title: Natural Product Vibsanin A Induces Differentiation of Myeloid Leukemia Cells through PKC Activation.
abstract: All-trans retinoic acid (ATRA)-based cell differentiation therapy has been successful in treating acute promyelocytic leukemia, a unique subtype of acute myeloid leukemia (AML). However, other subtypes of AML display resistance to ATRA-based treatment. In this study, we screened natural, plant-derived vibsane-type diterpenoids for their ability to induce differentiation of myeloid leukemia cells, discovering that vibsanin A potently induced differentiation of AML cell lines and primary blasts. The differentiation-inducing activity of vibsanin A was mediated through direct interaction with and activation of protein kinase C (PKC). Consistent with these findings, pharmacological blockade of PKC activity suppressed vibsanin A-induced differentiation. Mechanistically, vibsanin A-mediated activation of PKC led to induction of the ERK pathway and decreased c-Myc expression. In mouse xenograft models of AML, vibsanin A administration prolonged host survival and inhibited PKC-mediated inflammatory responses correlated with promotion of skin tumors in mice. Collectively, our results offer a preclinical proof of concept for vibsanin A as a myeloid differentiation-inducing compound, with potential application as an antileukemic agent. Cancer Res; 76(9); 2698-709. ©2016 AACR.
authors.affiliation: Department of Pathophysiology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Zu-Yin
authors.initials: ZY
authors.lastname: Yu
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing, China.
authors.forename: He
authors.initials: H
authors.lastname: Xiao
authors.affiliation: Department of Pathophysiology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Li-Mei
authors.initials: LM
authors.lastname: Wang
authors.affiliation: Department of Pathophysiology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Shen
authors.affiliation: Department of Hematology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Jing
authors.affiliation: Department of Pathophysiology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pathophysiology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Wen-Feng
authors.initials: WF
authors.lastname: Sun
authors.affiliation: Department of Pathophysiology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Yan-Feng
authors.initials: YF
authors.lastname: Zhang
authors.affiliation: Department of Pathophysiology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Department of Pathophysiology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Ya-Jun
authors.initials: YJ
authors.lastname: Shan
authors.affiliation: Department of Pathophysiology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Wen-Bing
authors.initials: WB
authors.lastname: Zhou
authors.affiliation: Department of Pathophysiology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Xing
authors.affiliation: Department of Pathophysiology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Guo-Lin
authors.initials: GL
authors.lastname: Xiong
authors.affiliation: Department of Pathophysiology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Xiao-Lan
authors.initials: XL
authors.lastname: Liu
authors.affiliation: Department of Pathophysiology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Dong
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing, China.
authors.forename: Jian-Nan
authors.initials: JN
authors.lastname: Feng
authors.affiliation: Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Li-Sheng
authors.initials: LS
authors.lastname: Wang
authors.affiliation: Department of Pathophysiology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Qing-Liang
authors.initials: QL
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China. congyw@nic.bmi.ac.cn qinshizhao@mail.kib.ac.cn.
authors.forename: Qin-Shi
authors.initials: QS
authors.lastname: Zhao
authors.affiliation: Department of Pathophysiology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China. congyw@nic.bmi.ac.cn qinshizhao@mail.kib.ac.cn.
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Cong
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects*; D004224:Diterpenes / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007951:Leukemia, Myeloid / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008517:Phytotherapy / Q000379:methods*; D011493:Protein Kinase C / Q000187:drug effects; D060888:Real-Time Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004224:Diterpenes; C000596469:vibsanin A; D011493:Protein Kinase C