<p>Brevilin A Inhibits STAT3 Signaling and Induces ROS-Dependent Apoptosis, Mitochondrial Stress and Endoplasmic Reticulum Stress in MCF-7 Breast Cancer Cells</p>

Abstract

Breast cancer is the most common malignancy among women across the globe. Despite concerted efforts to improve the prevailing treatment modalities, the overall prognosis of breast cancer remains unsatisfactory. Recently, antiproliferative activity of Brevilin A (Brv-A), a sesquiterpene lactone compound of Centipeda minima, has been unveiled in various cancer types. Here, we have explored anticancer activity of Brv-A in MCF-7 breast carcinoma cells by targeting various pathways. Materials and Methods: Cell proliferation rate was determined by CCK-8 and clonogenic assay. Cellular morphological changes were observed under phase contrast microscope while calcein-AM and PI was used for live/dead assay. Cell cycle assay was performed by flow cytometry. Apoptotic cell percentage was determined by Hoechst 33258 staining and flow cytometric analysis. ROS generation and mitochondrial membrane potential were measured using commercially available kits while protein expression was measured by Western blotting. Results: In our study, Brv-A exerted antiproliferative effect through mitotic arrest at G 2 /M phase of cell cycle and induced apoptosis in MCF-7 cells in a dose-dependent manner. Induction of apoptosis by Brv-A was found to be associated with ROS generation by targeting NOX2 and NOX3, mitochondrial dysfunction (MMP dissipation and Bcl-2 family proteins modulation), DNA fragmentation, JNK and p38 MAPK activation, endoplasmic reticulum (ER) stress by increasing Bip/GRP78, ATF4 and CHOP protein expressions and inhibition of STAT3 activation via decreased phosphorylation of JAK2 and SRC. Pretreatment of NAC, a ROS scavenger, partially reversed the aforesaid cellular events indicating ROS generation as the primary event to modulate cellular targets for induction of apoptosis. Besides, Brv-A has also been documented for inhibition of cell migration via decrease in COX-2 and MMP-2 expression. Conclusion: Taken together, Brv-A induces G 2 /M phase arrest, ROS-dependent apoptosis, ER stress, mitochondrial dysfunction and inhibits STAT3 activation in MCF-7 cells signifying it to be one of the potential anticancer therapeutics in future.

Ginsenoside Rh1 Induces MCF-7 Cell Apoptosis and Autophagic Cell Death through ROS-Mediated Akt Signaling

“…There are a variety of sources of ROS, such as NADPH oxidases (NOX), mitochondrial electron transport chain, nitric oxide synthases, cytochrome P450 reductase, and xanthine oxidase. Among them, NOX are the main source to generate ROS, and NOX isoforms have been found to be involved in apoptosis, autophagy, and cell cycle regulation in breast cancer cells [ 24 , 25 ]. To investigate whether Rh1-produced ROS are involved in NOX activity, MCF-7 cells were pretreated with the ROS scavenger, N-acetylcysteine (NAC), the nonspecific NOX inhibitor, diphenyleneiodonium (DPI), or the specific NOX2 inhibitor, apocynin (APO).…”

Mechanisms for Modulating Anoikis Resistance in Cancer and the Relevance of Metabolic Reprogramming

“…Hypoxia and low pH are some of the major attributes of tumor milieu, enhancing anoikis evasion and therapy resistance. Several studies have shown that the therapeutic potential of small molecules (such as salinomycin) induced ROS production in cancer cells to inhibit anoikis resistance, invasiveness, migration, and metastasis (62, 90,[196][197][198]. This suggested that unexplored drugs, which demonstrate their pharmacological targets by inducing oxidative stress capable of restricting AIG in cancer cells without affecting normal cells, may be considered for future therapies.…”

Upregulation of V-ATPase by STAT3 Activation Promotes Anoikis Resistance and Tumor Metastasis

“…STAT3 had been reported to play a crucial role in suppressing ROS signaling to favor tumorigenesis [26,27]. Also, STAT3 activation had been reported in anchorage-independent cancer cells [21][22][23]28].…”