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http://dx.doi.org/10.14348/molcells.2016.0023

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)
Publication Information
Molecules and Cells / v.39, no.12, 2016 , pp. 869-876 More about this Journal
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;
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1 Shi, X., Chen, X., Li, X., Lan, X., Zhao, C., Liu, S., Huang, H., Liu, N., Liao, S., Song, W., et al. (2014). Gambogic acid induces apoptosis in imatinib-resistant chronic myeloid leukemia cells via inducing proteasome inhibition and caspase-dependent Bcr-Abl downregulation. Clin. Cancer Res. 20, 151-163.   DOI
2 Li, W., Chen, Z., Gong, F.R., Zong, Y., Chen, K., Li, D.M., Yin, H., Duan, W.M., Miao, Y., Tao, M., et al. (2011a). Growth of the pancreatic cancer cell line PANC-1 is inhibited by protein phosphatase 2A inhibitors through over activation of the c-Jun Nterminal kinase pathway. Eur. J. Cancer 47, 2654-2664.   DOI
3 Li, W., Chen, Z., Zong, Y., Gong, F.R., Zhu, Y., Zhu, Y., Lv, J., Zhang, J., Xie, L., Sun, Y., et al. (2011b). PP2A inhibitors induce apoptosis in pancreatic cancer cell line PANC-1 through persistent phosphorylation of $IKK{\alpha}$ and sustained activation of the NF-${\kappa}B$ pathway. Cancer Lett. 304, 117-127.   DOI
4 Li, W., Xie, L., Chen, Z., Zhu, Y., Sun, Y., Miao, Y., Xu, Z., and Han, X. (2010). Cantharidin, a potent and selective PP2A inhibitor, induces an oxidative stress-independent growth inhibition of pancreatic cancer cells through G2/M cell-cycle arrest and apoptosis. Cancer Sci. 101, 1226-1233.   DOI
5 Shou, L.M., Zhang, Q.Y., Li, W., Xie, X., Chen, K., Lian, L., Li, Z.Y., Gong, F.R., Dai, K.S., Mao, Y.X., et al. (2013). Cantharidin and norcantharidin inhibit the ability of MCF-7 cells to adhere to platelets via protein kinase C pathway-dependent downregulation of ${\alpha}2$ integrin. Oncol. Rep. 30, 1059-1066.   DOI
6 Su, C.C., Liu, S.H., Lee, K.I., Huang, K.T., Lu, T.H., Fang, K.M., Wu, C.C., Yen, C.C., Lai, C.H., Su, Y.C., et al. (2015) Cantharidin induces apoptosis through the Calcium/PKC-regulated endoplasmic reticulum stress pathway in human bladder cancer cells. Am. J. Chin. Med. 43, 581-600.   DOI
7 Tian, X., Zeng, G., Li, X., Wu, Z., and Wang, L. (2015). Cantharidin inhibits cell proliferation and promotes apoptosis in tongue squamous cell carcinoma through suppression of miR-214 and regulation of p53 and Bcl-2/Bax. Oncol. Rep. 33, 3061-3068.   DOI
8 Wang, G.S. (1989). Medical uses of mylabris in ancient China and recent studies. J. Ethnopharmacol. 26, 147-162.   DOI
9 Wolanin, K., Magalska, A., Mosieniak, G., Klinger, R., McKenna, S., Vejda, S., Sikora, E., and Piwocka, K. (2006). Curcumin affects components of the chromosomal passenger complex and induces mitotic catastrophe in apoptosis-resistant Bcr-Ablexpressing cells. Mol. Cancer Res. 4, 457-469.   DOI
10 Wu, M.Y., Xie, X., Xu, Z.K., Xie, L., Chen, Z., Shou, L.M., Gong, F.R., Xie, Y.F., Li, W., and Tao, M. (2014). PP2A inhibitors suppress migration and growth of PANC-1 pancreatic cancer cells through inhibition on the $Wnt/{\beta}$-catenin pathway by phosphorylation and degradation of ${\beta}$-catenin. Oncol. Rep. 32, 513-522.   DOI
11 Xiao D., Zeng Y., and Singh S.V. (2009). Diallyl trisulfide-induced apoptosis in human cancer cells is linked to checkpoint kinase 1-mediated mitotic arrest. Mol. Carcinog. 48, 1018-1029.   DOI
12 Apperley, J.F. (2015). Chronic myeloid leukaemia. Lancet 385, 1447-1459.   DOI
13 Baselga, J., and Arribas, J. (2004). Treating cancer's kinase 'addiction'. Nat. Med. 10, 786-787.   DOI
14 Bixby, D., and Talpaz, M. (2010). Seeking the causes and solutions to imatinib-resistance in chronic myeloid leukemia. Leukemia 25, 7-22.
