Repurposing Drugs against Cancer

1. Introduction

Cancer is a group of disorders characterized by aberrant cell proliferation and resistance to growth-suppressing signals. It is a multi-tutorial genetic disease that may be detected early if diagnostic parameters are promising, and it can be successfully treated by focusing on potential therapeutic targets. While the emphasis on lifestyle may rule out an epigenetic role in cancer progressions, such as reducing bodily exposure to carcinogens in both diet and usable materials for example avoiding excessive sun exposure and tanning materials can lower the risk of skin cancer (Cancer Statistics, 2018). Today, cancer is one of the most common causes of death around the world. For the year 2018, there were an anticipated 1.8 million new cancer diagnoses and 600,000 deaths in the United States alone (Cancer Statistics, 2018).

Cancer growth is triggered by a failure in the genetic processes that regulate cell growth and proliferation. In most situations, oncogenesis is caused by accumulated damage to numerous genes (the "multi-hit" model) caused by physical and chemical agents, replication errors, and other factors. However, a person's inherited genetic background may also play a significant role. In cancer, a single altered cell develops to create a primary tumor, then metastasizes to another tissue and becomes a secondary tumor after accumulating more mutations and becoming more aggressive. Metastasis is often nonrandom, with tissues that generate growth factors and angiogenic factors being the most susceptible to invasion. The potential of a malignant tumor to penetrate and metastasize to other tissues is what distinguishes it from a benign tumor. Tumors are categorized based on the embryonic origin of the tissue from which they develop. Cancers of endodermal (e.g., gut epithelial cancers) or ectodermal (e.g., skin, neural epithelia) origin are referred to as carcinomas. Sarcomas are the cancer of mesodermal origin (e.g., muscle, blood cells). Carcinomas account for more than 90% of all malignant tumors.

Mutations that impact growth factor receptors and signal transduction genes, cell cycle regulatory genes, DNA repair genes, or apoptosis genes induce alterations in cellular growth. The mutant gene is classified as an oncogene or a tumor-suppressor gene based on whether it typically stimulates or inhibits proliferation respectively.  

Very often (particularly in early stages) the diagnosis of cancer involves a histological examination of the affected tissue. Microscopically, cancer cells show abnormal location and morphology, loss of structural features characteristic of a differentiated cell, and an abnormally large nucleus and prominent nucleoli. The cytoskeleton typically also is abnormal. Karyotyping may show gross chromosomal abnormalities in advanced tumors. Such large tumors, in fact tumors larger than 2 mm in diameter, develop their own blood supply. To do this, cancerous cells secrete growth and angiogenic factors such as basic fibroblast growth factor (b-FGF), transforming growth factor a (TGFa), and vascular endothelial growth factor (VEGF).

Most malignant tumor cells eventually acquire the ability to metastasize. To do so they must degrade the basement membranes of connective tissue underlying epithelial cells and surrounding the endothelial cells of blood vessels. This can be accomplished by secretion of plasminogen activator, which activates the blood protease, plasmin. Malignant cells form structures called invadopodia which contain protein components needed for crossing basement membranes.

Table. - Classes of genes implicated in the onset of cancer

Drug repurposing against cancer includes the screening of drugs against cancer already present in the market. It could be human/veterinary and their pharmacokinetics and toxicology studies are done. Moreover, pre-analysis of unexpected side effects and in-vivo efficacy has already been done. There are several classes of drugs based on their type of disease against which it is used.

Sedatives: Bortezomib, antipsychotic drugs, Pomalidomide, lenalidomide, thalidomide, and dexamethasone. Thalidomide - inhibits DNA replication, angiogenesis, chondrogenesis, and cell death, inhibits mRNAprocession of TNFa and VEGF. Their anti-cancer properties have been seen against multiple myeloma. They upregulate p21 expression and induce apoptosis. Lenalidomide - The combination of lenalidomide and dexamethasone along with proteasome inhibitor bortezomib extended the survival rate. Dexamethasone - Along with thalidomide yield a 60% response rate against multiple myeloma.

NSAID: Acetylsalicylic acid (Aspirin) reduces metastasis in mice. Celecoxib against colon, lung, breast cancers and it is COX-2 inhibitor. Risk of breast cancer reduced to 71% in female patients using celecoxib. Taxanes, Letrozoles, Tamoxifen, Anastrozole in combination with COX-2 inhibitor but still further evaluation is needed. 

