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
- Author(s)
- Kuroda, J; Kimura, S; Strasser, A; Andreeff, M; O'Reilly, LA; Ashihara, E; Kamitsuji, Y; Yokota, A; Kawata, E; Takeuchi, M; Tanaka, R; Tabe, Y; Taniwaki, M; Maekawa, T;
- Details
- Publication Year 2007-09,Volume 14,Issue #9,Page 1667-1677
- Journal Title
- CELL DEATH AND DIFFERENTIATION
- Publication Type
- Journal Article
- Abstract
- 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-X-L, greatly enhanced the apoptosis by INNO-406, even in INNO-406-less sensitive cells with Bcr-Abl point mutations except T315l 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.
- Publisher
- NATURE PUBLISHING GROUP
- Keywords
- CHRONIC MYELOID-LEUKEMIA; CHRONIC MYELOGENOUS LEUKEMIA; TYROSINE KINASE INHIBITOR; BH3 MIMETIC ABT-737; IMATINIB MESYLATE; PROTEASOME INHIBITORS; BH3-ONLY PROTEINS; CHRONIC PHASE; CELL-DEATH; RESISTANCE
- Publisher's Version
- https://doi.org/10.1038/sj.cdd.4402168
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2007-09-01 12:00:00