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| REVIEW ARTICLE |
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| Year : 2023 | Volume
: 55
| Issue : 5 | Page : 322-331 |
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Drug repurposing a compelling cancer strategy with bottomless opportunities: Recent advancements in computational methods and molecular mechanisms
Rasmita Dash1, Madhulika Yadav2, Jyotirmaya Biswal2, Shrabani Samanta2, Tripti Sharma2, Sujata Mohapatra2
1 Department of Pharmaceutics, School of Pharmaceutical Sciences, Siksha ‘O’ Anusandhan (Deemed to be University); Department of Pharmaceutics, School of Pharmacy and Life Sciences, Centurion University of Technology and Management, Bhubaneswar, Odisha, India
2 Department of Pharmaceutics, School of Pharmaceutical Sciences, Siksha ‘O’ Anusandhan (Deemed to be University), Bhubaneswar, Odisha, India
| Date of Submission | 01-Sep-2022 |
| Date of Decision | 05-Aug-2023 |
| Date of Acceptance | 29-Aug-2023 |
| Date of Web Publication | 02-Nov-2023 |
Correspondence Address:
Sujata Mohapatra
School of Pharmaceutical Sciences Siksha ‘O’ Anusandhan (Deemed to be University) Kalinganagar, Bhubaneswar - 751 003 Odisha
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/ijp.ijp_626_22
Drug discovery has customarily focused on a de novo design approach, which is extremely expensive and takes several years to evolve before reaching the market. Discovering novel therapeutic benefits for the current drugs could contribute to new treatment alternatives for individuals with complex medical demands that are safe, inexpensive, and timely. In this consequence, when pharmaceutically yield and oncology drug efficacy appear to have hit a stalemate, drug repurposing is a fascinating method for improving cancer treatment. This review gathered about how in silico drug repurposing offers the opportunity to quickly increase the anticancer drug arsenal and, more importantly, overcome some of the limits of existing cancer therapies against both old and new therapeutic targets in oncology. The ancient nononcology compounds' innovative potential targets and important signaling pathways in cancer therapy are also discussed. This review also includes many plant-derived chemical compounds that have shown potential anticancer properties in recent years. Here, we have also tried to bring the spotlight on the new mechanisms to support clinical research, which may become increasingly essential in the future; at the same time, the unsolved or failed clinical trial study should be reinvestigated further based on the techniques and information provided. These encouraging findings, combined together, will through new insight on repurposing more non-oncology drugs for the treatment of cancer.
Keywords: Cancer treatment, clinical research, de novo design strategy, drug discovery, in silico drug repurposing, therapeutic targets
How to cite this article:
Dash R, Yadav M, Biswal J, Samanta S, Sharma T, Mohapatra S. Drug repurposing a compelling cancer strategy with bottomless opportunities: Recent advancements in computational methods and molecular mechanisms. Indian J Pharmacol 2023;55:322-31 |
How to cite this URL:
Dash R, Yadav M, Biswal J, Samanta S, Sharma T, Mohapatra S. Drug repurposing a compelling cancer strategy with bottomless opportunities: Recent advancements in computational methods and molecular mechanisms. Indian J Pharmacol [serial online] 2023 [cited 2023 Nov 28];55:322-31. Available from: https://www.ijp-online.com/text.asp?2023/55/5/322/389240 |
| » Introduction | |  |
Being the most dominant genesis of death “cancer” also hindrances the increasing life expectancy in every country worldwide. Cancers/malignant tumors/neoplasms are a massive group of diseases which has the potential to invade or spread to further regions of the body by implicating abnormal cell growth. Cancer in a universal scene represents more than 277 different types of cancer disease. As per the estimation of the World Health Organization till December 17, 2020, it is the first or second cause of death. According to the latest GLOBOCAN 2020 report by the International Agency for Research on Cancer on December 14, the cancer load surged to 10.3 million cancer-related deaths and 19.3 million fresh cases worldwide in 2020. In addition, it was found that 1 in 5 individuals will be faced with cancer during their lifetime, with 1 in 8 men and 1 in 11 women dying from the deadly condition. There are more than 50 million people living with 5 years of past cancer history.[1]
