title: Abacavir, an anti-HIV-1 drug, targets TDP1-deficient adult T cell leukemia.
abstract: 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.
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin-kawaracho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Tada
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin-kawaracho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin-kawaracho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Takiuchi
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin-kawaracho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Fumie
authors.initials: F
authors.lastname: Iwai
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin-kawaracho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Sakamoto
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin-kawaracho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Nagata
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin-kawaracho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Shinohara
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin-kawaracho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Io
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin-kawaracho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Shirakawa
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin-kawaracho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Hishizawa
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin-kawaracho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Shindo
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin-kawaracho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Norimitsu
authors.initials: N
authors.lastname: Kadowaki
authors.affiliation: Department of Chemistry, Graduate School of Science and Engineering, Tokyo Metropolitan University, 1-1 Minami-Osawa, Hachioji-shi, Tokyo 192-0397, Japan.
authors.forename: Kouji
authors.initials: K
authors.lastname: Hirota
authors.affiliation: Division of Chemistry, Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531, Japan.
authors.forename: Junpei
authors.initials: J
authors.lastname: Yamamoto
authors.affiliation: Division of Chemistry, Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531, Japan.
authors.forename: Shigenori
authors.initials: S
authors.lastname: Iwai
authors.affiliation: Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sasanuma
authors.affiliation: Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Shunichi
authors.initials: S
authors.lastname: Takeda
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin-kawaracho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Akifumi
authors.initials: A
authors.lastname: Takaori-Kondo
keywords: Abacavir; Adult T-cell leukemia; DNA repair; nucleoside-analog reverse-transcriptase inhibitor; tyrosyl-DNA-phosphodiesterase 1