TY - JOUR
T1 - Apoptosis-based dual molecular targeting by INNO-406, a second-generation Bcr-Abl inhibitor, and ABT-737, an inhibitor of antiapoptotic Bcl-2 proteins, against Bcr-Abl-positive leukemia
AU - Kuroda, J.
AU - Kimura, S.
AU - Strasser, A.
AU - Andreeff, M.
AU - O'Reilly, L. A.
AU - Ashihara, E.
AU - Kamitsuji, Y.
AU - Yokota, A.
AU - Kawata, E.
AU - Takeuchi, M.
AU - Tanaka, R.
AU - Tabe, Y.
AU - Taniwaki, M.
AU - Maekawa, T.
N1 - Funding Information:
Acknowledgements. We are grateful to Professor Nakahata T, Drs. Heike T (Department of Pediatrics, Kyoto University), Huang DCS, Alexander W, Bouillet P, Puthalakath H, Cragg MS, Kaufmann T, Kelly PN (all WEHI) and Nakagawa Y (Kyoto University) for their gifts of transgenic and knockout mice, reagents, scientific advice and technical support. This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, Japan Leukemia Research Fund and Yasuda Medical Figure 8 Cell death-inducing pathways utilized by INNO-406, PS-341, 17-AAG and ABT-737. ER, endoplasmic reticulum; MOMP, mitochondrial outer membrane permeabilization Research Foundation (TM), the Public Trust Haraguchi Memorial Cancer Research Fund (Tokyo, Japan), Kurozumi Medical Foundation (Tokyo, Japan), Long-Term Research Grants from the TOYOBO Biotechnology Foundation (Osaka, Japan), the Uehara Memorial Biochemical Foundation (Tokyo, Japan) (JK), Grant-in-Aid of the Japan Medical Association and the Princess Takamatsu Foundation for Cancer Research (SK) and by fellowships and grants from the National Health and Medical Research Council (Australia; program no. 257502), the Leukemia and Lymphoma Society (New York; SCOR grant no. 7015) and the National Cancer Institute (NIH, US; CA 80188 and CA 43540) (AS). Supplementary information is available at Cell Death and Differentiation’s website.
PY - 2007/9
Y1 - 2007/9
N2 - Bcr-Abl is the cause of Philadelphia-positive (Ph+) leukemias and also constitutes their principal therapeutic target, as exemplified by dramatic effects of imatinib mesylate. However, mono-targeting of Bcr-Abl does not always achieve complete leukemia eradication, and additional strategies those enable complete elimination of leukemic cells are desired to develop. Here we demonstrate that INNO-406, a much more active Bcr-Abl tyrosine kinase inhibitor than imatinib, augments the activities of several proapoptotic Bcl-2 homology (BH)3-only proteins (Bim, Bad, Bmf and Bik) and induces apoptosis in Ph+ leukemia cells via Bcl-2 family-regulated intrinsic apoptosis pathway. ABT-737, an inhibitor of antiapoptotic Bcl-2 and Bcl-XL, greatly enhanced the apoptosis by INNO-406, even in INNO-406-less sensitive cells with Bcr-Abl point mutations except T315I mutation. In contrast, co-treatment with INNO-406 and other pharmacologic inducers of those BH3-only proteins, such as 17-allylaminogeldanamycin, an heat shock protein-90 inhibitor, or PS-341, a proteasome inhibitor, did not further increase the BH3-only protein levels or sensitize leukemic cells to INNO-406-induced apoptosis, suggesting a limit to how much expression levels of BH3-only proteins can be increased by anticancer agents. Thus, double-barrelled molecular targeting for Bcr-Abl-driven oncogenic signaling and the cell protection by antiapoptotic Bcl-2 family proteins may be the rational therapeutic approach for eradicating Ph+ leukemic cells.
AB - Bcr-Abl is the cause of Philadelphia-positive (Ph+) leukemias and also constitutes their principal therapeutic target, as exemplified by dramatic effects of imatinib mesylate. However, mono-targeting of Bcr-Abl does not always achieve complete leukemia eradication, and additional strategies those enable complete elimination of leukemic cells are desired to develop. Here we demonstrate that INNO-406, a much more active Bcr-Abl tyrosine kinase inhibitor than imatinib, augments the activities of several proapoptotic Bcl-2 homology (BH)3-only proteins (Bim, Bad, Bmf and Bik) and induces apoptosis in Ph+ leukemia cells via Bcl-2 family-regulated intrinsic apoptosis pathway. ABT-737, an inhibitor of antiapoptotic Bcl-2 and Bcl-XL, greatly enhanced the apoptosis by INNO-406, even in INNO-406-less sensitive cells with Bcr-Abl point mutations except T315I mutation. In contrast, co-treatment with INNO-406 and other pharmacologic inducers of those BH3-only proteins, such as 17-allylaminogeldanamycin, an heat shock protein-90 inhibitor, or PS-341, a proteasome inhibitor, did not further increase the BH3-only protein levels or sensitize leukemic cells to INNO-406-induced apoptosis, suggesting a limit to how much expression levels of BH3-only proteins can be increased by anticancer agents. Thus, double-barrelled molecular targeting for Bcr-Abl-driven oncogenic signaling and the cell protection by antiapoptotic Bcl-2 family proteins may be the rational therapeutic approach for eradicating Ph+ leukemic cells.
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U2 - 10.1038/sj.cdd.4402168
DO - 10.1038/sj.cdd.4402168
M3 - Article
C2 - 17510658
AN - SCOPUS:34548039481
SN - 1350-9047
VL - 14
SP - 1667
EP - 1677
JO - Cell death and differentiation
JF - Cell death and differentiation
IS - 9
ER -