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The synthetic heat shock protein 90 (Hsp90) inhibitor EC141 induces degradation of Bcr-Abl p190 protein and apoptosis of Ph-positive acute lymphoblastic leukemia cells

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Summary

The prognosis of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) is poor. Chemotherapy is rarely curative and tyrosine kinase inhibitors (TKIs) induce only transient responses. Heat shock protein 90 (Hsp90) is a chaperone protein that is important in signal transduction, cell cycle control, and transcription regulation in both normal and leukemia cells. In the current study, we tested the growth inhibitory and apoptotic effects of a novel Hsp90 inhibitor, EC141 on the Ph+ ALL lines Z-119, Z-181, and Z-33, as well as primary bone marrow-derived blasts from patients with newly diagnosed Ph+ ALL. We found that EC141 inhibited the growth of Ph+ ALL cells in a concentration-dependent manner with IC50 ranged from 1 to 10 nM. EC141 also inhibited the proliferation of primary bone marrow-derived blasts using the ALL blast colony assay. EC141 down-regulated Hsp90 and up-regulated Hsp70 protein levels, inhibited CrkL phosphorylation, and induced degradation of Bcr-Abl p190 protein through ubiquitin-dependent proteasomal pathway. Furthermore, exposure of Ph+ ALL cells to EC141 resulted in activation of caspase-3, cleavage of poly (ADP-ribose) polymerase (PARP), and induction of apoptosis. In conclusion, our data suggest that EC141 is a potent Hsp90 inhibitor with activity against Ph+ ALL. Further studies to investigate the anticancer effect of EC141 either as a single agent, or in combination in Ph+ ALL and other hematological malignancies are warranted.

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Acknowledgments

We thank Biogen Idec. for providing EC141 for these studies, and Donald R. Norwood from the Department of Scientific Publication at the M.D. Anderson Cancer Center for editing the manuscript.

Disclosure of Potential Conflicts of Interest

There is no conflict of interest to disclose.

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Authors and Affiliations

  1. Department of Leukemia, Unit 428, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA

    Wei-Gang Tong, Zeev Estrov, Yongtao Wang, Susan O’Brien, Stefan Faderl, David M. Harris, Quin Van Pham, Inbal Hazan-Halevy, Zhiming Liu, Patricia Koch, Hagop Kantarjian, Michael J. Keating & Alessandra Ferrajoli

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  1. Wei-Gang Tong
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  2. Zeev Estrov
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Correspondence to Alessandra Ferrajoli.

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Tong, WG., Estrov, Z., Wang, Y. et al. The synthetic heat shock protein 90 (Hsp90) inhibitor EC141 induces degradation of Bcr-Abl p190 protein and apoptosis of Ph-positive acute lymphoblastic leukemia cells. Invest New Drugs 29, 1206–1212 (2011). https://doi.org/10.1007/s10637-010-9465-8

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