Targeting progesterone metabolism in breast cancer with l-proline derived new 14-azasteroids.
Abstract
Breast cancer cell proliferation is promoted by a variety of mitogenic signals. Classically estrogen is considered as most predominant mitogenic signal in hormone-dependent breast cancer and progesterone is primarily considered to have protective effect. However, it is suggested that some progesterone metabolite may promote breast cancer and progesterone metabolites like 5α-pregnane and 4-pregnene could serve as regulators of estrogen-responsiveness of breast cancer cells. Here, we estimated the potential of alternate targeting of breast cancer via progesterone signalling. l-Proline derived novel 14-azasteroid compounds were screened against MCF-7 and MDA-MB-231 cell lines using MTT assay. In silico studies, cell cycle, Annexin-V-FITC/PI, JC-1 mitochondrial assay, ROS analysis were performed to analyse the impact of hit compound 3b on breast cancer cells. Further, we analysed the impact of hit 3b on the progesterone, its metabolites and enzymes responsible for the conversion of progesterone and its metabolites using ELISA. Data suggests that compound 3b binds and down regulates of 5α-reductase by specifically inhibiting production of progesterone metabolites that are capable of promoting breast cancer proliferation, epithelial mesenchymal transition and migration. This study establishes the proof of concept and generation of new leads for additional targeting of breast cancer.
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Progesterone
Singh J1, Singh R2, Gupta P2, Rai S1, Ganesher A2, Badrinarayan P3, Sastry GN3, Konwar R4, Panda G5.
Author Information
1. Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
2. Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
3. Centre for Molecular Modelling, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
4. Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific & Innovative Research (AcSIR), Chennai 600 113, India. Electronic address: [email protected].
5. Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific & Innovative Research (AcSIR), Chennai 600 113, India. Electronic address: [email protected].
Bioorg Med Chem. 2017 Aug 15;25(16):4452-4463. doi: 10.1016/j.bmc.2017.06.031. Epub 2017 Jun 19.
Copyright © 2017 Elsevier Ltd. All rights reserved.
Link: https://www.ncbi.nlm.nih.gov/pubmed/28693914
by Gary Khodanian | Jun 19, 2017