Natural Product Vibsanin A Induces Differentiation of Myeloid Leukemia Cells through PKC Activation

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-deriv...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2016-05, Vol.76 (9), p.2698-2709
Main Authors: Yu, Zu-Yin, Xiao, He, Wang, Li-Mei, Shen, Xing, Jing, Yu, Wang, Lin, Sun, Wen-Feng, Zhang, Yan-Feng, Cui, Yu, Shan, Ya-Jun, Zhou, Wen-Bing, Xing, Shuang, Xiong, Guo-Lin, Liu, Xiao-Lan, Dong, Bo, Feng, Jian-Nan, Wang, Li-Sheng, Luo, Qing-Liang, Zhao, Qin-Shi, Cong, Yu-Wen
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents, Phytogenic - pharmacology
Blotting, Western
Cell Differentiation - drug effects
Diterpenes - pharmacology
Enzyme Activation - drug effects
Humans
Leukemia, Myeloid - pathology
Male
Mice
Mice, Inbred C57BL
Phytotherapy - methods
Protein Kinase C - drug effects
Real-Time Polymerase Chain Reaction
Xenograft Model Antitumor Assays
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Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-15-1616