Abstract 4515: A novel obatoclax derivative is a promising agent to overcome bortezomib's resistance in acute leukemia cells

Abstract

Abstract Background: Our previous work showed that bortezomib, a reverse-inhibitor of the 26S proteasome, exerts differential cytotoxic effects to acute leukemia cells through down-regulation of phosphor-Akt (AACR 2010 abstract 1575). Interestingly, some acute leukemia cells (MOLT-3 and K562) are resistant to bortezomib. One of the resistant mechanisms of bortezomib involves the abnormality in intrinsic apoptotic pathway members, the bcl-2 family. Of particular, it has been shown that bortezomib induces upregulation of Mcl-1 and that Mcl-1 accumulation may delay bortezomib-induced apoptosis. Obatoclax, a small molecule inhibitor of pro-survival BCL-2 members, including MCL-1, synergizes with bortezomib in mantle cell lymphoma (Blood 2007) and may overcome bortezomib resistance. Here, we designed a novel Mcl-1 inhibitor deriving from obatoclax, SC-2001, to overcome the resistance. Methods: MOLT-3 and K562 cell lines were used for in vitro studies. Apoptosis was examined by both flow cytometry and Western blot. Signal transduction pathways in cells were assessed by Western Blot. Gene silencing was done by small interference RNA (siRNA). Results: MOLT-3 and K562 were resistant to bortezomib up to 100nM. Upregulation of Mcl-1 expression after bortezomib treatment were evident in these cells. Interestingly, the addition of either obatoclax or SC-2001, restored the sensitivity of K562 and MOLT-3 cells to bortezomib. SC-2001, comparing to obatoclax, exerted better efficacy in sensitivity restoration of bortezomib in association with Mcl-1 downregulation in MOLT-3 cells. Moreover, down-regulation of Mcl-1 by siRNA overcame the apoptotic resistance to bortezomib in K562 cells. These data indicate that novel Mcl-1 inhibitors could restore bortezomib sensitivity in resistant acute leukemia cells. Conclusions: a novel Mcl-1 inhibitor SC-2001, is a promising agent to overcome bortezomib's resistance in acute leukemia, further elucidating the drug mechanism regulating Mcl-1 inhibition is needed. Supported by VGHTPE 99DHA0100332 and 100DHA0100591 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4515. doi:10.1158/1538-7445.AM2011-4515