Deltonin induces apoptosis in MDA-MB-231 human breast cancer cells via reactive oxygen species-mediated mitochondrial dysfunction and ERK/AKT signaling pathways

Abstract

Abstract. Deltonin, a steroidal saponin isolated from Dioscorea zingiberensis Wright, exhibits high cytotoxic activity in cancer cells. In the present study, the effects of deltonin on cell proliferation and apoptosis were evaluated in the MDA-MB-231 human breast carcinoma cell line. Following treatment with deltonin, the viability of MDA-MB-231 cells was analyzed using MTT assay and apoptosis, mitochondrial membrane potential (∆Ψm) alternation and intracellular reactive oxygen species (ROS) generation was determined by flow cytometry. In addition, western blot analysis was performed to examine the expression of apoptosis-associated proteins. The results demonstrated that deltonin induced apoptosis in MDA-MB-231 cells in a time-and concentration-dependent manner. Apoptosis was associated with depolarization of ∆Ψm and time-dependent ROS generation. Deltonin treatment also resulted in Bax upregulation, Bcl-2 downregulation, activation of caspase-3 and -8 and poly (ADP ribose) polymerase cleavage. Decreased levels of phosphorylated extracellular signal-regulated kinase (ERK) and phosphorylated AKT were also observed. Results indicate that the proliferation inhibitory effect of deltonin is associated with its apoptosis-inducing effect, which may correlate with ROS-mediated mitochondrial dysfunction as well as activation of the ERK/AKT signaling pathways. Therefore, deltonin may be a potential chemotherapeutic agent for the treatment of breast cancer. IntroductionBreast cancer is the most commonly diagnosed cancer and the leading cause of cancer mortality among females, accounting for 23% of total cancer cases and 14% of cancer mortalities (1). In developing countries, including China, breast cancer remains a significant public health issue due to its prevalence (2). In recent years, medical advances have increased the availablity and efficacy of breast cancer treatments, including improved surgical methods for lumpectomy and mastectomy and radiation, hormone and chemotherapies. However, the majority of drugs currently used as chemotherapeutic agents exhibit low efficacy and are associated with the development of drug resistance (3,4). Therefore, new drugs with a higher therapeutic index are urgently required to effectively treat this malignancy.Over the last two decades, an increasing number of bioactive compounds have been identified in traditional Chinese medical herbs (5). Specific compounds have been reported to kill tumor cells by generation of reactive oxygen species (ROS). ROS are known to affect mitochondrial membrane potential (∆Ψm) and trigger a series of mitochondria-associated events (6,7). The generation of ROS may contribute to mitochondrial damage, reduction of ∆Ψm, release of cytochrome c and Smac and subsequent caspase activation and apoptosis (8,9). Apoptosis is a major control mechanism of cell death when DNA damage is not repaired. Apoptosis is a gene-directed programmed cell death characterized by cell shrinkage, blebbing of the plasma membrane, chromosomal DNA fragmentation and a number of oth...

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