DRUG REPURPOSING A COMPELLING CANCER STRATEGY [Auto-saved].pptx

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1. Drug repurposing a compelling cancer strategy with bottomless opportunities: Recent advancements in computational methods and molecular mechanisms Mentor Presented by:- Dr. Tulika Singhal Dr. Asmita Pandey ASSISTANT PROFESSOR PG-I YEAR

2. Introduction Being the most dominant genesis of death “cancer” also hinders 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. Universally, more than 277 different types of cancer disease are reported. As per the estimation of the World Health Organization till December 17, 2020, it is the first or second cause of death. GLOBOCAN 2020 report by the International Agency for Research on Cancer on December 14, 10.3 million cancer-related deaths and 19.3 million fresh cases were reported. 1 in 5 individuals will be faced with cancer during their lifetime. 1 in 8 men and 1 in 11 women are dying from cancer.

3. The discovery of novel drugs by advanced techno-communication and inventive awareness of the neoplastic disorder have condensed the death rate of cancer.

4. The four clinical trial phases where humans are involved. One in every 5000–10,000 potential anticancer drugs gets approval from the USFDA, and 5% these enter phase I clinical trial. Patients with worsening diseases or comorbidities possibly die before alternative treatment becomes available.

5. Drug repurposing, also known as (drug reprofiling, redirecting, repositioning and drug rediscovery) states the investigation of existing drugs for new therapeutic purposes. Due to high prices and steady steps of novel drug discovery and development, r epurposing of preexisting drugs have progressively become an eye-catching proposition. Advantages are- The possibility of failing is minimum . Safety of the drug is established. The time period for drug development could be shortened . It costs less to repurpose a drug candidate.

6. Anticancer Agents: A Present Scenario The treatment of cancer has undergone many evolutionary changes. Despite many cancer treatments being accessible, they are insufficient. Chemotherapy is the most preferred way to deal with cancer. It is cytotoxic and is used as a line of treatment by itself or with surgery or radiation therapy. The benefits of chemotherapy is that it minimizes metastasis . Since the first chemotherapeutic agent, i.e., nitrogen mustard, for non-Hodgkin lymphoma, around 200 anti-cancerous drugs have been discovered.

7. January 2021 data shows, The overall licensed anticancer drugs - 270, Among which sanctioned by FDA - 243 (90%) Accepted by EMA - 168 (62%) 50 (19%) were permitted for use in different European countries through national approval only .

8. E xamp les of newer genomic drugs which identify molecular abnormality include- Control of chronic myeloid leukemia and gastrointestinal stromal cancers with BCR-ABL1 and c-kit-targeting agents. Non small-cell lung cancer, controlled with epidermal growth factor receptor (EGFR) inhibitors, T he effective achievement in targeting HER2 with a monoclonal antibody.

9. Need of Alternative Strategy for Drug Development in the Present Demanding Era Side effects of chemotherapeutics, are very common. 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. The cells in the major organs such as the lungs, heart, kidneys, bladder, and nervous system may be damaged. D rug accessibility and financial toxicity are other considerable aspects. The harmful consequences associated with chemotherapy and most affected organs are pictorially represented in  Figure.

10. Beginning of Drug Repurposing Episode The drawbacks of chemotherapies have drawn the attention of researchers to the field of drug repurposing. It represents the use of existing medications in the management of nonmalignant conditions, to be used as anticancer agents . There are three currently repurposed cancer drugs- I )Thalidomide, II) A rsenic Trioxide, III) All-Trans-Retinoic Acid (ATRA). 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 , was licensed by the FDA in 1998. Currently, mentioned under National Comprehensive Cancer Network guidelines as a basic management approach in association with bortezomib and dexamethasone in the section “ useful under certain circumstances” for multiple myeloma.

11. Strategies for Ascertaining Repurposable Drug Candidates 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. R epurposed medication possibilities has been aided by the molecular pathophysiology of cancer. Single gene genomic research and “omics” technologies have build a linkage between biological data and medication repurposing.

