Inhibition of the Pan-Bcl-2 Family by the Small Molecule GX15-070 Induces Apoptosis in Mantle Cell Lymphoma (MCL) Cells and Enhances the Activity of Two Proteasome Inhibitors (NPI-0052 and Bortezomib), and Doxorubicin Chemotherapy.

Mantle cell lymphoma (MCL) accounts for 6–8% of all non-Hodgkin lymphomas (NHLs). It is an aggressive lymphoma with a poor prognosis--it is generally considered incurable with conventional treatments, and median survival is 3–4 years with a 10-year survival of only 10–15%. There is no accepted standard of care and effective treatments are greatly needed. Bcl-2 family proteins are important regulators of the intrinsic apoptotic pathway and are involved in oncogenesis and chemoresistance of a variety of tumor types, including lymphoma. Antiapoptotic proteins of the Bcl-2 family are overexpressed in mantle cell lymphoma (MCL) cells and may be responsible, in part, for drug resistance. GX15-070 is a small-molecule antagonist of the BH3-binding groove of the Bcl-2 family of proteins, and is currently in Phase I clinical trials. Consequently, we determined the activity of GX15-070 in 3 MCL cell lines (Jeko-1, Mino, and SP53). Cell viability was determined by MTS assay, apoptosis by Annexin-V binding and FACS analysis, and molecular changes by western blot. GX15-070 induced apoptosis in all three MCL cell lines in a dose and time-dependent manner. In the SP53 cell line, GX15-070 decreased MCL-1 and Bak levels, increased Bax and cleaved caspase 3. Furthermore, GX15-070 activated both the extrinsic and intrinsic apoptotic pathway as evident by cleavage of caspase 8, 9, and Bid. Both bortezomib and the novel proteasome inhibitor NPI-0052 induced single agent antiproliferative activity in MCL. GX15-070 enhanced the effect of both proteasome inhibitors. Additionally, GX15-070 showed an additive effect with doxorubicin. These studies suggest that GX15-070 may have a therapeutic value in MCL either alone or in combination with proteasome inhibitors or chemotherapy.