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Kirsten Rat Sarcoma (KRAS) is a potent target for cancer therapy because it acts as a signaling hub, engaging in various signaling pathways and regulating a number of cellular functions like cell differentiation, proliferation, and survival. Recently, an emergency approval from the US-FDA has been issued for KRAS G12C inhibitors (sotorasib and adagrasib) for metastatic lung cancer treatment. However, clinical studies on covalent KRAS G12C inhibitors have rapidly confronted resistance in patients. Many methods are being assessed to overcome this resistance, along with various combinatorial clinical studies that are in process. Moreover, because KRAS G12D and KRAS G12V are more common than KRAS G12C , focus must be placed on the therapeutic strategies for this type of patient, along with sustained efforts in research on these targets. In the present review, we try to focus on various strategies to overcome rapid resistance through the use of combinational treatments to improve the activity of KRAS G12C inhibitors., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The present study aimed to investigate the anti-cancer mechanism of canagliflozin (CANA) and dapagliflozin (DAPA), sodium-glucose co-transporter-2 (SGLT2) inhibitors, using in silico and in vitro approaches. Network pharmacology was employed to predict the targets of the inhibitors and GO gene enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation conducted to explore the interacting pathways. Molecular docking and molecular dynamic (MD) simulation studies were performed to confirm the important targets and assess conformational stability. In vitro cytotoxicity assays, MIA-PaCa-2 and DU-145 cell lines CANA and DAPA was performed. Protein-protein interaction (PPI) network analysis indicated that CANA and DAPA exert anticancer effects through MAPK, mTOR, EGFR-KRAS-BRAF, FGFR, and PI3KA pathways. KEGG analysis revealed that these inhibitors could be used in the treatment of various cancers, including breast, prostate, pancreatic, chronic myeloid leukemia, thyroid, small cell lung, gastric, and bladder cancer. Docking results showed highest affinity for MAPK1 for CANA (- 9.60 kcal/mol) and DAPA (- 9.58 kcal/mol). MD simulation results showed that RMSD values for the MAPK1-compound exhibit remarkable stability over a timeframe of 100 ns. In cytotoxicity assays using MIA-PaCa-2 and DU-145 cell lines, CANA demonstrated a potential antiproliferative effect on the pancreatic cell line MIA-PaCa-2 after 48 h of treatment at a concentration of 100 µg/ml. Furthermore, CANA arrested the cell cycle in the sub-G1 phase and induced late apoptosis and necrosis in MIA-PaCa-2 cell line. Based on these findings, CANA shows promise as a potential novel treatment strategy for pancreatic cancer., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Prostate cancer (PCa) remains a significant health concern globally, prompting a continual search for novel therapeutic strategies. In this study, we employed a comprehensive approach combining network pharmacology, molecular docking and dynamic simulation to explore the potential impact of a polyherbal formulation on PCa., Methods: Utilizing comprehensive network pharmacology approaches, we elucidated the complex interactions between the bioactive compounds within the polyherbal formulation and key targets associated with PCa progression, highlighting their multitarget mechanisms through integrated protein‒protein interaction and KEGG pathway analyses. Molecular docking simulation studies were performed to predict the binding affinities and modes of interaction between the identified bioactive compounds and their respective protein targets., Results: Complex connections comprising 486 nodes and 845 edges were found by the compound-target network analysis. Significant interactions were observed, and the average node degree was 4.23. KEGG research revealed that PCa and the PI3K-Akt signalling pathway are implicated in modulating prostate cancer. The Quercetin docking investigations revealed that the binding energies for AR and PIK3R1 were -9 and -9.5 kcal/mol, respectively. Based on the results of the MD simulations, it appears that tiny molecules and proteins have formed stable complexes with low fluctuations., Conclusion: In conclusion, this comprehensive method emphasises the value of network pharmacology in conjunction with molecular docking and dynamic simulation in revealing the anti-PCa therapeutic potential of polyherbal formulations, opening up new possibilities for the creation of efficient anti-cancer medicines., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Vitamin D 3 , a fat-soluble vitamin known for its critical function in calcium homeostasis and bone health, is gaining interest for its anticancer properties. Observational studies have suggested a negative relationship between vitamin D levels and the incidence of some malignancies throughout the years, prompting substantial investigation to find its anticancer effects. The purpose of this comprehensive review is to investigate the diverse function of vitamin D 3 in cancer prevention and therapy. We explored the molecular mechanism underlying its effects on cancer cells, which range from cell cycle control and death to angiogenesis and immune response modulation. Insights from in vitro and in vivo studies provide valuable evidence supporting its anticancer potential. Furthermore, we look at epidemiological and clinical studies that investigate the relationship between vitamin D 3 levels and cancer risk or treatment results. Vitamin D 3 supplementation's safety profile and cost-effectiveness increase its attractiveness as an adjuvant therapy in conjunction with traditional treatment regimens. Our critical review of the current literature provides an in-depth understanding of vitamin D 3 's anticancer effect, covering the obstacles and possibilities in realizing its promise for cancer prevention and therapy. The findings of this study might pave the way for the development of innovative treatment techniques that take use of the advantages of vitamin D 3 to fight cancer and improve patient care. As research progresses, a better understanding of vitamin D 3 's anticancer processes will surely simplify its incorporation into personalized cancer care techniques, hence enhancing patient outcomes in the battle against cancer., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