The discovery of novel drugs by advanced techno communication and inventive awareness of the neoplastic disorder have condensed the death rate of cancer. Although it is lifesaving, one of the major challenges has been translating such drugs into clinical practice, which has taken far longer than expected, as drug discovery takes almost 13 years of research. Furthermore, passing a new drug from bench to bedside is immensely pricy, which is almost 2–3 billion USD. The most time-consuming step in drug development is examining a new entity's safety profile and effectiveness on humans in clinical trial. In general, there are four clinical trial phases where humans are involved. In phase I, the dose-ranging study on lesser individuals, for example, 20–80, is done to establish the safety and to recognize the side effects of the new entity. To further evaluate and better understand the safety and efficacy, a phase II clinical trial study is carried out in a larger cohort of about 100–300 humans. In the case of phase III trial, the efficacy, effectiveness, safety, and comparison of the new intervention among other standards or existing interventions are considered in larger participants ranging between hundred and thousand. The information from phase III will permit the intervention to be used safely and get approval from the FDA. In the phase IV clinical study, the validated drug entity in phase III is released into the market for use, and the safety has been constantly monitored over a longer period of time (i.e. postmarketing surveillance). In the case of anticancer agents, one in every 5000–10,000 potential anticancer drugs gets approval from the USFDA, and merely 5% of cancer drugs enter phase I clinical trial. Patients with worsening diseases or comorbidities possibly die before alternative treatment becomes available due to the rising cost and duration needed for new drug development.[2]
Drug repurposing, also known as (drug reprofiling, redirecting, repositioning and drug rediscovery) states the investigation of existing drugs for new therapeutic purposes.[3] At a high attrition rate, considerable prices and steady steps of novel drug discovery and development and repurposing of preexisting drugs to deal with cancers have progressively become an eye-catching proposition. The intensifying budget and the requisite time period for novel drug development cost millions of dollars, and for every dollar expended on research and development, it has been assessed that below a dollar of worth is refunded on average. This decelerates the desire of investors to invest in the pharmaceutical industry. In the case of repurposed drugs, first, the possibility of failing is minimum, since the repurposed drug has earlier been revealed for its safety in both preclinical animal models and humans. If initial phase trials seemed accomplished and successful, it is barely expected to flop on safety grounds. Second, the time period for drug development could be shortened, since the majority of preclinical analysis, safety assessment, and perhaps formulation development have already been accomplished. Third, it costs less to repurpose a drug candidate, although the level of investment depends significantly on the stage of development. It is a fact that repurposing drugs has historically been opportunistic and serendipitous when a drug's off-target effects or newly identified on-target effects have resulted in its commercial exploitation.[4]
| » Anticancer Agents: A Present Scenario | | |
The treatment of cancer has undergone many evolutionary changes. Despite the fact that there are many cancer treatments accessible, they are still insufficient. Among all the therapies for cancer, chemotherapy is the most preferred way to deal with cancer. Although it uses cytotoxic or anticancer drugs to eradicate the cancer-affected cells, it is also used as a line of treatment by itself or with surgery or radiation therapy. One of the most prominent benefits of chemotherapy is that it minimizes the chance of metastasis. There are dozens of chemotherapeutics that act on demolishing or shrinking cancer cells in different ways.[5]
Since the first chemotherapeutic agent, i.e., nitrogen mustard, for non-Hodgkin lymphoma, in the last several decades, there are numerous (around 200) anticancerous drugs that have been discovered. As of January 2021, the overall licensed anticancer drugs was 270, among which 243 (90%) were sanctioned by FDA, 168 (62%) had been accepted by EMA, and 50 (19%) were permitted for use in different European countries through national approval only. There are several remarkable newer drug discoveries by identifying molecular abnormality of cancer (also called genomic drug). Some examples include the controlling of chronic myeloid leukemia and gastrointestinal stromal cancers with BCR-ABL1 and c-kit-targeting agents, in nonsmall-cell lung cancer, the imposing outcome of epidermal growth factor receptor (EGFR) inhibitors, and the effective achievement in targeting HER2 with a monoclonal antibody.[6]
| » Need of Alternative Strategy for Drug Development in the Present Demanding Era | | |
Apart from the benefits of chemotherapeutics, their side effects are also very common. Some common types of cells that are most prone to be damaged are hair follicles, blood-forming cells in the bone marrow, cells in the mouth digestive tract, and reproductive system. Certain chemotherapeutics can likewise damage the cells in the major organs such as the lungs, heart, kidneys, bladder, and nervous system. The harmful consequences associated with chemotherapy and most affected organs are pictorially represented in [Figure 1]. In addition to the chemotherapies concerning their clinical efficacy underscores, the parallel efforts for improved and highest treatment benefit should be considered by drug repurposing. Besides the aforementioned, there are two more aspects that merit discussion, i.e., drug accessibility and financial toxicity.[7]