Anticonvulsant//Antiepileptic: these include lamotrigine, Valproic Acid (HDAC inhibitor) interacts with oxidative metabolism, γ−Amino butyric acid, 1-methyl-1-cyclohexanecarboxylic acid (MCCA), GSK-3b, Akt signalling, TCA, Erk pathway etc. Phenytoin is voltage gated sodium channel blocker. It inhibits migration and invasion of MDA-MB-231 cells.

Antihyperlipidemic: Statins include simvastatin, atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin and pitavastatin, are agents that inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase, that catalyzes the important step in cholesterol biosynthesis. They inhibit proliferation, promote cell cycle arrest, apoptosis and differentiation in tumor cells. Statins potentiate TNF induced apoptosis in CML and reduced incidence of colorectal cancer.

Antidiabetic: Metformin inhibits cancer cells growth and proliferation and different cell lines demonstrated sensitivity to the inhibition of oxygen consumption by metformin, with relatively small variation [1]. The anticancer effects of metformin by both direct (insulin-independent) and indirect (insulin-dependent) mechanisms are discussed in terms of metformin-targeted processes and the ontogenesis of cancer stem cells [2]. Combination of disulfiram and metformin inhibited fibrosarcoma growth in hamsters [3]. Metformin reduces intracellular reactive oxygen species levels via the AMPK-FOXO3 pathway [4]. Metformin has rare but potentially serious side effects, such as idiosyncratic hepatotoxicity but usually Metformin is not considered intrinsically hepatotoxic [5]. Metformin may prevent or ameliorate gentamicin-induced acute renal failure, and therefore it might be beneficial in patients under treatment with this medicine [6]. It can cross the blood-brain barrier. Metformin up-regulated the rat brain endothelial barrier function by increasing the phosphorylation levels of AMPK in brain endothelial cells [7]. Metformin prevents ischemia-induced brain injury by alleviating neutrophil infiltration by down-regulating ICAM-1 in an AMPK-dependent manner [8].

Antimalarial: ART caused dose-dependent decreases in cell number, which were associated with either increased cytotoxicity or cytostasis in MCF and A549 cells [9]. It induces oxidative stress in the mechanism of ART action in tumor cells and suggests that antioxidant defenses act in combination to affect the cellular response to ART [10]. It induces mild liver toxicity but enhances bone marrow toxicity.  Administration of artesunate for 14 days caused a significant increase in the levels of ALT, AST, ALP and GGT in serum, inducing hepatic injury [11, 12]. Generation of mitochondrial ROS prompted by artesunate was found to be the principal mechanism of cell death in renal carcinoma [13]. It caused irreversible vascular irritation, reversible nephrotoxicity and no neurotoxicity at high doses. Artesunate could preserve blood–brain barrier integrity and improve neurological outcome after subarachnoid hemorrhage, by activating S1P1 [14]. It has high permeability of artemisinin across biological membranes and can cross the blood-brain barrier [15].

Antiviral: Acyclovir monophosphate exhibited concentration-dependent cytotoxicity against H460 cells and increased S-phase arrest [16]. Ethyl phosphoramidate derivatives show promising antioxidant activity [17]. Acyclovir group showed significant decrease of serum albumin, elevation of alkaline phosphatase activity associated with a severe apoptotic changes as evidenced by Bc12 overexpression in liver cells [18]. Acute renal insufficiency associated with high-dose of acyclovir administered intravenously. Nephrotoxicity developed despite precautions to avoid volume contraction [19, 20]. Zidovudine is a dideoxynucleoside used in the treatment of HIV infection [21]. Zidovudine induced liver toxicity and oxidative stress [22]. hepatotoxicity, oxidative stress and hyperlipidaemia induced by AZT in rat liver [23]. It induces liver toxicity and oxidative stress. It is responsible for mitochondrial myopathy, mitochondrial DNA depletion, lactic acidosis alone or associated with hepatic abnormalities [24]. AZT at a dose of 400 mg/kg/day for 17 days caused clear hematotoxicity and nephrotoxicity[25]. It can cross the blood brain barrier and Zidovudine passes the monolayer mainly by passive diffusion [26] [27]. DDI is transported from the brain into circulating blood across the blood-brain barrier via a probenecid-sensitive carrier-mediated efflux transport system [28]. Didanosine is a hypoxanthine attached to the sugar ring, unlike other nucleoside analogues. Dideoxyinosine derivatives show anti-cancer activity [29]. DDI may or may not be the only potential cause of hepato-toxicity [30] and passage across the BBB was demonstrated to be via non-saturable and saturable processes [31, 32]. 

