1. ¹Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine (SJU-SM, formerly Shanghai Second Medical University), Shanghai, China
2. ²Department of Hematology, Rui-Jin Hospital, SJU-SM
3. ³Division of Functional Genomics of Cancer, Institute of Health Science, SJTU-SM/Shanghai Institutes for Biological Sciences, Shanghai, China

Correspondence: Dr G-Q Chen, Department of Pathophysiology, Shanghai Jiao-Tong University School of Medicine. No. 280, Chong-Qing South Road, Shanghai 200025, China. E-mail: chengq@shsmu.edu.cn or gqchen@sibs.ac.cn

⁴These authors equally contributed to this work

Received 16 January 2007; Revised 23 March 2007; Accepted 11 April 2007; Published online 10 May 2007.

Abstract

Arsenic trioxide (ATO) and proteasome inhibitor bortezomib have been successfully applied to treat acute promyelocytic leukemia (APL) and multiple myeloma (MM), respectively. Their synergistic effects with other anticancer drugs have been widely studied. Here, we investigated the potential synergy of bortezomib and ATO on Bcr-Abl⁺ leukemic K562 cells. The results showed that cotreatment of bortezomib at 32 nM, a half concentration for growth arrest, and ATO at 1 M, a dose with no significant cytotoxic effect, synergistically induced apoptosis in the cell line, followed by enhanced mitochondrial dysfunction, release of cytochrome c and apoptosis-inducing factor, caspase-3 cleavage and degradation of poly-adenosine diphosphate-ribose polymerase together with the decreased Bcr-Abl protein. These two drugs synergistically induced proteolytic activation of protein kinase C (PKC) with enhanced activation of two mitogen-activated protein kinases phospho-c-Jun NH₂-terminal kinase and p38. The specific PKC inhibitor rottlerin markedly decreased bortezomib plus ATO-induced apoptosis, suggesting that PKC plays an important role in bortezomib plus ATO-induced apoptosis. Moreover, apoptosis synergy of bortezomib and ATO could also be seen in some kinds of acute leukemic cell lines and primary cells. Totally, our results indicate that combined regimen of bortezomib and ATO might be a potential therapeutic remedy for the treatment of leukemia.