| » Beginning of Drug Repurposing Episode | | |
The remarkable drawbacks of the newer chemotherapies have drawn the attention of researchers to the field of drug repurposing. Here, in cancer, it represents the use of existing medications that have previously been licensed in the management of nonmalignant conditions, whose targets have now been identified. Sildenafil (Viagra: Pfizer) is one of the most well-known examples in drug repurposing of a noncancerous drug, which was originally created as an anti-angina drug, but later due to its side effect (persistent penile erection), it was used to treat impotence. There are three currently repurposed cancer drugs, i.e., thalidomide, arsenic trioxide, and all-trans-retinoic acid (ATRA), available as anticancer therapy. ATRA and arsenic trioxide, which have been used for skin disorders since 1962, were FDA approved in 2000 for the management of acute promyelocytic leukemia. Thalidomide, a repurposed chemotherapeutic agent, was considered standard therapy and was licensed by the FDA in 1998 for the use in combination with dexamethasone in the management of primarily identified multiple myeloma. It is presently mentioned in the National Comprehensive Cancer Network guidelines as a basic management approach in association with bortezomib and dexamethasone in the section “useful under certain circumstances.”[8]
| » Strategies for Ascertaining Repurposable Drug Candidates | | |
The repurposing process is still in its infancy, especially in the field of therapeutic cancer. The use of three presently repurposed cancer medications (ATRA, arsenic trioxide, and thalidomide) as anticancer therapy emerged from chance, and their chemical mechanism of action was later confirmed. Finding repurposed medication possibilities has also been aided by new insights into the molecular pathophysiology of cancer. Now, it is feasible to build a linkage between enormous biological data and medication repurposing screens due to the rising discovery of important driving pathways through single gene genomic research and “omics” technologies. Here, we describe the computational as well as the experimental strategies for effective drug repurposing using current data, several slews of issues concerning drug accessibility for patients in need, financial toxicity, minimizing study time, and assisting in the reduction of superfluous animal tests and regulatory duties.[9]
| » Computational Approaches | | |
Bioinformatics and computer technology have made remarkable advances in the field of drug repurposing. It uses computational biology and bioinformatics skills to facilitate the virtual screening of public databases of large drug libraries. The discovery of possible bioactive compounds is accomplished using a method, which is focused on the molecular interplay between active compound and the target protein. To effectively accomplish some goals, a careful selection of preclinical experimental system is crucial. Regardless of the scarcity of systematization, computational techniques are increasingly used, and several of the already-found repurposing candidates are derived from this strategy. Here, we report some computational approaches such as transcriptomics, side effects and phenotypes, human genetics and genomics, text mining, and integrated approaches.[10]
Transcriptomics
It aids in the exploration of an organism's transcriptome, where gene expression profiles can reveal genes that are highly expressed in cancer cells compared to normal. For example, the connectivity map (CMap) is a huge database of transcriptomes from cell lines that have been cultured with over 1000 drug-like compounds as part of a sequence toning approach for detecting commonalities and variances as a preliminary point of drug repurposing in cancers.[11] One more example is the functional module CMap, where the identification of complexly associated and highly expressed hub genes is done by condition-specific function–function networks and applying a gene assortment by the direction of progression technique.
Human genetic and genomics
Druggable targets could be identified by recognizing and networking particular genes and specific cancers. The discovery of genes encoding tamoxifen therapeutic targets (ESR1) and aromatase inhibitors (CYP19A1), which relate to genetic discrepancy linked with breast and endometrial cancer risk, are efficacious examples of this strategy.[12]
Side effects and phenotypes
To comprehend unexpected drug reactions and foresee drug repurposing possibilities, impartial assessments of pharmacological activities are necessary. A unique platform called Drug Voyager, which was used to build and validate 82 drug-signaling pathways, was considerably saturated in known drug route databases, as predicted.[13] The researchers investigated phenotypic adverse reaction correlations to determine if two drugs could share a target, and then created a network of 1018 concomitant-driven drug–drug interactions. 261 interactions were constructed from these chemically different drugs with completely distinct therapeutic indications. The resulting network of drugs with at least a 25% possibility of having a target expcted drug-drug correlation were all experimentally validated.
