
cancer cases. Hanna, J.M.et.al reported the inflation in population of BASC [a
subset of distal adult lung epithelial stem cells] associated with tumor
progression in KRAS-mutant mice. The epidermal growth factor receptor
[EGFR] gene is the most important cancer related genes which affects NSCLC.
MET gene codes for tyrosine kinase receptor associated with lung cancer
metastasis and pathogenesis. EML4-ALK [a lymphoma kinase gene] and KRAS
[Kristen rat sarcoma viral oncogene homolog genes] is the gene responsible for
adenocarcinoma. Fibroblast growth factor receptor type 1[FGFR1] gene and
discoidin domain receptor 2 [DDR2] gene codes for tyrosine kinase cell surface
receptor is responsible for squamous cell carcinomas by 20%. The repurposed
drugs used for the treatment of NSCLC are as follows:
1. Beta-blockers: These are anti-hypersensitive and anti-arrhythmic drug.
Sidorova.et.al studied the beta-blocker effect on the viability and colony
formation of NSLC cells, revealed that propranolol and betaxolol are the most
responsive in colony formation of lung cancer cells at 90% of EC50 value.
Propranolol decreases angiogenesis of tumor, makes β receptors insensitive
towards the use of chronic β-agonist which increases the expression of IL-6
stimulating the proliferation of cell and inhibits liver kinaseB1 [LKB1] tumor
suppressor in EGFR-positive adenocarcinoma lung tumors. Angiotensin I
converting enzyme inhibitors [ACEIs] and angiotensin II receptor blockers
[ARBs] are repurposed for treatment of NSLC because rennin-angiotensin-
aldosterone system are the major hallmarks of cancer. Telmisartan and losartan
is an ARB which activates PPARγ results in cessation of metastasis of tumor.
Godugu, C.et.al reported that telmisartan had 2.7 fold greater intratumoral
distributions as compare to losartan.
2. Nonsteroidal anti-inflammatory drugs [NSAIDs], Anti-inflammatory drugs:
These inhibit Cyclooxygenase [COX] enzymes. Upregulation of COX2 is seen
in lung adenocarcinomas. The specific inhibitor of COX2 is Celecoxib used as
an anti-analgesic for rheumatoid arthritis and osteoarthritis. Celecoxib helps in
down regulation of NF-κ B, BAX, caspases-9, and BCL-X. It binds to 3-
phosphoinositidne-dependent protein kinease-1[PDK-1] which inhibits
PDK1/AkT pathway that controls coupling of nucleus-centrosome and regulates
binding of MAP to microtubules. Indomethacin is a NSAID which inhibits
COX-2 enzyme inhibitor. Sarvepalli.et.al prepared IND liposomal formulations
to enhance its potential of anticancer by inhibiting the enzymatic activity of
caspases-3 by upregulation of Bax, Bak, and PPAR-γ pathway.
3. Anti-hyperlipidemic drugs: Statins are used as repurposed drug for lung
cancer treatment. Statins inhibits the enzyme β-hydroxy β-methylglutaryl-CoA
[HMG-CoA] which is essential for synthesis of cholesterol. They also decrease
the production level of mevalonate derivatives which are important for cell
proliferation and differentiation. Atrovastatin is a statin that results in the
inhibition of AkT/m TOR and activation of MAPK pathway. It also leads to the
depletion of isoprenoid derived growth proteins which are important for the
cell-growth-stimulating proteins [Rac, Rho, and Ras] functioning.
Hosseinimehr.et.al reported that the apoptosis rate of both atrovastatin and
irradiated treated A549 lung cancer cell was higher than of irradiated cells
alone. Lovastatin increases the expression of COX2 and activates PPAR-γ that
induces cytotoxicity in cancerous cell of lungs. Simvastatin induces apoptosis in
mutated cells with p53. Gefitinib plus simvastatin showed higher response rate
in treating NSCLC as compare to gefitinib is in 2 nd phase trails. Pitavastatin in
combination with erlotinib showed a collaborative cytotoxic effect on EGFR-
TKI-resistant lung adenocarcinoma human cell line that inhibits mevalonic acid
pathway and pan-caspase inhibitor z VAD.
4. Anti-malarial drugs: Atovaquone inhibits the consumption of mitochondrial
oxygen that decreases tumor hypoxia in NSCLC patients. Dihydroartemisinin
causes NSCLC metastasis inhibition by modulation of glucose metabolism,
inhibits NF-κ B pathway. Quainacrine leads to the FACT resistance [facilitates
chromatin transcription complex which is involved in tyrosine kinease inhibitor
[TKI]. Bhateja, P.et.al suggested that erlotinib and quinacrine combination is in
phase 1 clinical trial for treatment of NSCLC.
5. Anti-retroviral drug: Lopinavir is a protease inhibitor used in combination
with ritonavir used for lung cancer treatment by arresting cell cycle, decreasing
viability of cell, and apoptosis of cell. Nelfinavir inhibits the activity of
proteosome in cancerous cell of lung. Efavirenz has been shown a coordinative
effect in combination with radiation therapy of lung cancer.