In our previous study Alysicarpus vaginalis (AV) has appeared as a promising target for breast cancer hence we have screened potential targets by in silico , In Vitro and In Vivo methods. A network pharmacology (NP) approach involves prediction and validating of targets via molecular modeling, western blotting and In Vivo MNU-induced mammary cancer. The PPI network showed the 573 edges between 214 nodes (targets) that are involved in breast cancer and important one are ESR-1, ESR-2, AR, EGFR, NOS3, MAPK, KDR, SRC and MET. Compound-target-pathway network involves 04 compounds and 221 interactive protein targets associated with breast cancer. GO and KEGG enrichment analysis predicted the ERR, c-MET, PDGFR-α/β, EGFR, and VEGF as a key targets in the breast cancer treatment which are validated via molecular modeling. Expression of ER-α, AR and EGFR were significantly down regulated by AV in MCF-7 cell line. In addition, the immunoreactivity of ER-α was reduced significantly in MNU-induced mammary carcinoma, which is a key target in ER + breast cancer. Overall, this study scientifically light ups the pharmacological mechanism of AV in the treatment of breast cancer, strongly associated with the regulation of ESR signaling pathway.

Novel coronavirus (SARS-CoV-2), turned out to be a global pandemic with unstoppable morbidity and mortality rate. However, till date there is no effective treatment found against SARS-CoV-2. We report on the major in-depth molecular and docking analysis by using antiretroviral (Lopinavir and ritonavir), antimalarial (Hydroxychloroquine), antibiotics (Azithromycin), and dietary supplements (Vitamin C and E) to provide new insight into drug repurposing molecular events involved in SARS-CoV-2. We constructed three drug-target-pathways-disease networks to predict the targets and drugs interactions as well as important pathways involved in SARS-CoV-2. The results suggested that by using the combination of Lopinavir, Ritonavir along with Hydroxychloroquine and Vitamin C may turned out to be the effective line of treatment for SARS-CoV-2 as it shows the involvement of PARP-1, MAPK-8, EGFR, PRKCB, PTGS-2, and BCL-2. Gene ontology biological process analysis further confirmed multiple viral infection-related processes (P < 0.001), including viral life cycle, modulation by virus, C-C chemokine receptor activity, and platelet activation. KEGG pathway analysis involves multiple pathways (P < 0.05), including FoxO, GnRH, ErbB, Neurotrophin, Toll-like receptor, IL-17, TNF, Insulin, HIF-1, JAK-STAT, Estrogen, NF-kappa, Chemokine, VEGF, and Thyroid hormone signaling pathway in SARS-CoV-2. Docking study was carried out to predict the molecular mechanism Thus, the potential drug combinations could reduce viral infectivity, viral replication, and abnormal host inflammatory responses and may be useful for multi-target drugs against SARS-CoV-2., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Caesalpinia pulcherima (CP) is a traditional herb used for the treatment of asthma, bronchitis, cancer, anti-bacterial, anti-fungal and as abortifacient. In the present study, bioactive components and potential targets in the treatment of breast cancer validated through in silico, in vitro and in vivo approach. The results for the analysis were as among 29 components, only four components were found active for further study which proved the use of CP as a multi-target herb for betterment of clinical uses. The results found by PPI states that our network has significant interactions which include the ESR-1, ESR-2, ESRRA, MET, VEGF, FGF, PI3K, PDK-1, MAPK, PLK-1, NEK-2, and GRK. Compound-target network involves 4 active compound and 150 target genes which elucidate the mechanisms of drug action in breast cancer treatment. Furthermore, on the basis of the above results the important proteins were fetched for the docking study which helps in predicting the possible interaction between components and targets. The results of the western blotting showed that CP regulates ER and EGFR expression in MCF-7 cell. In addition to this animal experimentation showed that CP significantly improved immunohistological status in MNU induced carcinoma rats. Network pharmacology approach not only helps us to confirm the study of the chosen target but also gave an idea of compound-target network as well as pathways associated to the CP for treating the complex metabolic condition as breast cancer and they importance for experimental verification.

