Cantharidin Overcomes Imatinib Resistance by Depleting BCR-ABL in Chronic Myeloid Leukemia

被引：11
作者：
Sun, Xiaoyan [1 ,2 ]
Cai, Xueting [1 ,2 ]
Yang, Jie [1 ,2 ]
Chen, Jiao [1 ,2 ]
Guo, Caixia [3 ]
Cao, Peng [1 ,2 ]
机构：
[1] Nanjing Univ Chinese Med, Affiliated Hosp Integrated Tradit Chinese & Weste, Nanjing 210028, Jiangsu, Peoples R China
[2] Jiangsu Prov Acad Tradit Chinese Med, Lab Cellular & Mol Biol, Nanjing 210028, Jiangsu, Peoples R China
[3] Chinese Acad Sci, Key Lab Genom & Precis Med, China Gastrointestinal Canc Res Ctr, Beijing 100101, Peoples R China
来源：
MOLECULES AND CELLS | 2016年 / 39卷 / 12期
基金：
中国国家自然科学基金;
关键词：
BCR-ABL; cantharidin; chronic myeloid leukemia; imatinib resistance; MITOCHONDRIA-DEPENDENT PATHWAYS; INDUCED MITOTIC ARREST; G2/M PHASE ARREST; CELL-LINE PANC-1; CANCER CELLS; DOWN-REGULATION; PROTEIN-KINASE; DNA-DAMAGE; APOPTOSIS; INHIBITION;
D O I：
10.14348/molcells.2016.0023
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
Cantharidin (CTD) is an active compound isolated from the traditional Chinese medicine blister beetle and displayed anticancer properties against various types of cancer cells. However, little is known about its effect on human chronic myeloid leukemia (CML) cells, including imatinib-resistant CML cells. The objective of this study was to investigate whether CTD could overcome imatinib resistance in imatinib-resistant CML cells and to explore the possible underlying mechanisms associated with the effect. Our results showed that CTD strongly inhibited the growth of both imatinib-sensitive and imatinib-resistant CML cells. CTD induced cell cycle arrest at mitotic phase and triggered DNA damage in CML cells. The ATM/ATR inhibitor CGK733 abrogated CTD-induced mitotic arrest but promoted the cytotoxic effects of CTD. In addition, we demonstrated that CTD downregulated the expression of the BCR-ABL protein and suppressed its downstream signal transduction. Real-time quantitative PCR revealed that CTD inhibited BCR-ABL at transcriptional level. Knockdown of BCR-ABL increased the cell-killing effects of CTD in K562 cells. These findings indicated that CTD overcomes imatinib resistance through depletion of BCR-ABL. Taken together, CTD is an important new candidate agent for CML therapy.
引用
收藏
页码：869 / 876
页数：8
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