Antifungal: Triazole induces anti-angiogenic activity and inhibits hedgehog signalling pathway, induces autophagic growth arrest. Against  leukemia, ovarian, breast and pancreatic cancers. Thiabendazole TBZ induces anti-angiogenic activity and decreases vascular density. Rapamycin induces its analogues against breast cancer. Inhibits mTOR signalling pathway.

Anthelmintic: Cyclodextrin complexes of niclosamide show enhanced anticancer activity both in in-vitro and in-vivo mice model [33, 34]. Antioxidant - it increases ROS production in AML, lung cancer cells and enhances ROS production mediated cell death via c-jun activation [35, 36]. It targets Wnt/b-catenin signalling and attenuates cancer stemness [37]. No known nephrotoxicity of niclosamide has been reported even improvement of renal ischemia/reperfusion injury has been validated [38]. Mebendazole inhibited the growth of breast, ovary, colon carcinomas and osteosarcoma with IC50 values in the range of 0.1 to 0.8 μM. Mebendazole is a benzimidazole anthelmintic used to treat helminth infections. Inhibitory effects of MBZ against breast, ovary, colon carcinomas, and osteosarcoma, producing IC50s that varied from 0.1 to 0.8 μM [39]. Mebendazole blocked anticancer activity of disulfiram and metformin combination [3]. The comparative analysis of results between intact group and control pathology showed a significant mebendazole-induced neurotoxicity [40]. Mebendazole has not shown any major liver toxicity and renal toxicity [41, 42]. Mebendazole crosses the blood-brain barrier and among patients with cystic echinococcosis, there is significant variab ility in absorption [43]. Its different polymorphs can cross BBB and reach upto brain tumor as seen in mice [44]. It crosses BBB and reaches well into brain tumor tissue [45].

Drugs for osteoporosis: Zoledronic acid induces caspase-dependent apoptosis in renal cancer cell lines [46]. ZA induces rabbit liver oxidative stress and decreases antioxidant levels in liver tissue [47]. ZA induces apoptosis through promoting ROS production and subsequently activating chloride channels in nasopharyngeal carcinoma [48]. Zoledronic acid may cause hepato-toxicity [49, 50] but helps in preventing bone loss after liver transplantation [51]. Patients with multiple myeloma or different types of metastatic cancer, who had experienced renal impairment during zoledronic acid therapy [52]. It causes renal toxicity in patients with multiple myeloma and bone metastasis [53, 54]. Blood-brain barrier - Information not found but Transferrin-targeted self-assembled nanoparticles (NPs) incorporating zoledronic acid increases the antitumor efficacy of this drug in glioblastoma through the acquisition of ability to cross the BBB [55].

2. Potential Anticancer Drugs

Celecoxib

4-[5-(4-methylphenyl)–3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide, a COX-2-selective NSAID, is known as celecoxib. The US Food and Drug Administration (FDA) authorised the oral capsule version in 1999, and Pfizer, Inc. (New York, NY, USA) began marketing it in 2000. Celecoxib is an analgesic, anti-inflammatory, and antipyretic medication and known for its decreased risk of causing gastrointestinal. Celecoxib appears to have a substantial chemopreventive effect on breast cancer, according to preclinical studies [56, 57]. In various animal models of breast cancer, celecoxib therapy (500–1,500 mg/kg diet) reduces tumour incidence, multiplicity, and volume [58, 59]. Furthermore, metastasis to the lungs and brain might be avoided and clinical trials, in addition to preclinical investigations, yielded good findings. A standard dose of celecoxib (200 mg/day) for more than 12 months was related to a significantly decreased risk of breast cancer in two cases–control trials [60, 61]. It reduces precancerous polyps in the colon and NSAIDS are known to exhibit anti-colon cancer effects for 2 decades [62]. Cyclooxygenase 2 converts arachidonic acid into prostaglandins E2 (PGE2) and its overexpression helps in breast cancer progression [63]. In turn, PGE2 governs anti-tumor immunity suppression, increased metastasis, lymphangiogenesis and stem cell like properties [64-67].

