Bcl-2-like proteins prevent cell death through expression level, post transcriptional modification, and protein-protein-interaction. Recent studies have shown that antiapoptotic Bcl-2-like members are overexpressed in many haematological malignancies. BH3 mimetics are promising anticancer agents by directly target these proteins and their interactions. S1 (8-oxo-3-thiomorpholin-4-yl-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile) is an authentic BH3 mimetic and a triple inhibitor of Bcl-2, Mcl-1, and Bcl-XL. In the present study, we found S1 exhibited a variant sensitivity with LD50 values ranging >2 logs (0.24-80.4 μM) in five established leukemia cell lines (Jurkat, K562, HL60, U937 and PTA-3920) and forty-one primary leukemic cells (including Acute myeloid leukemia (AML), Acute lymphoblastic leukemia (ALL), Chronic Myeloid Leukemia (CML), and Chronic lymphoblastic leukemia (CLL)). Through a semi-quantitative approach by analyzing western blotting bands via imaging software, it revealed that the index value phosphoralated Bcl-2 (pBcl-2) to Bcl-2 and Mcl-1 provided a highly significant linear correlation with S1 sensitivity (r = 0.69, P < 0.001 in primary cells, and r = 0.76, P = 0.05 in cell lines). In contrast, antiapoptotic Bcl-2-like protein levels, used individually or in combination could not predict S1 sensitivity. Phosphorylated Bcl-2 antagonized S1 by sequestering the Bak and Bim proteins that were released from Mcl-1 in leukemia cell lines. Furthermore, pBcl-2/Bak, pBcl-2/Bax, and pBcl-2/Bim complexes cannot be disrupted by S1. The shift of proapoptotic proteins from being complexed with Mcl-1 to being complexed with pBcl-2 is revealed for the first time, and it could be the mechanism underlying the index value described herein. This study defines the antiapoptotic role of pBcl-2 linked with the protein-protein interaction network within Bcl-2 family.

Citation Format: Yubo Liu, Zhichao Zhang. An anti-apoptotic Bcl-2 family protein index predicts the response of leukemic cells to the pan-Bcl-2 inhibitor S1. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1710. doi:10.1158/1538-7445.AM2013-1710

Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

©2013 American Association for Cancer Research
2013