Cyrille Touzeau 1 , Christelle Dousset , Linda Bodet , Patricia Gomez-Bougie , Stéphanie Bonnaud , Anne Moreau , Philippe Moreau , Catherine Pellat-Deceunynck , Martine Amiot , Steven Le Gouill Show Affiliations »
Abstract
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 (n = 13) were used. Sensitivity to ABT-737 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) = 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(high)/Mcl-1(low) profile, whereas resistant MCL cells contained high levels of Mcl-1. ABT-737 induced a rapid disruption of both Bcl-2/Bax and Bcl-2/Bik complexes. In addition, silencing of Mcl-1 by siRNA sensitized MCL cell lines to ABT-737. 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(high)/Mcl-1(low) 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 ABT-737 according to the Bcl-2/Mcl-1 tumor cell profiles in the treatment of MCL. ©2011 AACR.
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 (n = 13) were used. Sensitivity to ABT-737 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) = 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 (high)/Mcl-1 (low) profile, whereas resistant MCL cells contained high levels of Mcl-1 . ABT-737 induced a rapid disruption of both Bcl-2 /Bax and Bcl-2 /Bik complexes. In addition, silencing of Mcl-1 by siRNA sensitized MCL cell lines to ABT-737 . 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 (high)/Mcl-1 (low) 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 ABT-737 according to the Bcl-2 /Mcl-1 tumor cell profiles in the treatment of MCL. ©2011 AACR.
Entities: Chemical
Disease
Gene
Species
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Year: 2011
PMID： 21821698 DOI： 10.1158/1078-0432.CCR-11-0955
Source DB: PubMed Journal: Clin Cancer Res ISSN： 1078-0432 Impact factor: 12.531