3-O-(E)-p-Coumaroyl betulinic acid possess anticancer activity and inhibit Notch signaling pathway in breast cancer cells and mammosphere

Kushwaha, Prem Prakash; Singh, Atul Kumar; Shuaib, Mohd; Prajapati, Kumari Sunita; Vardhan, P. Seshu; Gupta, Sanjay; Kumar, Shashank

doi:10.1016/j.cbi.2020.109200

Cited by 30 publications

(23 citation statements)

References 33 publications

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“…Therefore, there is an urgent need to identify potential natural SARAS-CoV-2 drugable target inhibitors. Plant-based small molecules showed efficacy against different diseases/ailment including antiviral disease in in silico and in vitro experiments (Gupta et al, 2020;Kushwaha et al, 2020a;Kushwaha et al, 2020b;Kushwaha et al, 2021a). In the present study we selected two Indian medicinal plants (Azadirachta indica and Aloe vera) based on the rationale reviewed through the literature.…”

Section: Introductionmentioning

confidence: 99%

Identification of Natural Inhibitors Against SARS-CoV-2 Drugable Targets Using Molecular Docking, Molecular Dynamics Simulation, and MM-PBSA Approach

Kushwaha

Singh

Bansal

et al. 2021

Front. Cell. Infect. Microbiol.

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The present study explores the SARS-CoV-2 drugable target inhibition efficacy of phytochemicals from Indian medicinal plants using molecular docking, molecular dynamics (MD) simulation, and MM-PBSA analysis. A total of 130 phytochemicals were screened against SARS-CoV-2 Spike (S)-protein, RNA-dependent RNA polymerase (RdRp), and Main protease (Mpro). Result of molecular docking showed that Isoquercetin potentially binds with the active site/protein binding site of the Spike, RdRP, and Mpro targets with a docking score of -8.22, -6.86, and -9.73 kcal/mole, respectively. Further, MS 3, 7-Hydroxyaloin B, 10-Hydroxyaloin A, showed -9.57, -7.07, -8.57 kcal/mole docking score against Spike, RdRP, and Mpro targets respectively. The MD simulation was performed to study the favorable confirmation and energetically stable complex formation ability of Isoquercetin and 10-Hydroxyaloin A phytochemicals in Mpro-unbound/ligand bound/standard inhibitor bound system. The parameters such as RMSD, RMSF, Rg, SASA, Hydrogen-bond formation, energy landscape, principal component analysis showed that the lead phytochemicals form stable and energetically stabilized complex with the target protein. Further, MM-PBSA analysis was performed to compare the Gibbs free energy of the Mpro-ligand bound and standard inhibitor bound complexes. The analysis revealed that the His-41, Cys145, Met49, and Leu27 amino acid residues were majorly responsible for the lower free energy of the complex. Drug likeness and physiochemical properties of the test compounds showed satisfactory results. Taken together, the study concludes that that the Isoquercetin and 10-Hydroxyaloin A phytochemical possess significant efficacy to bind SARS-Cov-2 Mpro active site. The study necessitates further in vitro and in vivo experimental validation of these lead phytochemicals to assess their anti-SARS-CoV-2 potential.

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Section: Introductionmentioning

confidence: 99%

Identification of Natural Inhibitors Against SARS-CoV-2 Drugable Targets Using Molecular Docking, Molecular Dynamics Simulation, and MM-PBSA Approach

Kushwaha

Singh

Bansal

et al. 2021

Front. Cell. Infect. Microbiol.

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“… 155 3-O-(E)-p-Coumaroyl betulinic is a powerful inhibitor of the Notch pathway, and interferes with BC proliferation by blocking the G0/G1 stage cell cycle of BC cells. 156 Oridonin, a compound derived from red terpene, has a viable anticancer activity and represses the migration and metastasis of BC by essentially inhibiting Indent receptor expression and in this manner hindering Notch signaling, thus accelerating the initiation of apoptosis in BC cells. 157 Resveratrol has antitumor effects, and the expression of Notch1, Dll4 mRNA and protein in BC cells was found to be down-regulated in the cells treated with resveratrol, while the growth of breast cells was inhibited, which could suggest that resveratrol regulates the proliferation of BC by suppressing the Notch pathway.…”

