B-cell-specific transcription factor BACH2 modifies the cytotoxic effects of anticancer drugs.
The transcription factor Bach2, a member of the CNC family of proteins, binds to the Maf recognition element (MARE) by forming homodimers or dimerizing with small Maf transcription factors. Bach2-expressing cells show reduced proliferation and undergo spontaneous cell death. The inhibition of BCR/ABL tyrosine kinase activity by STI571 in chronic myeloid leukemia (CML) cell lines and CD34+ cells from patients with CML in lymphoid crisis results in induction of BACH2 expression. We show here that BACH2 modifies the in vitro cytotoxicity of anticancer drugs. The cytotoxic effects of commonly used anticancer agents were studied by overexpression of BACH2 in RAJI lymphoid cells, a cell line that does not express endogenous BACH2. Cell growth inhibition was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. Clones overexpressing BACH2 were more sensitive to etoposide, doxorubicin, and cytarabine than control RAJI cells, whereas there were no significant differences in the sensitivity of either cells to methotrexate or vincristine. Interestingly, we found that the former drugs were oxidative stressors that induced the nuclear accumulation of BACH2. In contrast, methotrexate or vincristine did not induce production of intracellular reactive oxygen species (ROS) and nuclear accumulation of BACH2. These results, coupled with our previous data showing that BACH2 promotes oxidative stress-induced cell death, suggest that combination chemotherapy involving STI571 and anticancer drugs that produce ROS may be of benefit in the treatment of Philadelphia chromosome 1 (Ph1)-positive leukemia.
Kamio
Takuya
T
Department of Pediatrics, Hirosaki University School of Medicine, Hirosaki, Aomori 036-8563 Japan.
Toki
Tsutomu
T
Kanezaki
Rika
R
Sasaki
Shinya
S
Tandai
Satoru
S
Terui
Kiminori
K
Ikebe
Dai
D
Igarashi
Kazuhiko
K
Ito
Etsuro
E
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D000975:Antioxidants / Q000494:pharmacology; D001402:B-Lymphocytes / Q000737:chemistry; D050976:Basic-Leucine Zipper Transcription Factors; D001549:Benzamides; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D018384:Oxidative Stress / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000032:analysis / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*
D000970:Antineoplastic Agents; D000975:Antioxidants; C491123:BACH2 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D000068877:Imatinib Mesylate