12. Computational Approaches Bioinformatics and computer technology uses skills to facilitate the virtual screening of public databases of large drug libraries. The discovery of possible bioactive compounds is by identifying active compound and the target protein. S election of preclinical experimental system is crucial. C omputational techniques are increasingly used to find re- purpos able drugs . S ome approaches such as transcriptomics, side effects and phenotypes, human genetics and genomics, text mining, and integrated approaches are reported here.

13. Transcriptomics It aids in the exploration of an organism's transcriptome, here gene expression profiles reveal genes that are highly expressed in cancer cells . 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 for detecting commonalities and variances. The functional module CMap , identifies complexly associated and highly expressed hub genes by condition-specific function–function networks and applying a gene assortment by 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 examples of this strategy.

14. Side effects and phenotypes To comprehend unexpected drug reactions and foresee drug repurposing possibilities, assessments of pharmacological activities are necessary. Drug Voyager , builds and validates 82 drug-signaling pathways . P henotypic adverse reaction correlations were investigated 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 distinct therapeutic indications. The resulting network of drugs with a 25% possibility of having a target expected correlation were experimentally validated .

15. Text mining C omputational programs have been created to build 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. Integrated approaches Diseasome networks, differential evolution, Bayesian networks, drug–drug and disease–disease resemblance, drug–target–disease networks, and gene–chemical structure–target networks are recently developed machine learning algorithms to predict drug interactions and pharmacological indications.

16. Experimental Approach Activity-based repurposing is another name for this approach . Experimental approaches such as binding assay and phenotypic screening are crucial for identifying target relations in drug repurposing. Binding A ssay Ligand–receptor interaction is used to discover the target interactions. Example - cellular thermostability assay methodology , was created to measure target engagement in cells by utilizing biophysical notations that could forecast the target protein's thermal stabilization. Phenotypic Screening Disease-related consequences in the model system are detected. Can screen a range of drugs in a variety of cell lines for drug repurposing. Example - Disulfiram , has been identified as a selective antineoplastic agent by high-throughput phenotypic screening.

17. Cancer from Molecular Prospective for Drug Repurposing Non-oncology medications, such as antibiotics, anti-inflammatory, antipsychotic, and cardiovascular drugs might be candidates for drug repurposing for cancer in the future. Drugs are safe since they have been used in patients for a long time . There are certain related pathways of repurposed drugs to act as anticancer. For example, Janus kinases (JAK)/STAT3 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.

18. Selected repurposed drugs and their cellular anticancer mechanism

19. One mechanism connected to carcinogenesis is metabolic changes in cholesterol production, 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 interfer e with tumor metabolism. A study by Warita   et al . suggested statin therapy as an effective way to target the cells most likely to disseminate. Metastasizing tumor cells undergo epithelial-to-mesenchymal transition during the commencement of the metastatic cascade.

20. Statin-sensitive, partially sensitive, and resistance cell lines are found based upon the expression of vimentin and E-cadherin. Statin sensitivity - high cytosolic vimentin expression and low cell surface E-cadherin expression, as seen in mesenchymal-like cells. A nticancer activity on various cancers, were investigated using the National Cancer Institute (NCI)-60. They have 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.

21. Molecular Consortia in Drug Repurposing The multidrug target method lessens the load of multidrug regimens for cancer treatment and reduces the side effects. Combination chemoprevention is more effective for cancer management. Molecular consortia symbolize molecular hybridization like association, conjugation, and heterodimerization to emerge multifunctional compounds. These structures are derived by selected active subunits with particular chemical reactions to form pharmaceutical complexes. They enable multiple entities to work together for a limited period and for a specific reason. 

22. The codrug-conjugated moiety may possess better bioavailability and a potent synergistic effect . 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 increase reactive oxygen species, and inhibit AKT pathway (signal transduction pathway). This allows for apoptosis to be activated .

