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Honokiol Induces a Necrotic Cell Death through the Mitochondrial Permeability Transition Pore

¹ Cancer Institute, The Second Affiliated Hospital, ² Department of Neurobiology, and ³ The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; ⁴ Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio

Requests for reprints: Xun Hu, Cancer Institute, Zhejiang University, 88 Jiefang Road, Hangzhou, Zhejiang, 310009 China. Phone: 86-571-8778-3656; E-mail: huxun{at}zju.edu.cn.

Previous reports have shown that honokiol induces apoptosis in numerous cancer cell lines and showed preclinical efficacies against apoptosis-resistant B-cell chronic lymphocytic leukemia and multiple myeloma cells from relapse-refractory patients. Here, we show that honokiol can induce a cell death distinct from apoptosis in HL60, MCF-7, and HEK293 cell lines. The death was characterized by a rapid loss of integrity of plasma membrane without externalization of phosphatidyl serine. The broad caspase inhibitor z-VAD-fmk failed to prevent this cell death. Consistently, caspase activation and DNA laddering were not observed. The death was paralleled by a rapid loss of mitochondrial membrane potential, which was mechanistically associated with the mitochondrial permeability transition pore regulated by cyclophilin D (CypD) based on the following evidence: (a) cyclosporin A, an inhibitor of CypD (an essential component of the mitochondrial permeability transition pore), effectively prevented honokiol-induced cell death and loss of mitochondrial membrane potential; (b) inhibition of CypD by RNA interference blocked honokiol-induced cell death; (c) CypD up-regulated by honokiol was correlated with the death rates in HL60, but not in K562 cells, which underwent apoptosis after being exposed to honokiol. We further showed that honokiol induced a CypD-regulated death in primary human acute myelogenous leukemia cells, overcame Bcl-2 and Bcl-X_L–mediated apoptotic resistance, and was effective against HL60 cells in a pilot in vivo study. To the best of our knowledge, this is the first report to document an induction of mitochondrial permeability transition pore–associated cell death by honokiol. [Cancer Res 2007;67(10):4894–903]

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