15 Blakemore, L.M., Boes, C., Cordell, R., and Manson, M.M. (2013). Curcumin-induced mitotic arrest is characterized by spindle abnormalities, defects in chromosomal congression and DNA damage. Carcinogenesis 34, 351-360.   DOI
16 Zhang, W., Ma, Y.Z., Song, L., Wang, C.H., Qi, T.G., and Shao, G.R. (2014). Effect of cantharidins in chemotherapy for hepatoma: a retrospective cohort study. Am. J. Chin. Med. 42, 561-567.   DOI
17 Bonness, K., Aragon, I.V., Rutland, B., Ofori-Acquah, S., Dean, N.M., and Honkanen, R.E. (2006). Cantharidin-induced mitotic arrest is associated with the formation of aberrant mitotic spindles and lagging chromosomes resulting, in part, from the suppression of PP2A alpha. Mol. Cancer Ther. 5, 2727-2736.   DOI
18 Chen, X., Shi, X., Zhao, C., Li, X., Lan, X., Liu, S., Huang, H., Liu, N., Liao, S., Zang, D., et al. (2014). Anti-rheumatic agent auranofin induced apoptosis in chronic myeloid leukemia cells resistant to imatinib through both Bcr/Abl-dependent and - independent mechanisms. Oncotarget 5, 9118-9132.   DOI
19 Crosio, C., Fimia, G.M., Loury, R., Kimura, M., Okano, Y., Zhou, H., Sen, S., Allis, C.D., and Sassone-Corsi, P. (2002). Mitotic phosphorylation of histone H3: spatio-temporal regulation by mammalian Aurora kinases. Mol. Cell Biol. 22, 874-885.   DOI
20 Danial, N.N., and Rothman, P. (2000). JAK-STAT signaling activated by Abl oncogenes. Oncogene 19, 2523-2531.   DOI
21 Deininger, M.W., Goldman, J.M., and Melo, J.V. (2000). The molecular biology of chronic myeloid leukemia. Blood 96, 3343-3356.
22 Deininger, M., Buchdunger, E., and Druker, B.J. (2005). The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood 105, 2640-2653.   DOI
23 Gautier, J., Solomon, M.J., Booher, R.N., Bazan, J.F., and Kirschner, M.W. (1991). cdc25 is a specific tyrosine phosphatase that directly activates p34cdc2. Cell 67, 197-211.   DOI
24 Gong, F.R., Wu, M.Y., Shen, M., Zhi, Q., Xu, Z.K., Wang, R., Wang, W.J., Zong, Y., Li, Z.L., Wu, Y., et al. (2015). PP2A inhibitors arrest G2/M transition through JNK/Sp1-dependent downregulation of CDK1 and autophagy-dependent up-regulation of p21. Oncotarget 6, 18469-18483.   DOI
25 Gesbert, F., Sellers, W.R., Signoretti, S., Loda, M., and Griffin, J.D. (2000). BCR/ABL regulates expression of the cyclin-dependent kinase inhibitor p27Kip1 through the phosphatidylinositol 3-Kinase/AKT pathway. J. Biol. Chem. 275, 39223-39230.   DOI
26 Han, W., Wang, S., Liang, R., Wang, L., Chen, M., Li H., and Wang, Y. (2013). Non-ionic surfactant vesicles simultaneously enhance antitumor activity and reduce the toxicity of cantharidin. Int. J. Nanomedicine 8, 2187-2196.