23. During the drug conjugate designing - drug targets and linker design are considered. Conjugates could be engineered to target cancer with specific phenotypes for potency. For example, to target breast cancer, intracellular signaling proteins could be targeted. Associating drugs with diverse pharmacological targets provides corresponding delivery to cancer cells. Linker designing is determined by the drugs themselves, their attachment location, and the intended anticancer activity. Non-cleavable linkers are crucial for the effectiveness. Examples of stable linkers , tamoxifen–melatonin drug conjugate , valine–citrulline linker (hydrophilic amides), and maleimidomethyl cyclohexane-1-carboxylate linker (ether-containing spacer).

24. Role of Natural Compounds in the Emerging Era of Repurposing There are four basic types of plant-derived anticancer drugs available - Etoposide, terpenoids (epipodophyllotoxins), Vincristine, vinblastine, vindesine (vinca alkaloids), Paclitaxel, docetaxel ( taxanes ), Camptothecin , and irinotecan ( camptothecin derivatives). The following sections go over a glimpse on a few plants and its derivatives that have shown their potential as anticancer agents.

25. Tinospora cordifolia HeLa cell-destroying ability of  T. cordifolia in vitro  ,was first reported by Jagetia in 1998. Alkaloidal extract of  T. cordifolia  “ palmatine ” reduces tumor occurrence in skin cancer caused by 7,12-dimethylbenz (a) anthracene (DMBA). Regeneration of glutathione level, superoxide dismutase, and catalase activity, and suppression of DMBA-induced DNA damage in the lymphocytes of cancerous cells, was observed. It inhibited the production of the antiapoptotic protein Bcl -XL and the G1/S phase-specific cyclin D1, halted cells in the G0/G1 and G2/M phases of the cell cycle.

26. Ziziphus nummularia The extracts of  Z. nummularia  have been shown to impede the cancer phenotype in a range of cancers. S tudy by Ray and Dewanjee on the ethanolic extract has declined the tumor size of Ehrlich ascites carcinoma in mice. A study by Mesmar   et al . confirmed its downregulating integrin 2 and increasing cell–cell aggregation ability in pancreatic cancer. It lowered vascular endothelial growth factor and nitric oxide levels and inhibit angiogenesis. Inhibited the ERK1/2 and NF-B signaling pathways that promote tumorigenesis and metastasis.

27. Andrographis paniculata A nticancer efficacy against renal cancer, breast cancer, lung cancer, ovarian cancer, leukemia, and prostate cancer. M ethanolic extract reduced the proliferation of KB (papillomavirus 18) and P388 (leukemia) cancer cells . Has the greatest effect at ED50s of 1.0 g/ml (P388 cells) and 1.50 g/ml (KB cells). BCL -2 can initiate apoptosis in cancer cells. P53 activation by increasing protein stabilization and photophosphorylation. The entire mechanism is facilitated by c-Jun NH2-terminal kinase activation and enhanced reactive oxygen species production.

28. Curcuma longa Curcumin has been explored for its ability to interfere with various molecular targets. It inhibits the antiapoptotic BCL-XL protein. U pregulates the expression of DR4 and DR5. Downregulates the intracellular transcription factors such as NF-kB, cyclooxygenase II, matrix metalloproteinase-9, activator protein 1, STAT3, and nitric oxide synthase and induces apoptosis. Inhibits pyruvate kinase M2 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.

29. Conclusion and Future Prospects Cancer is indeed a foremost public health concern around the world. C ontrol 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 dilemma of cancer patients not having access to the updated therapies, and to decrease financial toxicity. 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.

30. Effective drug discovery and development will necessitate connected multidisciplinary collaboration with natural product lead discovery, as well as optimization through combinatorial therapy. D rug repurposing has limited success rate, but is a promising option for therapeutic development against cancers. The development of computational, chemical, and biological tools will allow new prospective of existing non-oncology medications to new anticancer therapies in the future. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.