The present study intended to assess the anticancer potential of Alysicarpus vaginalis ethyl acetate fraction (AVEAF) in breast cancer cell lines (MCF-7 and MDA-MB-453) and against N -methyl- N -nitrosourea (MNU) induced mammary carcinoma in Sprague-Dawley rats which resemble the human estrogen dependent breast cancer. The SRB assay showed that the maximum growth inhibition rate of AVEAF on MCF-7 cell was 27.12 at 100 µg/ml. Flow cytometry analysis observed that AVEAF induced the cell cycle arrest at the S phases and decreased in mitochondrial membrane potential on the MCF-7 cells. AVEAF elevated intracellular ROS level in the MCF-7 cells which were reversed with N -acetycysteine (2 mM) pretreatment indicating that AVEAF induced mitochondrial-mediated apoptosis via augmentation of intracellular ROS. Western blotting exhibited that AVEAF increased the expression of pro-apoptotic protein Bax while decreasing anti-apoptotic proteins Bcl-2 and Bcl-xL expression which promoted the cleavage of caspase-9, PARP1, RIPK 1, and RIPK 3. Additionally, AVEAF exerted anticancer effect on tumor-bearing rats and the tumor inhibition rate is 50%. Data of the study indicate that AVEAF exhibits In Vitro and In Vivo anticancer activities that associate with its ROS-mediated mitochondrial-mediated intrinsic pathway of apoptosis and necroptosis in MCF-7 cells and may serve as a potential against breast cancer.

Background: Cancer is a complex disease involving genetic and epigenetic alteration that allows cells to escape normal homeostasis. Kinases play a crucial role in signaling pathways that regulate cell functions. Deregulation of kinases leads to a variety of pathological changes, activating cancer cell proliferation and metastases. The molecular mechanism of cancer is complex and the dysregulation of tyrosine kinases like Anaplastic Lymphoma Kinase (ALK), Bcr-Abl (Fusion gene found in patient with Chronic Myelogenous Leukemia (CML), JAK (Janus Activated Kinase), Src Family Kinases (SFKs), ALK (Anaplastic lymphoma Kinase), c-MET (Mesenchymal- Epithelial Transition), EGFR (Epidermal Growth Factor receptor), PDGFR (Platelet-Derived Growth Factor Receptor), RET (Rearranged during Transfection) and VEGFR (Vascular Endothelial Growth Factor Receptor) plays major role in the process of carcinogenesis. Recently, kinase inhibitors have overcome many problems of traditional cancer chemotherapy as they effectively separate out normal, non-cancer cells as well as rapidly multiplying cancer cells., Methods: Electronic databases were searched to explore the small molecule tyrosine kinases by polyphenols with the help of docking study (Glide-7.6 program interfaced with Maestro-v11.3 of Schrödinger 2017) to show the binding energies of polyphenols inhibitor with different tyrosine kinases in order to differentiate between the targets., Results: From the literature survey, it was observed that the number of polyphenols derived from natural sources alters the expression and signaling cascade of tyrosine kinase in various tumor models. Therefore, the development of polyphenols as a tyrosine kinase inhibitor against targeted proteins is regarded as an upcoming trend for chemoprevention., Conclusion: In this review, we have discussed the role of polyphenols as chemoreceptive which will help in future for the development and discovery of novel semisynthetic anticancer agents coupled with polyphenols., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: According to the latest global cancer data, cancer burden rises to 18.1 million new cases and 9.6 million cancer deaths in 2018. Among that female breast cancer ranks as the fifth leading cause of death (627000 deaths, 6.6%). The main causative factor involved in breast cancer development and progression is the Estrogen Receptor (ER) which is the essential target for anti-cancer drug discovery. Since millennia ER-α has been considered as an oncology mark for the treatment of breast cancer., Methods: A series of novel 6-methyl-3-(3-oxo-1-phenyl-3-(4-(2-(piperidin-1-yl)ethoxy)phenyl)propyl)-2Hchromen- 2-one was designed, synthesized and screened for their anti-breast cancer activity against estrogen receptor-positive MCF-7, ZR-75-1 and negative MDA-MB-435 human breast cancer cell lines. Estrogen level of all the potent cytotoxic compounds were measured on day 30 of intoxication was compared with the control and N-methyl-N-nitrosourea (MNU) group. The docking study was performed to predict binding orientation towards the estrogen receptor-α., Results: Among the synthesized compounds C-3, C-5 and C-15 were showing potent cytotoxicity against estrogen receptor-positive MCF-7. The potent cytotoxic compounds C-3, C-5 and C-15 were further evaluated for in vivo anti-cancer activity by MNU induced mammary carcinoma in female sprague-dawley rats. The in vivo anticancer activity result shows that the compound C-5 has protuberant affinity towards estrogen receptor as standard TAM (Tamoxifen). The docking of the synthesized chromen derivatives showed interaction modes comparable to that of the co-crystallized ligands., Conclusion: The designed class has very promising starting point for the development and further improvement in anti-breast cancer class of drugs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Methods: A novel series of isoxazole (S21-S30) derivatives were designed, synthesized and screened for their anticancer activity against estrogen receptor-positive MCF-7 and negative MDA-MB-435 breast cancer cell lines. The synthesized derivative has the ability to inhibit the growth of the human breast cancer cell line at low concentrations. In vivo anticancer activity was performed on virgin female sprague dawley rats., Results: The result shows that compound S23 has more selectivity and marked estrogen modulator activity than the standard tamoxifen., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

