Cancer Therapy: Preclinical ABT-737 Induces Apoptosis in Mantle Cell Lymphoma Cells with a Bcl-2/Mcl-1 Profile and Synergizes with Other Antineoplastic Agents

Purpose: Mantle cell lymphoma (MCL) is considered to be incurable. ABT-737 is a BH3 mimetic that targets Bcl-2, which is overexpressed in MCL and implicated in drug resistance. The present work investigated the antitumor effect of ABT-737. Experimental Design: Six MCL cell lines and primary MCL cells (n1⁄4 13) were used. Sensitivity to ABT737 was assessed, and expression levels of Bcl-2 and Mcl-1 were analyzed. Finally, ABT-737 was combined with other cytotoxic agents to promote tailored therapy. Results: MINO and GRANTA-519 cell lines were highly sensitive to ABT-737 [the median lethal dose (LD50) 1⁄4 20 and 80 nmol/L, respectively], whereas other cell lines were resistant. In primary MCL cells, 46% of patients’ samples were sensitive to ABT-737. The analysis of protein expression levels revealed that both sensitive cell lines and primary MCL cells could be characterized by a Bcl-2/Mcl-1 profile, whereas resistantMCL cells contained high levels ofMcl-1. ABT-737 induced a rapid disruption of both Bcl2/Bax and Bcl-2/Bik complexes. In addition, silencing of Mcl-1 by siRNA sensitized MCL cell lines to ABT737. Similarly, flavopiridol, which induces Mcl-1 downregulation, in combination with ABT-737 led to a synergistic anti-MCL effect in ABT-737–resistant cell lines. This synergy was also observed when ABT-737 was combined with either bortezomib or cytarabine. Conclusions: The present work shows that ABT-737 induces strong apoptosis in MCL cells expressing a Bcl-2/Mcl-1 profile. In ABT-737–resistant MCL cells, downregulation of Mcl-1 overcomes Mcl-1–induced resistance and synergizes ABT-737 effects. Our results strongly support the use of ABT737 according to the Bcl-2/Mcl-1 tumor cell profiles in the treatment of MCL. Clin Cancer Res; 17(18);