Honokiol induces a necrotic cell death through the mitochondrial permeability transition pore.
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.
Li
Ling
L
Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Han
Weidong
W
Gu
Ying
Y
Qiu
Shuang
S
Lu
Qinghua
Q
Jin
Jie
J
Luo
Jianhong
J
Hu
Xun
X
D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D001713:Biphenyl Compounds / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D021983:Cyclophilins / Q000378:metabolism; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D017705:Lignans / Q000494:pharmacology*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D033681:Mitochondrial Membrane Transport Proteins / Q000502:physiology*; D000083162:Mitochondrial Permeability Transition Pore; D009336:Necrosis; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000498:Allyl Compounds; D010636:Phenols; D000097322:Peptidyl-Prolyl Isomerase D
D000972:Antineoplastic Agents, Phytogenic; D051033:Apoptosis Inducing Factor; D001713:Biphenyl Compounds; D021983:Cyclophilins; D017705:Lignans; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; C494829:AIFM1 protein, human; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols; C114456:PPID protein, human; D000097322:Peptidyl-Prolyl Isomerase D