By utilizing concept of molecular hybridization, involving combination of various Pharmacophore, novel substituted coumarin-chalcone hybrids was synthesized and evaluated for anti-proliferative activity against estrogen receptor-positive MCF-7 and negative MDA-MB-435 breast cancer cell lines. In-vivo study was carried out by N-methyl nitrosourea (MNU) induced mammary carcinoma in virgin female Spraque Dawly (SD) rats. The compound 5b has highest potential than standard drug Adriamycin, comparable against Tamoxifen against ER-positive MCF-7 breast cancer cell lines. Docking study was performed to study the binding orientation and affinity of synthesized compounds on the ER-α enzyme., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

A novel series of substituted quinazoline derivatives were designed, synthesized and evaluated for their hypolipidemic activity in cholesterol induced hyperlipidemic rats. In vivo screening concluded that compounds A-4, C-5 and C-6 have shown potent antihyperlipidemic activity by decreasing the plasma level of triglycerides (TG), very low density lipoprotein (VLDL), low density lipoprotein (LDL), followed by increase in level of high density lipoprotein (HDL)., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The present study was undertaken to evaluate in-vivo hypolipidemic activity of a novel series of 2-methyl-2-(substituted phenyl isoxazol)phenoxyacetic acid derivatives by triton induced hyperlipidemia in rats. The newly synthesized compounds 5a, 5d and 5g showed significant decrease in the serum TCH, TG, LDL and VLDL along with an increase in serum HDL levels as compared to standard drug Fenofibrate. The treated groups also showed significant decrease in the atherogenic index and increase in % protective activity compared to control group., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Inhibition of Histone deacetylases (HDACs) has been emerged as important approach to reverse aberrant epigenetic changes associated with various cancerous and non-cancerous diseases. The field of histone deacetylase inhibitors (HDIs) is moving into a new phase of development. The structure of histone deacetylases is well-established and the active sites have been well identified. Various drugs targeting this enzyme are in the pipeline for the treatment of different diseases. Since first-generation HDAC inhibitors proved their clinical fruitfulness and also second generation inhibitors are rationally designed with improved specificity, experts believe that this class will emerge in the treatment of various diseases. Considering these facts present review focuses on HDACs and developments of HDIs in the treatment of various diseases.

A novel series of aminopyrimidines containing the phenoxy isobutyric acid group as a pharmacophore was synthesized using conventional and microwave assisted methods of synthesis. The compounds were synthesized in good yields (70-89%) by the microwave-assisted one-pot protocol in much shorter reaction times. The synthesized compounds were evaluated for their hypolipidemic and hypoglycemic activity by high-fat diet-induced hyperlipidemia and hyperglycemia in male Sprague-Dawley rats. The present investigation showed significant antihyperlipidemic and antihyperglycemic activity for all compounds of the series when compared with the standard drug. Structure-activity relationship (SAR) for the series were developed by comparing total lipid profile data of synthesized compounds with fenofibrate as standard drug., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)