School Of Basic And Applied Sciences
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Item Synthesis and Biological Evaluation of Inhibitors of Topoisomerases and Histone Deacetylase for In Vitro Anticancer Activity(Central University of Punjab, 2019) Joshi, Gaurav; Kumar, Raj & Singh, SandeepTopoisomerases (Topos) and histone deacetylases (HDACs) are validated oncotherapeutic targets due to their involvement in most of the cellular events such as initiation, proliferation, and survival of cancer cells. Widespread research has undergone to design and discover small molecule inhibitors of each protein which has led to the development of several drugs that are making their presence felt in clinic. Considering the issues of stability, toxicity, reported crosstalk(s) and resitance of existing pharmacophores, we herein report the discovery of target-based molecules pertaining to pyrazolo[1,5-c]quinazolines, 2-aryl quinolines and imidazo[1,2- a]quinoxaline scaffolds as inhibitors of TopoI or dual TopoI and II designed rationally via in silico tools. The chemical space of scaffolds was further exploited to design and synthesise dual/multi inhibitors of Topo-HDAC by connecting pharmacophoric features of HDAC inhibitors via a linker. Detailed biological evaluation of synthetics was performed using multiple cancer cell lines as well as normal cells/cell lines. Utilizing MTT, dye exclusion, redox potential, cell cycle and annexin V vs PI assays in 2D as well as 3D cultures, we established their preferential cytotoxic potential. Signaling responsible for anticancer mechanism was delineated using western immunoblotting and qPCR assays. Further, in vitro assays v for topoisomerases (DNA relaxation and catenation), and/or HDAC1 revealed target specificity of synthetics. In addition, we also demonstrated a novel bioreductive methodology, specific to cancer cells, exploiting cancer microenvironment leading to delivery of molecularly targeted agents as topo(s) inhibitors.Item Molecular mechanisms of action of epigallocatechin gallate in cancer: Recent trends and advancement(Academic Press, 2020) Aggarwal, V; Tuli, H.S; Tania, M; Srivastava, S; Ritzer, E.E; Pandey, A; Aggarwal, D; Barwal, T.S; Jain, A; Kaur, G; Sak, K; Varol, M; Bishayee, A.Epigallocatechin gallate (EGCG), also known as epigallocatechin-3-gallate, is an ester of epigallocatechin and gallic acid. EGCG, abundantly found in tea, is a polyphenolic flavonoid that has the potential to affect human health and disease. EGCG interacts with various recognized cellular targets and inhibits cancer cell proliferation by inducing apoptosis and cell cycle arrest. In addition, scientific evidence has illustrated the promising role of EGCG in inhibiting tumor cell metastasis and angiogenesis. It has also been found that EGCG may reverse drug resistance of cancer cells and could be a promising candidate for synergism studies. The prospective importance of EGCG in cancer treatment is owed to its natural origin, safety, and low cost which presents it as an attractive target for further development of novel cancer therapeutics. A major challenge with EGCG is its low bioavailability which is being targeted for improvement by encapsulating EGCG in nano-sized vehicles for further delivery. However, there are major limitations of the studies on EGCG, including study design, experimental bias, and inconsistent results and reproducibility among different study cohorts. Additionally, it is important to identify specific EGCG pharmacological targets in the tumor-specific signaling pathways for development of novel combined therapeutic treatments with EGCG. The present review highlights the ongoing development to identify cellular and molecular targets of EGCG in cancer. Furthermore, the role of nanotechnology-mediated EGCG combinations and delivery systems will also be discussed. � 2020 Elsevier LtdItem Epidermal growth factor receptor and its trafficking regulation by acetylation: Implication in resistance and exploring the newer therapeutic avenues in cancer(Bentham Science Publishers, 2020) Kumar, M; Joshi, G; Chatterjee, J; Kumar, R.Background: The EGFR is overexpressed in numerous cancers. So, it becomes one of the most favorable drug targets. Single-acting EGFR inhibitors on prolong use induce resistance and side effects. Inhibition of EGFR and/or its interacting proteins by dual/combined/multitargeted therapies can deliver more efficacious drugs with less or no resistance. Objective: The review delves deeper to cover the aspects of EGFR mediated endocytosis, leading to its trafficking, internalization, and crosstalk(s) with HDACs. Methods and Results: This review is put forth to congregate relevant literature evidenced on EGFR, its impact on cancer prognosis, inhibitors, and its trafficking regulation by acetylation along with the current strategies involved in targeting these proteins (EGFR and HDACs) successfully by involving dual/hybrid/combination chemotherapy. Conclusion: The current information on cross-talk of EGFR and HDACs would likely assist researchers in designing and developing dual or multitargeted inhibitors through combining the required pharmacophores. � 2020 Bentham Science