Anticancer Effects and Mechanisms of MAM, a Natural Naphthoquinone

[Speaker] Xiuping Chen:1
[Co-author] Wen Sun:1, Hongwei Gao:1, Jin-Jian Lu:1
1:Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau

Necroptosis is a recently identified programmed cell death. Here, we reported that MAM, a natural naphthoquinone isolated from Huzhang, caused hydrogen peroxide dependent activation of JNK and induced the expression of iNOS, thereby leading to nitric oxide generation in A549 lung cancer cells. In addition, a decrease in GSH/GSSG levels accompanied with increased ROS production was observed. Reversal of ROS generation and cell death in GSH pretreated cells indicated the involvement of GSH depletion in MAM mediated cytotoxicity. Furthermore, MAM treated HCT116 and HT29 cells, accompanied by mitochondrial ROS elevation, mitochondrial depolarization and ATP depletion. This process was identified as necroptosis, based on the experiments showing that MAM-induced cell death was attenuated by RIP1 inhibitor necrostatin-1s, siRNA-mediated gene silencing of RIP1 and RIP3. RIP1/RIP3 complex triggered necroptosis by accumulation of cytosolic calcium, followed by sustained JNK activation. Finally, we determined that both calcium chelator BAPTA-AM and JNK inhibitor SP600125 could mitochondrial ROS elevation, mitochondrial depolarization and ATP depletion. In addition, MAM induced necroptosis was independent of TNFα, p53, MLKL, and LMP. MAM dramatically inhibited the growth of lung cancer on A549 human lung cancer xenografts of nude mice. In summary, MAM induced necroptosis in cancer cells and showed anti-cancer effect in animal model.
Acknowledgments: This study was supported by the Science and Technology Development Fund of Macau (FDCT) (078/2016/A2) and the Research Fund of University of Macau (MYRG2016-00043-ICMS-QRCM).
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