Mahanine mediated therapeutic inhibition of estrogen receptor-α and CDK4/6 expression, decipher the chemoprevention-signaling cascade in preclinical model of breast cancer.

Autor: Samanta SK; Faculty of Science, Assam Down Town University, Panikhaiti, Guwahati, 781026, Assam, India; Traditional and Modern Drug Discovery and Diseases Diagnosis Laboratory, Life Sciences Division, Institute of Advanced Study in Science and Technology, Guwahati, 781035, Assam, India. Electronic address: sumansamanta699@gmail.com., Choudhury P; Traditional and Modern Drug Discovery and Diseases Diagnosis Laboratory, Life Sciences Division, Institute of Advanced Study in Science and Technology, Guwahati, 781035, Assam, India; Department of Zoology, Gauhati University, Guwahati, 781014, Assam, India. Electronic address: paramitachy@gmail.com., Kandimalla R; Traditional and Modern Drug Discovery and Diseases Diagnosis Laboratory, Life Sciences Division, Institute of Advanced Study in Science and Technology, Guwahati, 781035, Assam, India; Brown Cancer Center, University of Louisville, Louisville, KY40202, USA; Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY40202, USA. Electronic address: raghuram.pharma@gmail.com., Aqil F; Brown Cancer Center, University of Louisville, Louisville, KY40202, USA; Department of Medicine, University of Louisville, Louisville, KY40202, USA. Electronic address: farrukh.aqil@louisville.edu., Moholkar DN; Brown Cancer Center, University of Louisville, Louisville, KY40202, USA; Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY40202, USA. Electronic address: dishanagesh.moholkar@louisville.edu., Gupta RC; Brown Cancer Center, University of Louisville, Louisville, KY40202, USA; Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY40202, USA. Electronic address: ramesh.gupta@louisville.edu., Das M; Traditional and Modern Drug Discovery and Diseases Diagnosis Laboratory, Life Sciences Division, Institute of Advanced Study in Science and Technology, Guwahati, 781035, Assam, India. Electronic address: momitadas87@yahoo.in., Gogoi B; Department of Biotechnology, The Assam Royal Global University, Guwahati, 781035, Assam, India. Electronic address: gogoi.bhaskar2608@gmail.com., Gogoi N; Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, 786004, Assam, India. Electronic address: neelutpalg@gmail.com., Sarma PP; Traditional and Modern Drug Discovery and Diseases Diagnosis Laboratory, Life Sciences Division, Institute of Advanced Study in Science and Technology, Guwahati, 781035, Assam, India. Electronic address: ppsarma94@gmail.com., Devi R; Traditional and Modern Drug Discovery and Diseases Diagnosis Laboratory, Life Sciences Division, Institute of Advanced Study in Science and Technology, Guwahati, 781035, Assam, India. Electronic address: rajiasst@gmail.com., Talukdar NC; Faculty of Science, Assam Down Town University, Panikhaiti, Guwahati, 781026, Assam, India. Electronic address: nctalukdar@yahoo.com.
Jazyk: angličtina
Zdroj: Journal of ethnopharmacology [J Ethnopharmacol] 2024 Jan 30; Vol. 319 (Pt 2), pp. 117235. Date of Electronic Publication: 2023 Oct 05.
DOI: 10.1016/j.jep.2023.117235
Abstrakt: Ethnopharmacological Relevance: Mahanine (MH), a naturally occurring carbazole alkaloid, isolated from Ayurvedic medicinal plant Murraya koenigii (L.) Spreng, has been shown to have various pharmacological properties, including its inhibitory activity against different breast cancers (BC) subtypes.
Aim of the Study: While MH triggers apoptosis in BC cells regardless of subtype, the specific mechanism of MH action is not fully understood. In this study, we show the effect of MH in preventing BC progression by inducing apoptosis in relation to estrogen receptor-α (ERα) and cell cycle regulatory proteins.
Materials and Methods: To assess the pharmacological activity in various in vitro and in vivo tests, isolated and pure MH was used. To conclude the study, cutting edged molecular biology techniques including Western blot analysis, enzyme-linked immunosorbent assay (ELISA), molecular simulation study, and other related software analysis were employed.
Results: MH demonstrated dose dependent cell viability against drug sensitive (MCF-7 and MDA-MB-231) and paclitaxel resistant (MCF-7TR and MDA-MB-231TR) BC cells. MH also exhibited synergistic activity with tamoxifen (TAM) against estrogen receptor positive (ER+) BC cells by inhibiting ERα expression in MCF-7 cells and N-Methyl-N-nitrosourea (MNU)-induced mammary tumor in a dose-dependent manner while having no effect on vinculin expression. In addition, MH inhibited cell cycle regulatory genes namely CDK1/CDK4/CDK6/CDC25A and neo-angiogenesis through downregulation of CD31/PECAMs in MCF-7, MDA-MB-231 cells and mammary tumors from MNU-induced rats. MH therapy has been shown to be significantly able to lower the serum leptin level and to be beneficial against the initiation of tumor development in SD rats for up to 12 weeks. Molecular modeling study revealed that MH has antagonized the effectiveness of several types of estrogen those bind to the ERα and has comparable binding efficacy to TAM.
Conclusion: Overall, the current investigation showed the ability of MH to modify cell cycle genes especially CDK4 and CDK6 might be responsible for its anticancer activity against different breast cancer subtypes. Additionally, this study will aid in advancing MH translational research to the clinical trial stage.
Competing Interests: Declaration of competing interest 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.
(Copyright © 2023 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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