Abstract
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. 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. 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. 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.
Highlights
Sensitivity of mantle cell lymphoma (MCL) cell lines to ABT-737 The sensitivity of MCL cell lines to ABT-737 was investigated in normal culture conditions
The present study evaluated the antineoplastic activity of ABT-737 in MCL cells
It shows that MCL cells are quite heterogeneous with regard to their sensitivity to ABT-737
Summary
The presence of Bax or Bak is required to mediate mitochondrial damage These multidomain proapoptotic family members have to be activated to oligomerize; subsequently, oligomers form pores in the mitochondrial outer membrane. Previous studies have shown that ABT737 is effective as a single agent against some leukemia/ lymphoma cell lines both in vitro and in vivo [11, 15,16,17] This present study was focused on the antitumoral effect of ABT-737 in MCL. We aimed to identify prognostic biomarkers that may predict MCL tumor cell responses to ABT-737. Using this approach, we have developed a rationale for ABT-737–based tailored therapeutic strategies in MCL
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