Cyclooxygenase 2 is associated with breast cancer cell motility, metastasis and cancer progression [68]. Cyclooxygenase is highly expressed in breast cancer and ductal carcinoma in-situ as compared to normal tissue while it is also expressed in different types of tumor [69-71]. Celecoxib exerts anticancer effects by binding to the cadherin-11 (CDH11) protein, which is thought to be involved in the progression of tumors. Celecoxib inhibits promotion of mammary tumorigenesis in rats. It might contain antioxidant activity, not validated [72] and may also have a pro-oxidative anti-cancer effect [73]. The cholestatic hepatitis is temporally related to celecoxib use [74] while Celecoxib induced renal Injury in rats has also been reported [75]. The use of celecoxib is associated with renal effects similar to that of conventional nonselective NSAIDs [76].

Celecoxib was shown to reduce glioma cell viability by inducing DNA damage, leading to p53-dependent G1 cell-cycle arrest and autophagy. However, the use of celecoxib in patients with glioblastoma has seen mixed results, due in part to the low potential of the drug to cross the blood–brain barrier (BBB) [77]. Celecoxib showed a significant protective effect on HBMECs against irradiation, which involves inhibited apoptosis; celecoxib could alleviate radiation-induced brain injury in rats [78]. Celecoxib inhibits the expression of Snail, Slug, ZEB1, vimentin, focal adhesion kinase etc, thus blocking tumor cell mobility in in-vitro studies. In-vivo administration of celecoxib in tumor xenograft mice model exhibit 65% inhibition of oral squamous cell carcinoma. celecoxib administered tumor xenografts were well differentiated as compared to control [68].

Celecoxib inhibits the growth of breast cancer cells in vitro and protects rats from developing BC caused by 7,12-dimethylbenzanthracene (DMBA). As a result, celecoxib has anticancer properties and appears to be useful in cancer treatment. Bocca et al investigated celecoxib's antiproliferative efficacy in human breast cancer cells with varying levels of COX-2 expression. Celecoxib administration causes a significant reduction in cell growth in oestrogen receptor (ER) (+) MCF-7 cells, as well as a decrease in aromatase and ER expression and activation. Inhibition of ERK and Akt, as well as activation of PP2A and PTEN, may be involved in the linked pathway [79, 80]. Short-term COX-2 inhibition by celecoxib promotes transcriptional programmes that enable antitumor activity in primary breast cancer tissue, according to a research finding transcriptional alterations in breast cancer tissues of patients treated with the medication. Basu et al investigated the mechanisms by which celecoxib impacts tumour development in MDAMB-231 (very invasive) and MDA-MB-468 (moderately invasive) human breast cancer cell lines. In diverse human breast cancer cell lines, they established that the varied molecular pathways of celecoxib-induced growth suppression are dependent on COX-2 expression levels and invasiveness [81]. Celecoxib's tumour growth inhibition effect was found to be mostly due to promoting apoptosis rather than affecting cell proliferation [82].

COX-2 overexpression in celecoxib-resistant cell lines results in lower levels of Bax, a pro-apoptosis protein, and higher levels of anti-apoptosis proteins such as Bcl-2 or Bcl-xL [83]. COX-2 knockdown using a particular siRNA reduces clonogenicity and Bcl-xL and Bcl-2 levels in these cells considerably. Celecoxib causes apoptosis in breast cancer cells by lowering Akt phosphorylation, raising Bax expression, and activating caspase 3 and caspase 7. Celecoxib also inhibits the NF-B pathway, which causes apoptosis in the breast cancer cells. Another route of celecoxib-induced apoptosis is the p53-independent mitochondrial apoptosis pathway, which is independent of COX-2 and cannot be blocked by Bcl-2 overexpression [84, 85].

