ABSTRACT
Breast cancer displays high morbidity and mortality. Despite exerting certain effects, traditional treatments cannot eliminate every cancer cell and may kill normal cells due to inaccurate targeting. However, as a traditional Chinese medicine, capsaicin, an active compound extracted from chili peppers, has displayed potent anticarcinogenic activities in vitro and in vivo, but the underlying mechanism is not completely understood. The pharmacological effects of capsaicin on tumors was evaluated in MDA MB 231 breast cancer cells. The MTT, cell scratch assay, cell cycle analysis, cell transfection, reverse transcriptionquantitative PCR and western blotting were performed to investigate the potential antitumor mechanisms of capsaicin. In the present study, the potential anticancer mechanism underlying capsaicin in MDAMB231 cells in vitro was investigated. Capsaicin significantly inhibited MDAMB231 breast cancer cell viability and migration compared with the control group. The flow cytometry results indicated that capsaicin induced G2/M cell cycle arrest in MDAMB231 cells. In addition, capsaicin significantly reduced the expression of cyclindependent kinase 8 (CDK8) in breast cancer cells compared with the control group. Moreover, LVCDK8 small interfering RNAtransduced MDAMB231 cells displayed lower CDK8 mRNA and protein expression levels compared with LVnegative controlshRNAtransduced cells. Furthermore, capsaicin significantly reduced the expression levels of phosphorylated (p)PI3K, pAkt, Wnt and ßcatenin in vitro compared with the control group. Collectively, the results of the present study suggested that capsaicin inhibited breast cancer cell viability, induced G2/M cell cycle arrest, reduced CDK8 expression levels, decreased the phosphorylation of PI3K and Akt and downregulated Wnt and ßcatenin expression levels in MDAMB231 cells.
Subject(s)
Breast Neoplasms/drug therapy , Capsaicin/pharmacology , Apoptosis/drug effects , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Capsaicin/metabolism , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , China , Cyclin-Dependent Kinase 8/genetics , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Wnt Signaling Pathway/drug effects , Wnt Signaling Pathway/physiology , beta Catenin/metabolismABSTRACT
Parthanatos is a new form of programmed cell death that is regulated by hyper-activated PARP-1, and is emerging as a new strategy to kill cancer cells. Deoxypodophyllotoxin (DPT) is a natural chemical that is found to induce cancer cell death, in which the role of parthanatos is unknown. Thus, we investigated this issue in this study by using glioma cell lines and mice model of xenograft glioma. We found that DPT induced glioma cell death in vitro and inhibited the growth of xenograft glioma in vivo, which was accompanied with parthanatos-related biochemical events including expressional upregulation of PARP-1, cytoplasmic accumulation of PAR polymer, and nuclear translocation of AIF. In vitro study revealed that genetic knockdown of PARP-1 with small interfering RNA attenuated DPT-induced elevation in the cytoplasmic PAR-polymer and the nuclear AIF, as well as protected glioma cells against the toxicity of DPT. Further, antioxidant NAC, as well as PARP-1 inhibitor 3AB, not only alleviated the overproduction of ROS caused by DPT, but also reversed the above-mentioned biochemical events, maintained mitochondrial membrane potential and rescued glioma cells death. Therefore, we demonstrated that deoxypodophyllotoxin triggered parthanatos in glioma cells via induction of excessive ROS.