Jiyuan Oridonin A Overcomes Differentiation Blockade in Acute Myeloid Leukemia Cells With MLL Rearrangements via Multiple Signaling Pathways.

Abstract

Differentiation therapy with all-trans-retinoic acid (ATRA) in acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia (AML), has been extremely successful in inducing clinical remission in APL patients. However, the differentiation therapy of ATRA-based treatment has not been effective in other subtypes of AML. In this study, we evaluated a small molecule of ent-kaurene diterpenoid, Jiyuan oridonin A (JOA), on the differentiation blockade in AML cells with the mixed lineage leukemia (MLL) gene rearrangements (MLLr) in MV4-11, MOLM-13 and THP-1 cells. We found that JOA could significantly inhibit the proliferation of MOLM-13, MV4-11 and THP-1 cells. Moreover, JOA promoted cell differentiation coupled with cell-cycle exit at G0/G1 and inhibited the colony- forming capacity of these cells. We showed that the anti-proliferative effect of JOA attributed to cell differentiation is most likely through the martens tretinoin response up pathway in the MOLM-13 cell line, and the hematopoietic cell lineage pathway by the inhibition of c-KIT expression and cell adhesion pathway in the THP-1 cell line. Our findings suggest that JOA could be a novel therapeutic agent against human MLLr acute myeloid leukemia.

• Authors: Mei Qu, Yu Duan, Min Zhao, Zhanju Wang, Mengjie Zhao, Yao Zhao, Haihua Wang, Yu Ke, Ying Liu, Hong-Min Liu, Liuya Wei, Zhenbo Hu
• Journal: Frontiers in oncology (Front Oncol) Vol. 11 Pg. 659720 ( 2021) ISSN: 2234-943X [Print] Switzerland
• PMID: 33842376 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Qu, Duan, Zhao, Wang, Zhao, Zhao, Wang, Ke, Liu, Liu, Wei and Hu.