Abstract 2008: Broad spectrum BH3 mimetic BI-97D6 induces apoptosis of acute myeloid leukemia cells even when co-cultured with supporting stromal cells (2012)

Abstract The BCL2 family of proteins contains members that possess potent anti-apoptotic function (e.g. BCL2, MCL-1) as well as pro-death members (e.g. BAX, BIM). Aberrant expression of anti-apoptotic members such as BCL2 or suppression of pro-apoptotic members such as BAX or BIM can lead to tumor formation and promote resistance to therapy in many types of cancer including Acute Myeloid Leukemia (AML). A recent model of tumorigenesis/chemoresistance suggests cancer cells become dependent on pro-survival molecules including BCL2 and MCL-1. This model suggests that the “addicted” malignant cells can be eliminated by targeting the survival molecule that supports the tumor cell. Recent efforts to target a broad group of BCL2 family members has evolved using small molecule inhibitors to target the BH3 domain since the association between the two groups of BCL2 family members involves this domain. While compounds including ABT-737 have shown promise for treatment of some cancers, the compound binds poorly to MCL-1 and related BCL2 family members such as BCL2A1 and thus cells that rely on these anti-apoptotic BCL2 family members display resistance to the compound. Furthermore, we and others have recently found that ABT-737 can promote MCL-1 expression likely via a mechanism involving ERK. A superior approach would be to develop a single BH-3 mimetic agent that is effective at inhibiting MCL-1 as well as other BCL2 family members. In the current study, we examine if the Apogossypol analog BI-97D6 (Wei et al, J Med Chem. 2010), which has efficacy against MCL-1 as well as BCL2 and BCL-XL, has potential an effective anti-leukemia agent. BI-97D6 is novel as an Apogossypol compound since it acts as a true BH3 mimetic. Other gossypol and apopgossypol compounds have been shown to promote death by ER stress mediated mechanisms. In AML cells, we found that BI-97D6 does not induce CHOP expression or JNK activation, which are features of ER stress induction. Bax/Bak knock out MEFs were resistant BI-97D6, indicating that the drug acts specifically as a BH3 mimetic. BI-97D6 interferes with the association of MCL-1 with BIM and induces the death conformation of BAX in OCI-AML3 cells. The drug is effective at killing a variety of AML derived cell lines with IC50 values at 72 hours in the nanomolar range (i.e. below 50 nM for OCI-AML3, HL60, and MOLM13). Bone marrow-derived mesenchymal stromal cells (BM MSC) have been shown to protect leukemia cells from conventional chemotherapy agents such as AraC. There was no difference in BI-97D6 mediated killing of OCI-AML3 cells whether the cells were treated in co-culture with BM MSC or alone. These results suggest that BI-97D6 could have efficacy against AML, regardless of MCL-1 levels, which is not diminished by the protective effects of the BM microenvironment. Further mechanistic details are under investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2008. doi:1538-7445.AM2012-2008