Text mining
Various computational programs have been created to assist in building novel ideas by extracting biological terminology and their interrelationship from the scientific literature. OncoCL and oncoSearch are two instances of high-throughput omics data and scientific literature harvesting gene protein links as well as environmental–cancer associations.[14]
Integrated approaches
Many machine learning algorithms have developed recently to quickly and affordably predict drug interactions and probable pharmacological indications. Some of these are diseasome networks, differential evolution, Bayesian networks, drug–drug and disease–disease resemblance, drug–target–disease networks, and gene–chemical structure–target networks.[15]
| » Experimental Approach | | |
Activity-based repurposing is another name for experiment-based approach, and it involves with the application of experimental assays to evaluate existing medications for novel therapeutic indications. Experimental approaches such as binding assay and phenotypic screening are crucial for identifying pertinent target relations in drug repurposing and identifying principal compounds from huge chemical libraries. The binding assay uses the ligand–receptor interaction to discover the target interactions. An example of a binding assay approach is the cellular thermostability assay methodology, which was created as a way measuring target engagement in cells by utilizing biophysical notations that could forecast the target protein's thermal stabilization. On the other hand, phenotypic screening is used to detect drugs that have disease-related consequences in the model system. Phenotypic screening can screen a range of drugs in a variety of cell lines for drug repurposing. Disulfiram, commonly used to treat alcoholism, has been identified as a selective antineoplastic agent by high-throughput phenotypic screening.[16] Drug repurposing strategies could significantly boost with the use of these methods.
| » Cancer from Molecular Prospective for Drug Repurposing | | |
Many nononcology medications, such as antibiotics, anti-inflammatory, antipsychotic, and cardiovascular drugs are already authorized by the FDA, which might be attractive candidates for drug repurposing for cancer in the future. However, these drugs are extremely safe since they have been used in patients for a long time; hence, various novel methodologies might be used to discover links between their original purposes and anticancer effects. There are certain related pathways of repurposed drugs to act as anticancer. Such pathways could critically enlighten the path to discover the most suited repurposed candidate for cancer therapy. For example, Janus kinases (JAK)/START3 pathway, RAS/RAF/extracellular signal-regulated kinases (ERK) pathway, phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, and WNT/β-catenin pathway. [Figure 2] shows the different signaling pathways of cancer with some relevant repurposing drugs. In the RAS/RAF/ERK pathway, it includes protein chains of the cell that provide a signal from the cell receptor to the nucleus of cell DNA that expresses some proteins that cause alteration in cell division. In this pathway, a protein called ERK communicates by means of adding a phosphate group to the near protein and works like an on or off switch. If one protein is mutated in this pathway, it gets stuck in that on–off position, and this is the reason for the development of cancer. Hence, the target in altering the on or off switch could enlighten the path for drug repositioning. The PI3K/AKT/mTOR pathway is predominantly responsible for the existence during cellular stress condition as cancer exists in a stressful environment. It functions by integrating signals from growth factors and cellular stimuli to regulate protein synthesis, which promotes cell growth and metabolism, and through which gene mutations and genetic changes are found to affect the process. As a result, this could be a vital consideration pathway for cancer treatment. The WNT/β-Catenin pathway works by signaling the glycoprotein of the WNT family through the transcription coactivator. β-catenin regulates various functions of cell like cell proliferation, differentiation, genetic stability, and migration. As multiple aberrations occur in this pathway initiate numerous cancers, this pathway-mediated therapy is substantial for drug repurposing.[17] The JAK/signal transducer and activator of the transcription protein (STAT) pathway work by means of interaction between the cell protein which grounds processes such as cell death, division, and tumor formation. When a ligand binds to a receptor, the JAK adds a phosphate to it, and two STATS add to that phosphate at the same time. Finally, STATS are phosphorylated to form a dimer. The dimers then enter DNA and begin transcription of the target gene. As a result, signaling disruption can lead to cancer.[18] | Figure 2: Selected repurposed drugs and their cellular anticancer mechanism
