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
相关论文
共 41 条
[11]   The molecular biology of chronic myeloid leukemia [J].
Deininger, MWN ;
Goldman, JM ;
Melo, JV .
BLOOD, 2000, 96 (10) :3343-3356
[12]   CDC25 IS A SPECIFIC TYROSINE PHOSPHATASE THAT DIRECTLY ACTIVATES P34CDC2 [J].
GAUTIER, J ;
SOLOMON, MJ ;
BOOHER, RN ;
BAZAN, JF ;
KIRSCHNER, MW .
CELL, 1991, 67 (01) :197-211
[13]   BCR/ABL regulates expression of the cyclin-dependent kinase inhibitor p27Kip1 through the phosphatidylinositol 3-kinase/AKT pathway [J].
Gesbert, F ;
Sellers, WR ;
Signoretti, S ;
Loda, M ;
Griffin, JD .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (50) :39223-39230
[14]   Making better maize plants for sustainable grain production in a changing climate [J].
Gong, Fangping ;
Wu, Xiaolin ;
Zhang, Huiyong ;
Chen, Yanhui ;
Wang, Wei .
FRONTIERS IN PLANT SCIENCE, 2015, 6
[15]   Non-ionic surfactant vesicles simultaneously enhance antitumor activity and reduce the toxicity of cantharidin [J].
Han, Wei ;
Wang, Shengpeng ;
Liang, Rixin ;
Wang, Lan ;
Chen, Meiwan ;
Li, Hui ;
Wang, Yitao .
INTERNATIONAL JOURNAL OF NANOMEDICINE, 2013, 8 :2187-2196
[16]   Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia [J].
Hochhaus, A. ;
O'Brien, S. G. ;
Guilhot, F. ;
Druker, B. J. ;
Branford, S. ;
Foroni, L. ;
Goldman, J. M. ;
Mueller, M. C. ;
Radich, J. P. ;
Rudoltz, M. ;
Mone, M. ;
Gathmann, I. ;
Hughes, T. P. ;
Larson, R. A. .
LEUKEMIA, 2009, 23 (06) :1054-1061
[17]   Cantharidin induces DNA damage and inhibits DNA repair-associated protein levels in NCI-H460 human lung cancer cells [J].
Hsia, Te-Chun ;
Lin, Ju-Hwa ;
Hsu, Shu-Chun ;
Tang, Nou-Ying ;
Lu, Hsu-Feng ;
Wu, Shin-Hwar ;
Lin, Jaung-Geng ;
Chung, Jing-Gung .
ENVIRONMENTAL TOXICOLOGY, 2015, 30 (10) :1135-1143
[18]   Cantharidin induces apoptosis of H460 human lung cancer cells through mitochondria-dependent pathways [J].
Hsia, Te-Chun ;
Yu, Chien-Chih ;
Hsu, Shu-Chun ;
Tang, Nou-Ying ;
Lu, Hsu-Feng ;
Huang, Yi-Ping ;
Wu, Shin-Hwar ;
Lin, Jaung-Geng ;
Chung, Jing-Gung .
INTERNATIONAL JOURNAL OF ONCOLOGY, 2014, 45 (01) :245-254
[19]   Cantharidin induces G2/M phase arrest by inhibition of Cdc25c and Cyclin A and triggers apoptosis through reactive oxygen species and the mitochondria-dependent pathways of A375.S2 human melanoma cells [J].
Hsiao, Yu-Ping ;
Tsai, Chung-Hung ;
Wu, Ping-Ping ;
Hsu, Shu-Chun ;
Liu, Hsin-Chung ;
Huang, Yi-Ping ;
Yang, Jen-Hung ;
Chung, Jing-Gung .
INTERNATIONAL JOURNAL OF ONCOLOGY, 2014, 45 (06) :2393-2402
[20]   Cantharidin induces G2/M phase arrest and apoptosis in human colorectal cancer colo 205 cells through inhibition of CDK1 activity and caspase-dependent signaling pathways [J].
Huang, Wen-Wen ;
Ko, Shih-Wei ;
Tsai, Huei-Yann ;
Chung, Jing-Gung ;
Chiang, Jo-Hua ;
Chen, Kuan-Tin ;
Chen, Yen-Chen ;
Chen, Hung-Yi ;
Chen, Yuh-Fung ;
Yang, Jai-Sing .
INTERNATIONAL JOURNAL OF ONCOLOGY, 2011, 38 (04) :1067-1073
12345