Publishers.Item Emerging role of ZBTB7A as an oncogenic driver and transcriptional repressor(Elsevier, 2020) Gupta, S; Singh, A.K; Prajapati, K.S; Kushwaha, P.P; Shuaib, M; Kumar, S.ZBTB7A is a member of the POK family of transcription factors that possesses a POZ-domain at the N-terminus and Krüppel-like zinc-finger at the c-terminus. ZBTB7A was initially isolated as a protein that binds to the inducer of the short transcript of HIV-1 virus TAT gene promoter. The protein forms a homodimer through protein-protein interaction via the N-terminus POZ-domains. ZBTB7A typically binds to the DNA elements through its zinc-finger domains and represses transcription both by modification of the chromatin organization and through the direct recruitment of transcription factors to gene regulatory regions. ZBTB7A is involved in several fundamental biological processes including cell proliferation, differentiation, and development. It also participates in hematopoiesis, adipogenesis, chondrogenesis, cellular metabolism and alternative splicing of BCLXL, DNA repair, development of oligodendrocytes, osteoclast and unfolded protein response. Aberrant ZBTB7A expression promotes oncogenic transformation and tumor progression, but also maintains a tumor suppressive role depending on the type and genetic context of cancer. In this comprehensive review we provide information about the structure, function, targets, and regulators of ZBTB7A and its role as an oncogenic driver and transcriptional repressor in various human diseases. - 2020 Elsevier B.V.Item Legume lectins: Potential use as a diagnostics and therapeutics against the cancer(Elsevier B.V., 2020) Gautam A.K.; Sharma D.; Sharma J.; Saini K.C.Legume lectins are carbohydrate-binding protein and widely distributed in a variety of species of leguminous plants and have drawn increased attention toward cancer. Nowadays, the lectins have been studied for the screening of potential biomarkers which increased its importance in cancer research. Few plant lectins have been shown to destroy cancer cells, suggesting that lectins may have biological potential in cancer treatments. In this review, we present a focused outline of legume lectins in descriptive their complex anti-cancer mechanisms on the bases of their properties of recognition and interacting specifically with carbohydrates binding sites. Existing reports suggested the binding of lectins to cancerous cells with their cell surface markers speculated by histochemistry in vitro and in vivo. In this review, we illuminate the use of legume lectins as a natural source for diagnostics and therapeutics purpose against cancer.Item Steering the antitumor drug discovery campaign towards structurally diverse indolines(Academic Press Inc., 2020) Thakur A.; Singh A.; Kaur N.; Ojha R.; Nepali K.Indoline framework is often perpended as a privileged heterocycle present in medicinally valuable compounds of natural and synthetic origin. This review article presents the rational approaches/strategies employed for the design of anticancer indolines along with the structure activity relationship and mechanistic insights revealed in the in-vitro and in-vivo assays. The chemist has always been fascinated towards the indoline ring for the construction of antitumor scaffolds owing to its versatility as evidenced by its existence in scaffolds inducing antiproliferative effects via diverse mechanisms. To the delight of medicinal chemist, the applicability of indoline has also been expanded towards the design of dual inhibitors (multitargeting anticancer agents) as well as PROTACS. Overall, it can be concluded that indoline moiety is a magic bullet and the scaffolds containing this ring are foraying towards detailed preclinical and clinical stage investigations by leaps and bounds.Item Molecular mechanisms of action of genistein in cancer: Recent advances(Frontiers Media S.A., 2019) Tuli H.S.; Tuorkey M.J.; Thakral F.; Sak K.; Kumar M.; Sharma A.K.; Sharma U.; Jain A.; Aggarwal V.; Bishayee A.Background: Genistein is one among the several other known isoflavones that is found in different soybeans and soy products. The chemical name of genistein is 4?,5,7-trihydroxyisoflavone. Genistein has drawn attention of scientific community because of its potential beneficial effects on human grave diseases, such as cancer. Mechanistic insight of genistein reveals its potential for apoptotic induction, cell cycle arrest, as well as antiangiogenic, antimetastatic, and anti-inflammatory effects. Objective: The purpose of this review is to unravel and analyze various molecular mechanisms of genistein in diverse cancer models. Data sources: English language literature was searched using various databases, such as PubMed, ScienceDirect, EBOSCOhost, Scopus, Web of Science, and Cochrane Library. Key words used in various combinations included genistein, cancer, anticancer, molecular mechanisms prevention, treatment, in vivo, in vitro, and clinical studies. Study selection: Study selection was carried out strictly in accordance with the statement of Preferred Reporting Items for Systematic Reviews and Meta-analyses. Data extraction: Four authors independently carried out the