Click here to view |
Based on previous coincidental observations, using approved drugs for unique therapeutic attempts has proven to be a successful repositioning technique. One mechanism connected to carcinogenesis is metabolic changes in cholesterol production, and some cancer stem cells and cell lines demonstrated enhanced cholesterol synthesis through the mevalonate pathway. Antilipidemic drugs like statins impede the enzyme HMG-CoA reductase, which catalyzes the rate-limiting step of the mevalonate/cholesterol production pathway, and hence, have an anticancer impact by interfering with tumor metabolism. A study by Warita et al. suggested statin therapy as an effective way to target the cells most likely to disseminate because metastasizing tumor cells undergo epithelial-to-mesenchymal transition during the commencement of the metastatic cascade. They have reported statin-induced reductions in the intracellular cholesterol levels which correspond with cancer cell line growth suppression after treatment with statins. They have exposed statin-sensitive, partially sensitive, and resistance cell lines grounding on the expression of vimentin and E-cadherin. They described that statin sensitivity is also associated with high cytosolic vimentin expression and low cell surface E-cadherin expression, a configuration seen in mesenchymal-like cells. They have investigated the anticancer activity on breast cancer, colon cancer, ovarian cancer, lung cancer, prostate cancer, melanoma, and brain cancer using the National Cancer Institute (NCI)-60 cell line. They have also explored the cholesterol level in NCI-60 cancer cell lines that had been treated with atorvastatin and discovered that the cell lines expressed both E-cadherin and vimentin. Ample cytosolic vimentin and no cell surface E-cadherin expression were found in atorvastatin-sensitive cell lines. Except for HS-578T, all partly and completely resistant cell lines displayed some level of cell surface E-cadherin.[19]
Repurposing of old drugs for anticancer activity from their original indications has been outlined in [Table 1]. | Table 1: Some promising agents for drug repurposing in cancer and their proposed pathways[20]
Click here to view |
By understanding the importance of repurposing the clinical trial failed compounds could be reexamined for their anticancer activity by structural modification. All of the methods described above provide a wealth of opportunities for new discoveries.
| » Molecular Consortia in Drug Repurposing | | |
The multidrug target method of drug discovery has piqued the interest of scientists since it lessens the load of multidrug regimens for cancer treatment while simultaneously reducing the side effects. Combination chemoprevention has freshly been exposed to be a more effective and proficient strategy for cancer management. Molecular consortia symbolize molecular hybridization like association, conjugation, and heterodimerization to emerge novel multifunctional compounds. These structures are derived by selected active subunits with particular chemical reactions to form pharmaceutical complexes. They encompass of active molecules that have relatively well-known molecular formation earlier. The above-discussed problem for new drug discovery has dragged the attention on the well-known drugs taking into account their interaction with the target molecule. Molecular consortiums enable multiple entities to work together for a limited period and for a specific reason. The joint action is leading to implement a specific task. The codrug-conjugated moiety may possess better bioavailability and a potent synergistic effect that is missing in the parent drug guaranteeing supplementary effects. In addition, the conjugated moiety may function as an amplifier to evoke permeability-related issues and may mitigate some of the parent drug's adverse consequences. A study by Li et al. has shown that nanoparticle-delivered paclitaxel and tetrandrine can lead to increased levels of reactive oxygen species, which then promotes the inhibition of reactive oxygen species-dependent AKT pathway (signal transduction pathway). This allows for apoptosis to be activated, leading to cell death.[21]
