Withania somnifera Alter BCL2/Bax signaling and trigger apoptosis of MCF-7 and MDA-MB231 breast cancer cells exposed to γ-radiation

Abstract

Treatment strategies encompass synchronization of more than one therapy with specific dependence on zeroing side effects of natural products that might represent a niche in the continuous struggle against cancer. Thus, this study aimed at assessing the role of Withania somnifera; WS (Ashwagandha) in forcing MCF7 or MDA-MB 231 irradiated breast cancer cells to outweigh the route of programmed cell death. We check to what extent SIRT1-BCL2/Bax signaling pathway was interrelated to form apoptotic cancer cells. MDA or MCF7 cells are categorized into four groups: gp1, Control (C): MDA-MB-231 or MCF7 cells not treated with WS or exposed to γ-rays, gp2 (WS): cells challenged with WS for MDA-MB-231 or MCF7 cells respectively, gp3: irradiated (R) MDA-MB-231 or MCF7 cells exposed to γ-rays (4 Gy; one shot) and gp4 WS and irradiated (WS + R): cells challenged with WS as in gp2 and exposed to gamma rays as in gp3. The results revealed that, WS established IC50 equivalent to 4897.8 μg/ml in MDA-MB-231 cells or equivalent to 3801.9 μg/ml in MCF7 cells. The flowcytometric analysis (Annexin V and cell cycle) showed that WS induces apoptosis at pre-G phase and induces cell arrest at G2/M and preG1 phases for MDA-MB-231 and at the preG1 for MCF7 cells. Furthermore, the WS + R group of cells (MDA-MB-231 and MCF7) showed significant increases in the expression of SIRT1, and BCL2 and a decrease in BAX compared with WS or R group. It could be concluded that WS has an anti-proliferative action on MDA-MB-231 and MCF7 cells because of its capability to enhance apoptosis.

In silico design and cell-based evaluation of two dual anti breast cancer compounds targeting Bcl-2 and GPER

“…9 , in MCF-7 both compounds showed a better performance, measured as a decrease in the percentage of cell viability, than Gossypol, in a concentration-dependent manner without involving the cell number seeded; this finding is an outstanding insight into the probable mechanism of action conducted by 6 and 37 which points mainly to a probable Bcl-2 inhibition, reinforced for a GPER modulation, since, from the energetical analyzes yielded by in silico simulations over the two pharmacological targets, the affinity of both compounds is slightly more representative for GPER in comparison with Bcl-2 (< onefold), however, from the individual results analysis, 37 decreased cell proliferation in a better way than 6 probably due to the slightly finer binding energy of this ligand towards Bcl-2 as is possible to contrast it both docking calculations and molecular dynamics simulations. Astoundingly, MDA-MB-231 cancer cell were more sensitive to the assayed compounds than MCF-7 cells, owing largely to a over expression of Bcl-2 protein on MDA-MB-231 cell line 64 , 65 , added to a slight GPER expression that in a basal state, triggers proliferation and cancer cell survival 66 , 67 , although, from the individual results obtained for MCF-7 cancer cells, 37 depicted an IC 50 value significantly lower than Gossypol (18.66 vs. 65.67 μM, respectively), probably due to multiple effects of this ligand at inhibit both estrogen receptors (ERs α > β and GPER) and the anti-apoptotic protein Bcl-2, triggering a synergistic effect which leads to a best antiproliferative performance than showed by Gossypol, besides, we were unable to determine the IC 50 value for G-15, due to solubilization problems starting at a 20 μM concentration (Data not showed). The highlighted above place both compounds as potential therapeutic options against most aggressive cancer type TNCB (Triple-Negative Breast Cancer) represented by the two cancer cell lines assayed.…”

Mechanisms of traditional Chinese medicine overcoming of radiotherapy resistance in breast cancer

“…Flow cytometry analysis revealed that in the experimental group, consisting of MDA-MB-231 and MCF7 breast cancer cell lines treated with Withania prior to irradiation, there was an increased percentage of apoptotic cells (including early, late, and necrotic cells) compared to the control group, which only received irradiation. Additionally, it altered BCL2/Bax signal transduction and triggered apoptosis in breast cancer cells exposed to γ radiation ( 147 ).…”