extraction of articles. Data synthesis: One hundred one papers were found suitable for use in this review. Conclusion: This review covers various molecular interactions of genistein with various cellular targets in cancer models. It will help the scientific community understand genistein and cancer biology and will provoke them to design novel therapeutic strategies.Item Caulerpa taxifolia inhibits cell proliferation and induces oxidative stress in breast cancer cells(De Gruyter, 2019) Mehra R.; Bhushan S.; Yadav U.P.; Bast F.; Singh S.Caulerpa taxifolia (M. Vahl) C. Agardh or killer alga is known to possess several bioactive secondary metabolites with unique structural modifications. We investigated anti-oxidant and anti-proliferative activity of C. taxifolia extract (CTE) on breast and lung cancer cells, along with possible effects on mitochondrial membrane potential (MMP) and cell cycle progression. The results revealed up to 6-folds increase in reactive oxygen species (ROS), 2-folds increase in glutathione reductase (GR) activity, 1.7-fold increase in superoxide dismutase (SOD) activity and 1.8-fold change in catalase activity w.r.t. untreated cells i.e. 10.72 to 21.44 nmol/min/mL, 2.0 to 3.49 U/mL and 37.51 to 69.26 U/min/g FW, respectively, in MDA-MB-cells. Likewise, selective anti-proliferative activity with IC50 0.19 + 0.1, 0.27 + 0.1, and 0.43 + 0.1 μg/μL, was recorded in MDA-MB-231, T-47D, and H1299 cells. In addition, dose-dependent increase in MMP of up to 40% and G1/S phase mitotic arrest was documented by CTE treatment in MDA-MB-231 cells. The results suggest an anti-proliferative and oxidative stress inducing activity of CTE. Changes in MMP and cell cycle arrest further support the anti-cancer effects of CTE. It is believed that C. taxifolia may be considered as a potent source of anti-cancer drugs, subject to further validations.Item Antioxidant potential of ganoderic acid in Notch-1 protein in neuroblastoma(Springer New York LLC, 2019) Gill B.S.; Navgeet; Kumar S.Neuroblastoma is a childhood tumor arising from developing a sympathetic nervous system and causes around 10% of pediatric tumors. Despite advancement in the use of sophisticated techniques in molecular biology, neuroblastoma patient's survivability rate is very less. Notch pathway is significant in upholding cell maintenance and developmental process of organs. Notch-1 proteins are a ligand-activated transmembrane receptor which decides the fate of the cell. Notch signaling leads to transcription of genes which indulged in numerous diseases including tumor progression. Ganoderic acid, a lanosterol triterpene, isolated from fungus Ganoderma lucidum with a wide range of medicinal values. In the present study, various isoforms of the ganoderic acid and natural inhibitors were docked by molecular docking using Maestro 9 in the Notch-1 signaling pathway. The receptor-based molecular docking exposed the best binding interaction of Notch-1 with ganoderic acid A with GScore (? 8.088), kcal/mol, Lipophilic EvdW (? 1.74), Electro (? 1.18), Glide emodel (? 89.944) with the active participation of Arg 189, Arg 199, Glu 232 residues. On the other hand natural inhibitor, curcumin has GScore (? 7.644), kcal/mol, Lipophilic EvdW (? 2.19), Electro (? 0.73), Glide emodel (? 70.957) with Arg 75 residues involved in docking. The ligand binding affinity of ganoderic acid A in Notch-1 is calculated using MM-GBSA (? 76.782), whereas curcumin has (? 72.815) kcal/mol. The QikProp analyzed the various drug-likeness parameters such as absorption, distribution, metabolism, excretion, and toxicity (ADME/T) and isoforms of ganoderic acid require some modification to fall under Lipinski rule. The ganoderic acid A and curcumin were the best-docked among different compounds and exhibits downregulation in Notch-1 mRNA expression and inhibits proliferation, viability, and ROS activity in IMR-32 cells.Item Dihydropyrimidine dehydrogenase in the metabolism of the anticancer drugs(Springer Verlag, 2019) Sharma V.; Gupta S.K.; Verma M.Cancer caused by fundamental defects in cell cycle regulation leads to uncontrolled growth of cells. In spite of the treatment with chemotherapeutic agents of varying nature, multiple resistance mechanisms are identified in cancer cells. Similarly, numerous variations, which decrease the metabolism of chemotherapeutics agents and thereby increasing the toxicity of anticancer drugs have been identified. 5-Fluorouracil (5-FU) is an anticancer drug widely used to treat many cancers in the human body. Its broad targeting range is based upon its capacity to act as a uracil analogue, thereby disrupting RNA and DNA synthesis. Dihydropyrimidine dehydrogenase (DPD) is an enzyme majorly involved in the metabolism of pyrimidines in the human body and has the same metabolising effect on 5-FU, a pyrimidine analogue. Multiple mutations in the DPD gene have been linked to 5-FU toxicity and inadequate dosages. DPD inhibitors have also been used to inhibit excessive degradation of 5-FU for meeting appropriate dosage requirements. This article focusses on the role of dihydropyrimidine dehydrogenase in the metabolism of the anticancer drug 5-FU and other associated drugs.