Section: Notch Signaling Pathway Inhibitors and Treatment Prospects I...mentioning

confidence: 99%

The Notch Signaling Pathway Contributes to Angiogenesis and Tumor Immunity in Breast Cancer

Jiang¹,

Hu²,

Wang³

et al. 2022

BCTT

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Breast cancer in women is the first leading tumor in terms of incidence worldwide. Some subtypes of BC lack distinct molecular targets and exhibit therapeutic resistance; these patients have a poor prognosis. Thus, the search for new molecular targets is an ongoing challenge for BC therapy. The Notch signaling pathway is found in both vertebrates and invertebrates, and it is a highly conserved in the evolution of the species, controlling cellular fates such as death, proliferation, and differentiation. Numerous studies have shown that improper activation of Notch signaling may lead to excessive cell proliferation and cancer, with tumor-promoting and tumor-suppressive effects in various carcinomas. Thus, inhibitors of Notch signaling are actively being investigated for the treatment of various tumors. The role of Notch signaling in BC has been widely studied in recent years. There is a growing body of evidence suggesting that Notch signaling has a pro-oncogenic role in BC, and the tumor-promoting effect is largely a result of the diverse nature of tumor immunity. Immunological abnormality is also a factor involved in the pathogenesis of BC, suggesting that Notch signaling could be a target for BC immunotherapies. Furthermore, angiogenesis is essential for BC growth and metastasis, and the Notch signaling pathway has been implicated in angiogenesis, so studying the role of Notch signaling in BC angiogenesis will provide new prospects for the treatment of BC. We summarize the potential roles of the current Notch signaling pathway and its inhibitors in BC angiogenesis and the immune response in this review and describe the pharmacological targets of Notch signaling in BC, which may serve as a theoretical foundation for future research into exploring this pathway for novel BC therapies.

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“…The phytochemical altered the Notch target genes such as E-cadherin, Hey1, and Hes1, and breast cancer stemness markers viz. c-Myc, COX2, CD44, OCT4, NANOG, CD44, and EpCAM in MCF-7 cell-derived mammospheres [ 100 ].…”

Section: Other Dietary Phytochemicalsmentioning

confidence: 99%

Targeting Breast Cancer-Derived Stem Cells by Dietary Phytochemicals: A Strategy for Cancer Prevention and Treatment

Prajapati

Gupta

Kumar

2022

Cancers

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Breast cancer is heterogeneous disease with variable prognosis and therapeutic response. Approximately, 70% of diagnosed breast cancer represents the luminal A subtype. This subpopulation has a fair prognosis with a lower rate of relapse than the other clinical subtypes. Acquisition of stemness in luminal A subtype modifies the phenotype plasticity to accomplish increased aggressiveness and therapeutic resistance. Therefore, targeting luminal A-derived breast cancer stem cells (BCSCs) could be a promising strategy for its prevention and treatment. Extensive studies reveal that dietary phytochemicals have the potential to target BCSCs by modulating the molecular and signal transduction pathways. Dietary phytochemicals alone or in combination with standard therapeutic modalities exert higher efficacy in targeting BCSCs through changes in stemness, self-renewal properties and hypoxia-related factors. These combinations offer achieving higher radio- and chemo- sensitization through alteration in the key signaling pathways such as AMPK, STAT3, NF-ĸB, Hedgehog, PI3K/Akt/mTOR, Notch, GSK3β, and Wnt related to cancer stemness and drug resistance. In this review, we highlight the concept of targeting luminal A-derived BCSCs with dietary phytochemicals by summarizing the pathways and underlying mechanism(s) involved during therapeutic resistance.

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3-O-(E)-p-Coumaroyl betulinic acid possess anticancer activity and inhibit Notch signaling pathway in breast cancer cells and mammosphere

Cited by 30 publications

References 33 publications

Identification of Natural Inhibitors Against SARS-CoV-2 Drugable Targets Using Molecular Docking, Molecular Dynamics Simulation, and MM-PBSA Approach

Identification of Natural Inhibitors Against SARS-CoV-2 Drugable Targets Using Molecular Docking, Molecular Dynamics Simulation, and MM-PBSA Approach

The Notch Signaling Pathway Contributes to Angiogenesis and Tumor Immunity in Breast Cancer

Targeting Breast Cancer-Derived Stem Cells by Dietary Phytochemicals: A Strategy for Cancer Prevention and Treatment

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