ABT-737 is a useful component of combinatory chemotherapies for chronic myeloid leukaemias with diverse drug-resistance mechanisms.
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.
Kuroda
Junya
J
Division of Haematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan. junkuro@koto.kpu-m.ac.jp
Kimura
Shinya
S
Andreeff
Michael
M
Ashihara
Eishi
E
Kamitsuji
Yuri
Y
Yokota
Asumi
A
Kawata
Eri
E
Takeuchi
Miki
M
Tanaka
Ruriko
R
Murotani
Yoshihide
Y
Matsumoto
Yosuke
Y
Tanaka
Hideo
H
Strasser
Andreas
A
Taniwaki
Masafumi
M
Maekawa
Taira
T
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm; D006248:Harringtonines / Q000494:pharmacology; D000077863:Homoharringtonine; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000473:pathology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009596:Nitrophenols / Q000494:pharmacology* / Q000627:therapeutic use; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D016019:Survival Analysis; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
C501332:ABT-737; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D001713:Biphenyl Compounds; D006248:Harringtonines; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D000077863:Homoharringtonine