27 Hochhaus, A., O'Brien, S.G., Guilhot, F., Druker, B.J., Branford, S., Foroni, L., Goldman, J.M., Müller, M.C., Radich, J.P., Rudoltz, M., et al. (2009). Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia 23, 1054-1061.   DOI
28 Hsia, T.C., Yu, C.C., Hsu, S.C., Tang, N.Y., Lu, H.F., Huang, Y.P., Wu, S.H., Lin, J.G., and Chung, J.G. (2014). Cantharidin induces apoptosis of H460 human lung cancer cells through mitochondria-dependent pathways. Int. J. Oncol. 45, 245-254.   DOI
29 Hsia, T.C., Lin, J.H., Hsu, S.C., Tang, N.Y., Lu, H.F., Wu, S.H., Lin, J.G., and Chung, J.G. (2015). Cantharidin induces DNA damage and inhibits DNA repair-associated protein levels in NCI-H460 human lung cancer cells. Environ. Toxicol. 30, 1135-1143.   DOI
30 Hsiao, Y.P., Tsai, C.H., Wu, P.P., Hsu, S.C., Liu, H.C., Huang, Y.P., Yang, J.H., and Chung, J.G. (2014). Cantharidin induces G2/M phase arrest by inhibition of Cdc25c and Cyclin A and triggers apoptosis through reactive oxygen species and the mitochondriadependent pathways of A375.S2 human melanoma cells. Int. J. Oncol. 45, 2393-2402.   DOI
31 Huang, W.W., Ko, S.W., Tsai, H.Y., Chung, J.G., Chiang, J.H., Chen, K.T., Chen, Y.C., Chen, H.Y., Chen, Y.F., and Yang, J.S. (2011). 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. Int. J. Oncol. 38, 1067-1073.
32 Li, C.C., Yu, F.S., Fan, M.J., Chen, Y.Y., Lien, J.C., Chou, Y.C., Lu, H.F., Tang, N.Y., Peng, S.F., Huang, W.W., et al. (2016). Anticancer effects of cantharidin in A431 human skin cancer (Epidermoid carcinoma) cells in vitro and in vivo. Environ. Toxicol. 2016 doi: 10.1002/tox.22273 (in press).   DOI
33 Lu, Z., Jin, Y., Qiu, L., Lai, Y., and Pan, J. (2010). Celastrol, a novel HSP90 inhibitor, depletes Bcr-Abl and induces apoptosis in imatinib-resistant chronic myelogenous leukemia cells harboring T315I mutation. Cancer Lett. 290, 182-191.   DOI
34 Lugo, T.G., Pendergast, A.M., Muller, A.J., and Witte, O.N. (1990). Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science 247, 1079-1082.   DOI
35 Neviani, P., Santhanam, R., Trotta, R., Notari, M., Blaser, B.W., Liu, S., Mao, H., Chang, J.S., Galietta, A., Uttam, A., et al. (2005). The tumor suppressor PP2A is functionally inactivated in blast crisis CML through the inhibitory activity of the BCR/ABLregulated SET protein. Cancer Cell 8, 355-336.   DOI
36 Norbury, C., Blow, J., and Nurse P. (1991). Regulatory phosphorylation of the p34cdc2 protein kinase in vertebrates. EMBO J. 10, 3321-3329.
37 Pane, F., Frigeri, F., Sindona, M., Luciano, L., Ferrara, F., Cimino, R., Meloni, G., Saglio, G., Salvatore, F., and Rotoli, B. (1996). Neutrophilic-chronic myeloid leukemia: a distinct disease with a specific molecular marker (BCR/ABL with C3/A2 junction). Blood. 88, 2410-2414.
38 Sanchez, I., and Dynlacht, B.D. (2005). New insights into cyclins, CDKs, and cell cycle control. Semin. Cell Dev. Biol. 16, 311-321.   DOI
39 Huang, Y.P., Ni, C.H., Lu, C.C., Chiang, J.H., Yang, J.S., Ko, Y.C., Lin, J.P., Kuo, J.H., Chang, S.J., and Chung, J.G. (2013). Suppressions of migration and invasion by cantharidin in TSGH-8301 human bladder carcinoma cells through the inhibitions of matrix metalloproteinase-2/-9 signaling. Evid. Based Complement Alternat. Med. eCAM 2013, 190281.
40 Kuo, J.H., Chu, Y.L., Yang, J.S., Lin, J.P., Lai, K.C., Kuo, H.M., Hsia, T.C., and Chung, J.G. (2010). Cantharidin induces apoptosis in human bladder cancer TSGH 8301 cells through mitochondriadependent signal pathways. Int. J. Oncol. 37, 1243-1250.
41 Kuo, J.H., Shih, T.Y., Lin, J.P., Lai, K.C., Lin, M.L., Yang, M.D., and Chung, J.G. (2015). Cantharidin induces DNA damage and inhibits DNA repair-associated protein expressions in TSGH8301 human bladder cancer cell. Anticancer Res. 35, 795-804.