During the drug conjugate designing, certain things should be considered, such as drug targets and linker design. Conjugates could be engineered to target cancer with specific phenotypes for enhanced potency. For example, to target breast cancer, the modified phenotypes in the case of HER2 (ER−/PR−/HER2+), liminal A (ER+/HER2 + OR PR+/HER2−), and luminal B (ER+/HER2 + or PR+/HER2+), or in triple-negative breast cancer, certain intracellular signaling proteins such as PI3K, motor, TROP-2, VEGFR, EGFR, FGFR, MEK, CYP17A1, AKT, anti-CD52, anti-CD-27 MEK, and hedgehog could be targeted. In such instances, associating drugs with diverse pharmacological targets provides corresponding delivery to cancer cells. Simple (CH2) n chains could be used as stable linkers. Linker designing is determined by the drugs themselves, their attachment location, and the intended anticancer activity. Noncleavable linkers are crucial if the effectiveness of the conjugate depends on the linker strength since they cannot be destroyed once they are internalized by lysosomes within cells. For example, tamoxifen–melatonin drug conjugate (CH2) n chain, valine–citrulline linker (hydrophilic amides), and maleimidomethyl cyclohexane-1-carboxylate linker (ether-containing spacer) are some stable linker.[22]
| » Role of Natural Compounds in the Emerging Era of Repurposing | | |
For more than a half-century, natural compounds have been studied widely for their anticancer properties, owing to their amazing chemical assortment. The debut of molecularly focused treatment by natural compounds has transformed the cancer therapy landscape into molecularly targeted drug-hunting hub. There are four basic types of plant-derived anticancer drugs available, which include etoposide, terpenoids (epipodophyllotoxins), vincristine, vinblastine, vindesine (vinca alkaloids), paclitaxel, docetaxel (taxanes), camptothecin, and irinotecan (camptothecin derivatives). About 3000 plant species have been identified to demonstrate consistent anticancer activities by the NCI, where the testing of more than 35,000 plant species was done.[17] Some examples such as Tinospora cordifolia, Ziziphus nummularia, Andrographis paniculata, Curcuma longa, Phyllanthus amarus, Centella asiatica, Withania somnifera, Cedrus deodara, Catharanthus roseus, Allium sativum, and several citrus fruits have already depicted their potent antiproliferative activity. The following sections go over a glimpse on a few plants and its derivatives that have shown their potential as anticancer agents.
Tinospora cordifolia
HeLa cell-destroying ability of T. cordifolia in vitro makes it a potent candidate for cancer therapy, which was first reported by Jagetia in 1998. Alkaloidal extract of T. cordifolia “palmatine” has been testified in reducing tumor occurrence in skin cancer conceived by 7,12-dimethylbenz (a) anthracene (DMBA). Regeneration of glutathione level, superoxide dismutase, and catalase activity, as well as suppression of DMBA-induced DNA damage in the lymphocytes of cancerous cells, was observed. It also inhibited the production of the antiapoptotic protein Bcl-xL and the G1/S phase-specific cyclin D1, as well as halted C6 cells in the G0/G1 and G2/M phases of the cell cycle.[23]
Ziziphus nummularia
Z. nummularia has been used as folk medicine since long. The extracts of Z. nummularia have been shown to impede the cancer phenotype in a range of cancers, such as ovarian cancer (OVCAR-3), leukemia (K-562), breast cancer (MCF-7), colon adenocarcinoma (HT-29), and kidney cancer (A-498). A study by Ray and Dewanjee on the ethanolic extract of Z. nummularia bark has declined the tumor size of Ehrlich ascites carcinoma in mice and highly prolonged their survival. A current study by Mesmar et al. has confirmed the inhibition of Capan-2's migratory invasive abilities while simultaneously downregulating integrin 2 and increasing cell–cell aggregation ability of Z. nummularia in pancreatic cancer.[24] It also lowered vascular endothelial growth factor and nitric oxide levels while inhibiting ovo angiogenesis. Furthermore, it also inhibited the ERK1/2 and NF-B signaling pathways that are identified to promote tumorigenesis and metastasis.[25]
Andrographis paniculata
It has been reported that A. paniculata has anticancer efficacy against several cancers such as renal cancer, breast cancer, lung cancer, ovarian cancer, leukemia, and prostate cancer. The plant's methanolic extract reduced the proliferation of KB (papillomavirus 18) and P388 (leukemia) cancer cells the most. It has the greatest effect at ED50s of 1.0 g/ml (P388 cells) and 1.50 g/ml (KB cells). An in vivo study suggests that the increased production of interleukin-2, tumor necrosis factor-α (TNF-α), and CD marker expression in distinct cancer cell lines was in a dose-dependent manner, which was the reason behind the anticancer activity of Andrographis paniculata. The role of bcl-2 in cancer cells was well established and found to initiate apoptosis. It could also initiate caspase-8-dependent Bid cleavage, mitochondrial translocation, Bax conformational change, release of cytochrome c from mitochondria, and caspase 9 and 3 stimulation owing to apoptotic cell death. It can induce TNF-related apoptosis-inducing ligand, and extrinsic receptor pathway (TRAIL) apoptosis in TRAIL-resistant cells, by the upregulation of death receptor 4 (DR4). P53 activation could be commenced by A. paniculata by increasing protein stabilization and photophosphorylation. The entire mechanism is facilitated by c-Jun NH2-terminal kinase activation and enhanced reactive oxygen species production.[26]
