School Of Basic And Applied Sciences
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Item Medicinal chemistry perspective of pyrido[2,3-d]pyrimidines as anticancer agents(Royal Society of Chemistry, 2023-03-03T00:00:00) Kumar, Adarsh; Bhagat, Kuber Kumar; Singh, Ankit Kumar; Singh, Harshwardhan; Angre, Tanuja; Verma, Amita; Khalilullah, Habibullah; Jaremko, Mariusz; Emwas, Abdul-Hamid; Kumar, PradeepCancer is a major cause of deaths across the globe due to chemoresistance and lack of selective chemotherapy. Pyrido[2,3-d]pyrimidine is an emerging scaffold in medicinal chemistry having a broad spectrum of activities, including antitumor, antibacterial, CNS depressive, anticonvulsant, and antipyretic activities. In this study, we have covered different cancer targets, including tyrosine kinase, extracellular regulated protein kinases - ABL kinase, phosphatidylinositol-3 kinase, mammalian target of rapamycin, p38 mitogen-activated protein kinases, BCR-ABL, dihydrofolate reductase, cyclin-dependent kinase, phosphodiesterase, KRAS and fibroblast growth factor receptors, their signaling pathways, mechanism of action and structure-activity relationship of pyrido[2,3-d]pyrimidine derivatives as inhibitors of the above-mentioned targets. This review will represent the complete medicinal and pharmacological profile of pyrido[2,3-d]pyrimidines as anticancer agents, and will help scientists to design new selective, effective and safe anticancer agents. � 2023 The Royal Society of Chemistry.Item 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 Anti-cancer drug doxorubicin induced cardiotoxicity: Understanding the mechanisms involved in ros generation resulting in mitochondrial dysfunction(Rasayan Journal of Chemistry, c/o Dr. Pratima Sharma, 2020) Upadhayay, S; Sharma, N; Mantha, A.K; Dhiman, M.Doxorubicin (DOX), despite being an effective anti-cancer drug has offsite targets that affect the vital organs such as heart, brain and kidney. DOX-induced cardiotoxicity is reported as a multi-factorial process that interferes with mitochondrial bioenergetics. These responses increase the threshold of oxidant-mediated injury and redox-mediated apoptosis in the cardiomyocytes. Oxidative stress particularly mitochondrial dysfunction in cardiomyocytes associated with cardiovascular diseases. In the present study we examined the effect of DOX on H9c2 cardiomyocyte where cells were treated with 5 μM DOX. To rule out the source of reactive oxygen species (ROS) during DOX-induced toxicity, the DOX-treated cardiomyocytes were incubated with 100 ?M diphenyleneiodonium (DPI), 50 μM salicyl hydroxamic acid (SHX), 20 μM Carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP), which are specific inhibitors of NADPH oxidase (NOX), Myeloperoxidase (MPO), and mitochondrial oxidative phosphorylation respectively and 10 μM N-acetyl cysteine (NAC, free radical scavenger) was also used to perceive the role of ROS. H2O2 (100 ?M) treated H9c2 cardiomyocytes were used as positive controls. The cell viability, reactive oxygen species (ROS) level and oxidative stress were determined using MTT assay, NBT assay/Flow-cytometry and Western blotting based assays. The effect of DOX on mitochondria was evaluated using Amplex Red assay; fluorescent probes such as MitoSOX and MitoTracker were used to examine the DOX-induced ROS production from the mitochondrial matrix. The mitochondrial membrane potential was evaluated using JC-1 dye. Western blotting was performed for cytochrome c release and apoptosis was examined with Annexin V-FITC assay. DOX was found to reduce cell viability, increase ROS level followed by enhanced oxidative stress in the form of protein carbonyls. DOX also showed a reduction in the mitochondrial membrane potential and allowed the release of cytochrome c which further leads to apoptosis and cell death. Further to rule out the pathway/mechanism(s) of DOX-mediated cardiac pathologies, the treatment with inhibitors of the classical ROS sources such as NADPH oxidase, Myeloperoxidase, mitochondria and general ROS scavenger (NAC) suggested that ROS via NOX and MPO during DOX-induced toxicity plays a crucial role in cardiomyocytes. The mitochondrial integrity was conserved when the cells were treated with NOX and MPO inhibitors, the cytochrome C release and apoptosis reduced in presence of these inhibitors. Taken together, these results demonstrate that DOX leads to ROS production and oxidative stress in cardiomyocytes which ultimately affects the mitochondrial integrity and functions, most importantly the ROS released via NOX and MPO is critical during DOX-induced cardiotoxicity. - RAS?YAN. All rights reserved.Item Recent development in indole derivatives as anticancer agents for breast cancer(Bentham Science Publishers, 2019) Kaur K.; Jaitak V.Background: Breast Cancer (BC) is the second most common cause of cancer related deaths in women. Due to severe side effects and multidrug resistance, current therapies like hormonal therapy, surgery, radiotherapy and chemotherapy become ineffective. Also, the existing drugs for BC treatment are associated with several drawbacks such as poor oral bioavailability, non-selectivity and poor pharmacodynamics properties. Therefore, there is an urgent need for the development of more effective and safer anti BC agents. Objective: This article explored in detail the possibilities of indole-based heterocyclic compounds as anticancer agents with breast cancer as their major target. Methods: Recent literature related to indole derivatives endowed with encouraging anti BC potential is reviewed. With special focus on BC, this review offers a detailed account of multiple mechanisms of action of various indole derivatives: aromatase inhibitor, tubulin