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

  • Sun, Xiaoyan (Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine) ;
  • Cai, Xueting (Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine) ;
  • Yang, Jie (Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine) ;
  • Chen, Jiao (Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine) ;
  • Guo, Caixia (Key Laboratory of Genomics and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences) ;
  • Cao, Peng (Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine)
  • Received : 2016.01.25
  • Accepted : 2016.11.10
  • Published : 2016.12.31

Abstract

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.

Keywords

BCR-ABL;cantharidin;chronic myeloid leukemia;imatinib resistance

Acknowledgement

Supported by : National Natural Science Foundation of China, Natural Science Foundation of Jiangsu

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