Curcuma longa
Curcumin has been explored for its potential to conceal a wide range of cancers by interfering with various molecular targets. Curcumin shatters the mitochondrial membrane potential balance and intensifies the inhibition of the antiapoptotic Bcl-xL protein. The TNF-associated apoptosis is triggered by enhancing the DRs on cells in the extrinsic apoptotic pathway. Curcumin devotes to this pathway by upregulating the expression of DR4 and DR5. Downregulating the intracellular transcription factors such as NF-kB, cyclooxygenase II, matrix metalloproteinase-9, activator protein 1, STAT3, and nitric oxide synthase has been remarkably induced apoptosis in different cell lines with curcumin treatment.[27],[28],[29] By inhibiting pyruvate kinase M2 (PKM2), curcumin has been found to offer a novel anticancer mechanism that lowers glucose absorption and lactate generation (the Warburg effect) in cancer cells. The PKM2 downregulation was accomplished by subduing the mammalian targets of rapamycin–hypoxia-inducible factor 1α.
A study on the anticancer activity of curcumin and its nano-assemblies (with PEG in different molecular orientations) named PEG-curcumin (PC), PC-PEG (PCP), curcumin-PC (CPC), and a branched architecture of curcumin with PEG as 4 molecules PEG and 4 molecules of curcumin (PC4). They investigated the cytotoxicity of PC3 and HepG2 cancer cell lines in vitro. Curcumin nano-assemblies were testified to have potent anticancer efficacy. All of the nano-assemblies contributed to a reduction in tumor volume and weight. Curcumin and curcumin nanodrugs significantly reduced tumor growth compared to phosphate buffer saline treatment. Pure curcumin, PC, PCP, CPC, and PC4 had inhibitory rates of 42.5%, 51.1%, 54.3%, 22.3%, and 12.8%, respectively. During the therapy period, the body weight change of tumor-bearing mice was also measured. All of the findings from the in vivo trial showed that CPC and PC4 nanodrugs have obvious anticancer activity with no adverse effects, making them viable options for anticancer therapy.[30]
| » Conclusion and Future Prospects | | |
Cancer is indeed a foremost public health concern around the world. Hence, cancer control measures must be implemented to lower the mortality rates, and higher affordability of harmless and more effective anticancer medications is in demand. Drug repurposing can contribute to tackle the existing dilemma of many cancer patients not having access to the most up-to-date therapies, as well as to decrease financial toxicity. Only three repurposed drugs are currently included in widely accepted cancer recommendations, despite the fact that a huge number of them are being researched. Using powerful computational tools and large-scale datasets, drug repurposing can find logical combinations of conventional drugs or selective “nonselective” target drugs. On the basis of this assumption, we might predict a change in cancer treatments from highly selective, low-spectrum treatment to nonselective (multitargeted), high-spectrum treatments.
Acceptable biomarkers for cancer therapeutic strategies are limited, and large trials are essential to demonstrate efficacy. It is evident that effective drug discovery and development will necessitate connected multidisciplinary collaboration encompassing natural product lead discovery, as well as optimization through combinatorial therapy. Considering nature's infinite diversity, it is plausible to encourage that developed chemical leads could be capable of interacting with the maximum therapeutic targets. We attempted to compile a list of nononcology medications having therapeutic promise in cancer therapy, as well as their prospective targets and mechanism of action. Despite drug repurposing has limited success rate, it is a promising option for therapeutic development in the fight against cancers. The development of computational, chemical, and biological tools will allow new prospective of existing nononcology medications to new anticancer therapies in the future.
Acknowledgments
The authors of the manuscript are massively grateful to Prof. (Dr) Manoj Ranjan Nayak, President, Siksha 'O' Anusandhan (Deemed to be University), for his support. The review is a self-financing work, without any financial support from any organization.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1]
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