Abacavir, an anti-HIV-1 drug, targets TDP1-deficient adult T cell leukemia.
Abacavir, an anti-HIV-1 drug, targets TDP1-deficient adult T cell leukemia.
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DOI：
10.1126/sciadv.1400203
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发表时间：
2015-04
期刊：
影响因子：
13.6
通讯作者：
Takaori-Kondo A
中科院分区：
文献类型：
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作者：
Tada K;Kobayashi M;Takiuchi Y;Iwai F;Sakamoto T;Nagata K;Shinohara M;Io K;Shirakawa K;Hishizawa M;Shindo K;Kadowaki N;Hirota K;Yamamoto J;Iwai S;Sasanuma H;Takeda S;Takaori-Kondo A
一种抗hiv -1药物被发现可以摧毁成人的白血病细胞。成人T细胞白血病（Adult T cell leukemia， ATL）是由人类T细胞白血病病毒1型（HTLV-1）引起的侵袭性T细胞恶性肿瘤，预后较差。我们分析了针对HIV-1的各种核苷类似物逆转录酶抑制剂（NRTIs）对ATL细胞的细胞毒性作用，发现阿巴卡韦有效且选择性地杀死ATL细胞。尽管NRTIs对宿主细胞的基因毒性很小，但治疗浓度的阿巴卡韦在ATL细胞的染色体DNA中诱导了大量DNA双链断裂（DSBs）。随着时间的推移，dsb在ATL细胞中持续存在，但在其他细胞系中不存在，表明DNA修复受损。我们发现修复酶酪氨酸- dna磷酸二酯酶1 （TDP1）的表达减少可归因于阿巴卡韦对ATL细胞的细胞毒性作用。我们还发现TDP1可以在体外从DNA末端去除阿巴卡韦。这些结果表明，TDP1表达降低的ATL细胞无法切除整合到基因组DNA中的阿巴卡韦，从而导致不可修复的dsb。基于上述机制，我们建议阿巴卡韦作为一种有前景的ATL化疗药物。
An anti–HIV-1 drug is found to destroy leukemia cells in adults. Adult T cell leukemia (ATL) is an aggressive T cell malignancy caused by human T cell leukemia virus type 1 (HTLV-1) and has a poor prognosis. We analyzed the cytotoxic effects of various nucleoside analog reverse transcriptase inhibitors (NRTIs) for HIV-1 on ATL cells and found that abacavir potently and selectively kills ATL cells. Although NRTIs have minimal genotoxicities on host cells, the therapeutic concentration of abacavir induced numerous DNA double-strand breaks (DSBs) in the chromosomal DNA of ATL cells. DSBs persisted over time in ATL cells but not in other cell lines, suggesting impaired DNA repair. We found that the reduced expression of tyrosyl-DNA phosphodiesterase 1 (TDP1), a repair enzyme, is attributable to the cytotoxic effect of abacavir on ATL cells. We also showed that TDP1 removes abacavir from DNA ends in vitro. These results suggest a model in which ATL cells with reduced TDP1 expression are unable to excise abacavir incorporated into genomic DNA, leading to irreparable DSBs. On the basis of the above mechanism, we propose abacavir as a promising chemotherapeutic agent for ATL.