Silibinin, a natural flavonoid, induces autophagy via ROS-dependent mitochondrial dysfunction and loss of ATP involving BNIP3 in human MCF7 breast cancer cells

Abstract

Silibinin, derived from the milk thistle plant (Silybum marianum), has anticancer and chemopreventive properties. Silibinin has been reported to inhibit the growth of various types of cancer cells. However, the mechanisms by which silibinin exerts an anticancer effect are poorly defined. The present study aimed to investigate whether silibinin-induced cell death might be attributed to autophagy and the underlying mechanisms in human MCF7 breast cancer cells. Our results showed that silibinin-induced cell death was greatly abrogated by two specific autophagy inhibitors, 3-methyladenine (3-MA) and bafilomycin-A1 (Baf-A1). In addition, silibinin triggered the conversion of light chain 3 (LC3)-I to LC3-II, promoted the upregulation of Atg12-Atg5 formation, increased Beclin-1 expression, and decreased the Bcl-2 level. Moreover, we noted elevated reactive oxygen species (ROS) generation, concomitant with the dissipation of mitochondrial transmembrane potential (ΔΨm) and a drastic decline in ATP levels following silibinin treatment, which were effectively prevented by the antioxidants, N-acetylcysteine and ascorbic acid. Silibinin stimulated the expression of Bcl-2 adenovirus E1B 19-kDa-interacting protein 3 (BNIP3), a pro-death Bcl-2 family member, and silencing of BNIP3 greatly inhibited silibinin-induced cell death, decreased ROS production, and sustained ΔΨm and ATP levels. Taken together, these findings revealed that silibinin induced autophagic cell death through ROS-dependent mitochondrial dysfunction and ATP depletion involving BNIP3 in MCF7 cells.

Supercritical CO2 extraction of oil, fatty acids and flavonolignans from milk thistle seeds: Evaluation of their antioxidant and cytotoxic activities in Caco-2 cells

“…The anticancer activity of silymarin as well as silibinin was demonstrated against various cancer cells such as breast, skin, colon, cervix, ovary, prostate, lung and hepatocellular cancers (Bosch- Barrera and Menendez, 2015;Chu et al, 2004;Eo et al, 2015;Fan et al, 2014;Jiang et al, 2015;Mastron et al, 2015;Sharma et al, 2003;Thelen et al, 2004;Tyagi et al, 2004;Varghese et al, 2005).…”

Selecting molecular therapeutic drug targets based on the expression profiles of intrahepatic cholangiocarcinomas and miRNA-mRNA regulatory networks

“…The role of tumor metabolism has also been appreciated in recent years. The canonical PI3K/AKT/ mToR pathway has been widely studied, as has BnIP3 (19,20). We hypothesize that ICC may inhibit the PI3K/AKT/mToR pathway by upregulating BnIP3.…”

Facile One‐Pot Synthesis of Tellurium Nanorods as Antioxidant and Anticancer Agents

“…Therefore, the state of the mitochondria was determined to define if the tellurium‐based nanosystem had an anticancer mechanism similar to that of selenium chemotherapeutic agents. ΔΨm can cause the release of apoptotic factors from the mitochondria to the cytosol, which leads to apoptosis . Currently, JC‐1 is used as a mitochondrial probe to determine the status of the mitochondria .…”