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  • Title: Physalin A induces apoptosis via p53-Noxa-mediated ROS generation, and autophagy plays a protective role against apoptosis through p38-NF-κB survival pathway in A375-S2 cells.
    Author: He H, Zang LH, Feng YS, Chen LX, Kang N, Tashiro S, Onodera S, Qiu F, Ikejima T.
    Journal: J Ethnopharmacol; 2013 Jul 09; 148(2):544-55. PubMed ID: 23684722.
    Abstract:
    ETHNOPHARMACOLOGICAL RELEVANCE: Physalin A is a bioactive withanolide isolated from natural plant Physalis alkekengi L. var. franchetii (Mast.) Makino, a traditional Chinese herbal medicine named Jindenglong which has long been used for the treatment of cough, sore throat, hepatitis, eczema, dysuria and tumors in China. AIM OF THE STUDY: Based on the previous study that physalin A induced cytotoxic effect in human melanoma A375-S2 cells, this study was designed to further illustrate the molecular mechanisms underlying. MATERIALS AND METHODS: Cell viability was evaluated in A375-S2 cells by MTT assay, and the mechanisms involved in physalin A-induced A375-S2 cell death were investigated by phase contrast microscopy and fluorescence microscopy, siRNA transfection, flow cytometry and western blot analysis. RESULTS: We demonstrated that physalin A decreased the proportion of viable A375-S2 cells in a time- and dose-dependent manner, and exposure of A375-S2 cells to physalin A led to both apoptosis and autophagy. Moreover, physalin A-induced apoptosis was triggered by activation of p53-Noxa pathway and intracellular reactive oxygen species (ROS) generation. The administration of ROS scavengers NAC and GSH resulted in the complete inhibition of physalin A-induced ROS generation and apoptosis. Application of p53 inhibitor PFT-α or transfection with Noxa-siRNA could also lead to the same results. Autophagy, demonstrated by the punctuate distribution of monodansylcadaverine staining, as well as the change of LC3-II/LC3-I proportion and Beclin 1 activation, played a protective role against apoptosis via up-regulation of the p38-NF-κB survival pathway in A375-S2 cells. Additionally, inhibition of autophagy by the specific autophagic inhibitor 3MA or blocking the p38-NF-κB pathway with p38 inhibitor SB203580 or NF-κB inhibitor PDTC obviously promoted physalin A-induced apoptosis. CONCLUSIONS: Physalin A induced apoptotic cell death via p53-Noxa-mediated ROS generation, and autophagy played a protective role against apoptosis through up-regulating the p38-NF-κB survival pathway in A375-S2 cells. These results stated the possibility that physalin A would be a potential agent for the treatment of melanoma in the future.
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