Abstract
Abyssinone V-4′ methyl ether (AVME) isolated from Erythrina droogmansiana was recently reported to exhibit anti-mammary tumor effect in mice. The present work was therefore aimed at elucidating its cellular and molecular mechanisms. To achieve our goal, the cytotoxicity of AVME against tumoral and non-tumoral cell lines was evaluated by resazurin reduction test; flow cytometry allowed us to evaluate the cell cycle and mechanisms of cell death; the mitochondrial transmembrane potential, reactive oxygen species (ROS) levels, and caspase activities as well as apoptosis-regulatory proteins (Bcl-2 and Bcl-XL) were measured in MDA-MB-231 cells. Further, the antimetastatic potential of AVME was evaluated by invasion assay. AVME exhibited cytotoxic effects in all tested tumor cell lines and induced a significant increase in the percentage of MDA-MB-231 cells at G2/M and S phases of the cell cycle in a concentration-dependent manner. AVME also induced apoptosis in MDA-MB-231 cells, which was accompanied by the activation of caspase-3 and caspase-9 and downregulation of Bcl-2 and Bcl-XL proteins. Moreover, AVME suppressed cancer cell invasion by the inhibition of the metalloproteinase-9 activity. Findings from this study suggest that AVME has anti-breast cancer activities expressed through mitochondrial proapoptotic pathway including impairment of aggressive behaviors of breast cancer cells.
Highlights
Stephane Zingue,1,2,3 Abel Joel Gbaweng Yaya,4 Julia Cisilotto,2 Larissa Vanelle Kenmogne,5 Emmanuel Talla,4 Anupam Bishayee,6 Dieudonne Njamen,3,5 Tania Beatriz Creczynski-Pasa,2 and Derek Tantoh Ndinteh 3
The cytotoxicity of Abyssinone V-4′ methyl ether (AVME) against tumoral and non-tumoral cell lines was evaluated by resazurin reduction test; flow cytometry allowed us to evaluate the cell cycle and mechanisms of cell death; the mitochondrial transmembrane potential, reactive oxygen species (ROS) levels, and caspase activities as well as apoptosis-regulatory proteins (Bcl-2 and Bcl-XL) were measured in MDA-MB-231 cells
As shown in dot plots (Figure 2(a) and Supplementary Figure 1(a)), the viable cells exhibited low FITC and propidium iodide (PI) fluorescence, whereas the cells in early apoptosis presented high FITC fluorescence but low PI fluorescence. e viable, apoptotic, and necrotic control cells were 96.26%, 1.88%, and 1.86%, respectively. e concentration-dependent increase in the percentage of apoptotic cells with the maximum of 12.83% at 20 μM of AVME suggests that it induced apoptosis in MDA-MB-231 cells (Figure 2(b)) and 23.13% and 53.24% of apoptotic cells in MCF-7 cells (Supplementary Figures 1(a) and 1(b))
Summary
Stephane Zingue ,1,2,3 Abel Joel Gbaweng Yaya, Julia Cisilotto, Larissa Vanelle Kenmogne, Emmanuel Talla, Anupam Bishayee ,6 Dieudonne Njamen ,3,5 Tania Beatriz Creczynski-Pasa, and Derek Tantoh Ndinteh 3. Is is true of phytoestrogens which are plant metabolites with a chemical structure of 17β-estradiol, which mimic estrogenic actions in mammals [9] Since phytoestrogens possess both estrogenic and antiestrogenic activities, it is proposed that they could prevent estrogen-dependent malignancies such as breast, ovarian, uterine, and prostate cancers [10]. Tueche et al [23] reported the cytotoxic effect of AVME isolated from Erythrina droogmansiana on four tumoral cell lines [including estrogen receptor-positive breast adenocarcinoma (MCF-7)] and its ability to prevent breast tumors induced by 7,12-dimethylbenz(a)anthracene (DMBA) in mice. Cell death (apoptosis or necrosis), cell cycle, mitochondrial transmembrane potential, ROS formation, caspase activities, apoptotic regulating proteins (Bcl-2 and Bcl-XL), invasion and expression of its regulators, matrix metalloproteinase-2 (MMP-2), and MMP-9 were examined in MDA-MB-231 breast cancer cells
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