ABT-737 is a useful component of combinatory chemotherapies for chronic myeloid leukaemias with diverse drug-resistance mechanisms
- Author(s)
- Kuroda, J; Kimura, S; Andreeff, M; Ashihara, E; Kamitsuji, Y; Yokota, A; Kawata, E; Takeuchi, M; Tanaka, R; Murotani, Y; Matsumoto, Y; Tanaka, H; Strasser, A; Taniwaki, M; Maekawa, T;
- Details
- Publication Year 2008-01,Volume 140,Issue #2,Page 181-190
- Journal Title
- BRITISH JOURNAL OF HAEMATOLOGY
- Publication Type
- Journal Article
- Abstract
- The effect of ABT-737, a BH3-mimicking inhibitor for anti-apoptotic Bcl-2 and Bcl-X(L), but not Mcl-1, against Bcr-Abl-positive (Bcr-Abl(+)) leukaemic cells was examined. ABT-737 potently induced apoptosis in Bcr-Abl(+) chronic myeloid leukaemia (CML) cell lines and primary CML samples in vitro and prolonged the survival of mice xenografted with BV173 cells, a CML cell line. Higher expression of anti-apoptotic Bcl-2 proteins reduced cell killing by ABT-737 in each cell line, but there was no correlation between the sensitivities to ABT-737 and the specific expression patterns of Bcl-2 family proteins among cell lines. Thus, the cell killing effect of ABT-737 must be determined not only by the expression patterns of Bcl-2 family proteins but also by other mechanisms, such as high expression of Bcr-Abl, or a drug-efflux pump, in CML cells. ABT-737 augmented the cell killing effect of imatinib in Bcr-Abl(+) cells with diverse drug-resistance mechanisms unless leukaemic cells harboured imatinib-insensitive Abl kinase domain mutations, such as T315I. The combination of homoharringtonine that reduces Mcl-1 enhanced the killing by ABT-737 strongly in Bcr-Abl(+) cells even with T315I mutation. These results suggest that ABT-737 is a useful component of chemotherapies for CML with diverse drug-resistance mechanisms.
- Publisher
- WILEY-BLACKWELL
- Keywords
- TYROSINE KINASE INHIBITOR; BH3 MIMETIC ABT-737; CHRONIC MYELOGENOUS LEUKEMIA; IMATINIB MESYLATE; DOMAIN MUTATIONS; BCL-2 PROTEINS; CELL-LINE; APOPTOSIS; EXPRESSION; THERAPY
- Publisher's Version
- https://doi.org/10.1111/j.1365-2141.2007.06899.x
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- Refer to copyright notice on published article.
Creation Date: 2008-01-01 12:00:00