Centchroman altered the expressions of tumor‐related genes through active chromatin modifications in mammary cancer

Abstract

Centchroman (CC), a female oral contraceptive, has been shown to possess breast anti-cancer activities. Recently, we have shown CC-mediated antimetastatic effect through reversal of epithelial-to-mesenchymal transition (EMT) in breast cancer. The loss of tumor suppressor genes (TSGs) has been shown to promote EMT in breast cancer. Therefore, in the present study, we investigated the effect of CC-treatment on the expression of tumor-related genes including both tumor suppressor- and tumor promoter genes in breast cancer. CC treatment resulted in G /G phase cell cycle arrest in human breast cancer MDA-MB-231, SK-BR-3, and ZR-75-1 cells with the concomitant induction of TSGs such as p21 , p16 , and p27 . In addition, CC treatment also resulted in the downregulation of tumor promoter gene, human telomerase reverse transcriptase (hTERT). The induction of TSGs and downregulation of hTERT was found to be correlated with decreased expression levels of histone deacetylases (HDACs) and DNA methyltransferases (DNMTs). Further, mechanistic studies revealed CC-induced global DNA demethylation and alterations in the enrichment of chromatin modification markers at the promoters of p21 and hTERT. These in vitro results were corroborated with in vivo findings in 4T1-syngeneic mouse model, where CC-treatment resulted in tumor growth reduction accompanied with the induction of TSGs and alterations in the expression levels of HDACs, DNMT1, and histone modification markers. Overall, our findings suggest that CC-treatment induces the expression of TSGs and downregulates hTERT through histone modifications and DNA methylation changes. Therefore, CC could be further developed into a promising drug candidate against breast cancer. © 2015 Wiley Periodicals, Inc.

Comparative differential cytotoxicity of clinically used SERMs in human cancer lines of different origin and its predictive molecular docking studies of key target genes involved in cancer progression and treatment responses

“…Moreover, the molecule is reported to exert anti-tumor activity independent of estrogen regulation, exerting its effects via HDAC inhibition, down regulation of tumor promoter genes, human telomerase reverse transcriptase and expression of tumor suppressor genes which explains genetic and epigenetic modes of action which is very important in anti-cancer therapy ( Nigam et al., 2010 ; Nigam et al., 2008 ; Srivastava et al., 2011 ; Molinie and Georgel, 2009 ; Kachchap et al. 2010 ; Agrawal et al., 2016a ; Khan et al., 2016 ; Rama Raju et al., 2015 ; Khan et al., 2015 ; Singh et al. 2016 ; Mishra et al., 2010 ; Mukhopadhyay et al., 1999 ; Mukhopadhyay et al., 2001 ; K. Giri et al.…”

Diindolylmethane Promotes Metabolic Crisis and Enhances the Efficacy of Centchroman in Breast Cancer: A 1H NMR-Based Approach

“…Histopathological analysis was performed as described earlier. , Briefly, formalin-fixed tumors were subjected to histopathological analysis. For pathology assessment, sections (5 μm) were stained with Harris-hematoxylin and eosin.…”

Dietary Piperine Suppresses Obesity-Associated Breast Cancer Growth and Metastasis by Regulating the miR-181c-3p/PPARα Axis

“…Tumor volume was measured using (L × W 2 ) × 0.5, as described earlier. 31 Tumor progression was evaluated as the percentage change in tumor volume using the following formula: (end tumor volume-start tumor volume)/start tumor volume × 100. 32 Finally, the mice were sacrificed, and wet tumor weight was recorded; then, tumor tissues were collected for RNA extraction.…”

“…The determination of piperine dosage was based on previous literature demonstrating that the maximum activity of piperine was found at 50 mg/kg b.w./day. − Body weight and tumor size were recorded at regular intervals. Tumor volume was measured using ( L × W 2 ) × 0.5, as described earlier . Tumor progression was evaluated as the percentage change in tumor volume using the following formula: (end tumor volume-start tumor volume)/start tumor volume × 100 .…”