6. Anti-helminthic drugs: Mebendazole showed the cytotoxic effects on NSLC
cell lines A549, H1299, H460 by blocking polymerization of tubulin leads to
the inhibition of synthesis of microtubule. It leads to the downregulating
expression of MDM2 and p21. Ozdemir, A.et.al reported that a niclosamide and
piperazine hybrid also exhibits anti-proliferative properties on the cancerous cell
of human lung in vivo. Ivermectin exhibits antineoplastic properties by blocking
the canonical WNT [wingless-related integration site] signaling pathway which
affect T-cell factor [TCF] family transcriptional factor.
7. Other drugs: Sertraline is an antidepressant used in combination with
erlotinib for the treatment of lung cancer which results in AMPK/m TOR
pathway in cells of NSCLC. Nitroglycerin is a nitric oxide [NO] donner used in
treatment of angina but also downregulates HIF1 alpha and inhibits
angiogenesis. Combination of vinorelbine and cisplatin with nitroglycerin is in
IInd phase of clinical trial suggesting that the survival rate of untreated stage of
IIIB/IV non-squamous cell lung cancer has been improved.

5. PANCREATIC CANCER:
PC starts in the cell lining of the pancreatic duct known as pancreatic
adenocarcinoma. Pancreas is an organ lies behind the lower part of the stomach
that helps in metabolism of sugars. PC is late detected, rapidly spreads and has
poor prognosis with less than 8% of 5-year survival rate. According to
American Cancer Society, PC is found in 64,050 people and 44,330 deaths with
a 12% increase in 5-year survival rate. Street, w.et.al reported that PC will be
the second leading cause of cancer death by 2023. It remains a difficult disease
to treat because of its aggressive nature, early metastasis to distant and nearby
organs, delayed clinical presentation, and inherent resistance to current
treatment. 85% cases of PC are exocrine pancreatic in origin. Mutations in
KRAS [90%], CDKN2A [90%], TP53 [70%], SMAD4 [55%] genes are
responsible for occurrence of PC. CCAT2 gene [long non-coding RNA] is
oncogene responsible for PDAC. Shin SH, et.al reported SMAD4/DPC4 gene in
641 patients of PC. EGF, EGF-R, HER-2/neu, and p185 overexpression leads to
the advanced stage of PC. Hypermethlyation of RARb, p16, CACNAIG, TIMP-
3, Ecad, THBSI, Hmlh1, DAP kinase, MINT31 are also responsible for
occurrence of PC. RASSFIA [75%], inka/p16 [40%], OMGMT [40%], O-
MGMT [40%], RAR-B [25%], GSTπ, E-cadherin, APC, P14ARF genes
Hypermethlyation are associated with pancreatic neuroendocrine tumors at
advanced stage of tumor. The different repurposed drugs for PC treatment are as
follow:
1. Auranofin: It is an organogold complex containing an Au-S bond stabilized
by triethylphosphine group used for the treatment of rheumatoid arthritis. It
 exhibits antitumor action by inhibiting hypoxia-inducible factor-1α,
accumulation of mitochondrial ROS, activation of caspase 3/7, and cleavage
of proteolytic PARP. Cramer S.L., et.al demonstrated the cytotoxicity of
cancer cell by treatment with a combination of Auranofin with an
engineered human cystinase results in depletion of L-Cys extracellular pool
and oxidative stress.
2. Anti-psychotic drugs: Haloperidol and penfluridol are hydroxypiperidine
that blocks dopamine D2 receptor [DRD2] which promotes stress in ER. It
promotes DUSP6 gene demethylation in MIA PaCa-2 cells. Jandhagi.et.al
reported that the expression level of DRD2 is increased in PDAC.
Penfluridol activates protein phosphatase2 [PP2A] that inhibits PC tumor. It
targets the binding site of JAK2 in PRLR which suppress ERK/AKT and
JAK2-STAT3 signaling pathway.
3. Disulfiram: It is derivative of organic disulfide by oxidative dimerization of
N, N-diethyldithiocarbamic acid used in treatment of alcoholism. DSF leads
to chelating of copper cations [Cu2+] which forms DSF/Cu complex act as
inhibitors of proteosome that results in inactivation of NF-κ B. Han et.al
reported that diethyldithiocarbamate[DDTC] , a DSF metabolite which
forms a binuclear complex DDTC-Cu[I] affecting the proliferation of PC
cell. Disulfiram in combination with chemotherapy is in phase 1 clinical
trial for PC treatment.
4. Antiviral drugs: HIV inhibitors i.e. efavirenz, nelfinavir, and ritonavir used
in treatment of PC. Efavirenz results in production of ROS depolarization of
membrane of mitochondria, ERK1/2 and p38 MAPK stress pathways
phosphorylation in PC cells. Nelfinavir inhibits the phosphorylation of
AKT/PI3 signaling pathway. Batchu.et.al reported that ritonavir suppress the
phosphorylation of Rb.