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.
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 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.
Kuroda
J
J
Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan.
Kimura
S
S
Strasser
A
A
Andreeff
M
M
O'Reilly
L A
LA
Ashihara
E
E
Kamitsuji
Y
Y
Yokota
A
A
Kawata
E
E
Takeuchi
M
M
Tanaka
R
R
Tabe
Y
Y
Taniwaki
M
M
Maekawa
T
T
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000502:physiology; D001549:Benzamides; D016227:Benzoquinones / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000378:metabolism / Q000494:pharmacology*; D001897:Boronic Acids / Q000378:metabolism / Q000494:pharmacology; D000069286:Bortezomib; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D006801:Humans; D000068877:Imatinib Mesylate; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009596:Nitrophenols / Q000378:metabolism / Q000494:pharmacology*; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051562:Proto-Oncogene Proteins c-bcr / Q000378:metabolism; D011719:Pyrazines / Q000378:metabolism / Q000494:pharmacology; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology*; D013449:Sulfonamides / Q000378:metabolism / Q000494:pharmacology*
C501332:ABT-737; D000970:Antineoplastic Agents; D001549:Benzamides; D016227:Benzoquinones; D001713:Biphenyl Compounds; D001897:Boronic Acids; D047029:Lactams, Macrocyclic; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D011743:Pyrimidines; D013449:Sulfonamides; C112765:tanespimycin; D000069286:Bortezomib; D000068877:Imatinib Mesylate; D051562:Proto-Oncogene Proteins c-bcr; C506918:bafetinib