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ABT‐737 is a useful component of combinatory chemotherapies for chronic myeloid leukaemias with diverse drug‐resistance mechanisms
Author(s) -
Kuroda Junya,
Kimura Shinya,
Andreeff Michael,
Ashihara Eishi,
Kamitsuji Yuri,
Yokota Asumi,
Kawata Eri,
Takeuchi Miki,
Tanaka Ruriko,
Murotani Yoshihide,
Matsumoto Yosuke,
Tanaka Hideo,
Strasser Andreas,
Taniwaki Masafumi,
Maekawa Taira
Publication year - 2008
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2007.06899.x
Subject(s) - homoharringtonine , imatinib , myeloid leukemia , cancer research , cell culture , abl , myeloid , apoptosis , dasatinib , biology , philadelphia chromosome , tyrosine kinase , microbiology and biotechnology , signal transduction , chromosomal translocation , genetics , gene
Summary 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.