Dietary administration of celecoxib also produces anti-tumor effects in mice, decreasing tumor volume and cancer progression [86]. Despite the promising effectiveness described above, the mechanisms of celecoxib's anticancer activity remain unknown. In carcinogenesis and development, COX-2 plays a critical function. As a selective COX-2 inhibitor, celecoxib is thought to have multiple anticancer mechanisms, including proliferation suppression, apoptosis induction, immunoregulation, tumour microenvironment regulation, antiangiogenic action, and resensitization of other antitumor medicines. Meanwhile, celecoxib's anticancer action is aided by COX-2-independent mechanisms. 

Lamotrigine

Lamotrigine is an antiepileptic drug belonging to the phenyltriazine class. It is used in the treatment of both epilepsy and as a mood stabilizer in bipolar disorder. It inhibits the proliferation, the anchorage-dependent, and independent cell growth in breast cancer cells [87]. Lamotrigine has the most protective effects on oxidative stress [88]. Acute hepatitis is also associated with Lamotrigine [89], chronic exposure of rats to high doses of LTG reflects hepatocellular damage that may lead to hepatitis [90]. Lamotrigine induced neuroleptic malignant syndrome in a patient with renal failure caused by lithium [91]. Lamotrigine can also cross the blood-brain barrier [92]. Lamotrigine dramatically improved the oxidant/antioxidant milieu while decreasing acetylcholine esterase and glutamate levels in brain tissue [93]. Lamotrigine is a second-generation anti-epileptic drug with a broad activity range, a manageable adverse effect profile, easier dosage than previous medications, and improved effectiveness in a variety of epileptic syndromes. Unfortunately, lamotrigine is the most interacting medication among the new anti-epileptic drugs, and its metabolism is vulnerable to both enzyme inhibition and induction [93].

Lamotrigine is a voltage-gated sodium channel blocking medication that has anti-cancer efficacy based mostly on other mechanisms and is thought to work against cancer by inhibiting histone deacetylase [94]. Because there is very little and insufficient information in the current literature, we sought to investigate the potential antitumoral activity of lamotrigine, a synthetic phenyltriazine with anticonvulsant properties that has been commercially available since the mid-1990s for the treatment of epilepsy and bipolar disorder [95]. The capacity of lamotrigine to inhibit voltage-activated Na and Ca channels is thought to be the mechanism by which it exerts its anti seizure activity [96]. Lamotrigine inhibits breast cancer cell proliferation, anchorage-dependent and independent cell growth. These effects were linked to cell-cycle arrest and changes in related proteins and target genes of FoxO3a, a ubiquitous transcription factor that is adversely regulated by AKT. Lamotrigine also enhances the expression of another FoxO3a target, PTEN, which downregulates the PI3K/Akt signalling pathway, resulting in FoxO3a dephosphorylation and activation. Furthermore, in an autoregulatory mechanism, lamotrigine stimulates FoxO3a expression by boosting transcription [87].

Lamotrigine's site of action has already been explored using binding and neurochemical techniques. Lamotrigine does not bind to dopamine, adenosine, muscarinic, or sigma neuronal receptors, and it does not appear to be an N-methyl-D-aspartate receptor antagonist since it does not reduce the production of cyclic GMP in response to N-methyl-D-aspartate. Lamotrigine reduces veratrine-induced neurotransmitter release in rat cortical brain slices, according to neurochemical research [97]. It is used to treat seizures, other types of convulsions, and bipolar disorders. LTG's antiepileptic action is caused by its binding to voltage-gated sodium channels, which inhibits the release of endogenous amino acids and acetylcholine. LTG can also be used to treat colon cancer and chronic myelogenous leukaemia. Furthermore, both in vitro and in vivo investigations have shown that LTG has potent antiproliferative effects in breast cancer cells. LTG, at modest dosages, can boost felbamate's protective index against seizures by strengthening the anticonvulsant action without significantly increasing neurotoxicity [98].

However, because the effect of lamotrigine on signal transduction has not been widely studied, and because the most common therapeutic targets for antitumor drugs are receptors, protein tyrosine kinases, and the phosphatidylinositol 3-kinase (PI3K)/Akt cell survival pathway, we will examine the potential interference that lamotrigine could exert on intracellular signalling molecules in different cancer cells, either directly or indirectly. Lamotrigine's biological effects and molecular mechanism in many types of human malignancies have yet to be discovered, as has its impact on tumour growth. However, the positive benefits of the current generation of anti-epileptic drugs such as lamotrigine outweigh the harmful effects of mitochondria [93, 99]. 

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