Journal Article Abacavir, an anti-HIV-1 drug, targets TDP1-deficient adult T cell leukemia

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.

1 ( 3 ) 2015-04-24
抗HIV-1薬の新規抗癌作用の解明に成功 -難治性血液がんである成人T細胞白血病の新規治療に期待-. 京都大学プレスリリース. 2015-04-27.
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.

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