inhibitor, microtubule inhibitor, targeting estrogen receptor, DNA-binding mechanism, induction of apoptosis, inhibition of PI3K/AkT/NFkB/mTOR, and HDAC inhibitors, by which these derivatives have shown promising anticancer potential. Results: Exhaustive literature survey indicated that indole derivatives are associated with properties of inducing apoptosis and disturbing tubulin assembly. Indoles are also associated with the inhibition of NFkB/mTOR/PI3K/AkT and regulation of estrogen-mediated activity. Furthermore, indole derivatives have been found to modulate critical targets such as topoisomerase and HDAC. These derivatives have shown significant activity against breast cancer cells. Conclusion: In BC, indole derivatives seem to be quite competent and act through various mechanisms that are well established in case of BC. This review has shown that indole derivatives can further be explored for the betterment of BC chemotherapy. A lot of potential is still hidden which demands to be discovered for upgrading BC chemotherapy.Item Drug Targeting Strategies in Breast Cancer Treatment(Bentham Science, 2014) Mayank; Jaitak, VikasBreast cancer (BC) is the leading cause of death among women all over the world. Estrogen receptor (ER) based therapy is one of the major approaches to target BC and is associated with various problems such as primary as well as secondary resistance. ER signaling is a complex pathway as many factors are involved; including several types of ERs and their associated co-regulators. Increasing understanding of ER signals results in new approaches targeting towards BCs. In this context, ER co-regulators have been explored and many modulators of ER co-regulators have been found out. EGFR and mTOR pathways also have significant impact on BC endocrine therapy because of the complex crosstalk mechanism which is responsible for primary and secondary resistance. Triple negative breast cancer (TNBC) is majorly associated with BRCA mutations. Currently there is no approved targeted therapy available in such form of cancer. Although PARP inhibitors seem to be suitable candidates for it. The present review is focused on the current scenario of ER, EGFR, as well as mTOR signaling target therapy. We have also discussed the current status of PARP inhibitors in BC chemotherapy.Item Assessment of Extract of Syzygium cumini Against Doxorubicin Induced Cardiotoxicity(Central University of Punjab, 2018) Chayan, Mukherjee; Monisha DhimanFor the past four decades, doxorubicin (DOX) has been used to treat cancer, mainly solid tumours and haematological malignancies. However, clinical community is greatly concerned regarding the administration of this as DOX treatment is commonly associated with dose-dependent cardiotoxicity. Attempts at alleviating drug generated cardiac damage using an extract from different parts of plants with radical scavenging property are a promising area of research. Hydroalcoholic extract derived from fruit pulp of Syzygiumcumini which has a significant antiradical scavenging effect. This study aims to assess the effect of parallel administration of SC fruit pulp extract (SC) on mitigating or preventing DOX induced cardiotoxicity in vitro using H9c2 cardiomyoblast cell lines. Addition of SC fruit pulp extract and DOX were performed for both treatment and control sets on H9c2 cells. SC fruit pulp extract showed strong ABTS cation radical scavenging activity in a dose dependent manner. MTT assay was used to study the cytotoxic effect of SC fruit pulp extract and DOX. ROS levels were estimated using NBT assay and DHE assay. The results showed that DOX has significant cytotoxic effect in a dose dependent manner while SC fruit pulp extract did not display any significant cytotoxicity on H9c2 cells. The DOX induced ROS production was found to be significantly reduced in SC fruit pulp extract treated cells. Results of the current study also suggest that the treatment of SC fruit pulp extract along with DOX, displayed cardioprotective potential in H9c2 cells by: 1) reducing lipid peroxidation; 2) decreasing extracellular nitric oxide (NO); 3) decreasing the expression of the protein p47phox and iNOS/NOS-2. These results clearly suggest that treatment of SC fruit pulp extract along with DOX reduces the DOX induced toxicity and hence can be a promising therapeutic intervention in managing DOX mediated cardiotoxicity.Item Drug target strategies in breast cancer treatment: Recent developments(Bentham Science Publishers B.V., 2014) Mayank; Jaitak, Vikas; Mayank, Jaitak, V.Breast cancer (BC) is the leading cause of death among women all over the world. Estrogen receptor (ER) based therapy is one of the major approaches to target BC and is associated with various problems such as primary as well as secondary resistance. ER signaling is a complex pathway as many factors are involved; including several types of ERs and their associated co-regulators. Increasing understanding of ER signals results in new approaches targeting towards BCs. In this context, ER co-regulators have been explored and many modulators of ER co-regulators have been found out. EGFR and mTOR pathways also have significant impact on BC endocrine therapy because of the complex crosstalk mechanism which is responsible for primary and secondary resistance. Triple negative breast cancer (TNBC) is majorly associated with BRCA mutations. Currently there is no approved targeted therapy available in such form of cancer. Although PARP inhibitors seem to be suitable candidates for it. The present review is focused on the current scenario of ER, EGFR, as well as mTOR signaling target therapy. We have also discussed the current status of PARP inhibitors in BC chemotherapy. ? 2014 Bentham Science Publishers.