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

Tada, Kohei; Kobayashi, Masayuki; Takiuchi, Yoko; Iwai, Fumie; Sakamoto, Takashi; Nagata, Kayoko; Shinohara, Masanobu; Io, Katsuhiro; Shirakawa, Kotaro; Hishizawa, Masakatsu; Shindo, Keisuke; Kadowaki, Norimitsu; Hirota, Kouji; Yamamoto, Junpei; Iwai, Shigenori; Sasanuma, Hiroyuki; Takeda, Shunichi; Takaori‐Kondo, Akifumi

doi:10.1126/sciadv.1400203

Cited by 35 publications

(24 citation statements)

References 83 publications

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“…Like MMS, ABC sensitizes cells deficient in base excision repair, HR and TLS, as reported previously [ 17 ] (Figure 4 ). AZT also sensitizes isogenic mutants of the three pathways.…”

Section: Resultssupporting

confidence: 81%

“…An important pathway for the elimination of nucleotide analogs is Tyrosyl-DNA phosphodiesterase 1 (TDP1). TDP1 is capable of eliminating nucleotide analogs from 3′ end of primers [ 17 , 31 ] and also plays a role in cellular tolerance to Ara-C (Figure 4 ). This sensitivity profile of Ara-C is in stark contrast with that of FTD, which exhibited significantly higher cytotoxicity to both TLS and HR mutants in addition to POLE1 exo−/− cells.…”

Section: Resultsmentioning

confidence: 99%

“…Nonetheless, substantial quantities of anti-viral CTNAs are likely to be mis-incorporated into genomic DNA of the host by Polδ and Polε, considering that human genome is about five orders of magnitude larger than the average size of the retrovirus genome. In fact, ABC has been used for treating adult T cell leukemia (ATL), since ATL cells are unable to efficiently eliminate mis-incorporated ABC from the 3′ end of primers due to a defect in tyrosyl-DNA phosphodiesterase 1 (TDP1) [ 17 ]. An unsolved question is whether the proofreading activity of the replicative DNA polymerases are capable of efficiently eliminating nucleotide analogs as efficiently as it eliminates mis-incorporated dNTPs.…”

Section: Introductionmentioning

confidence: 99%

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The dominant role of proofreading exonuclease activity of replicative polymerase ε in cellular tolerance to cytarabine (Ara-C)

et al. 2017

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Chemotherapeutic nucleoside analogs, such as Ara-C, 5-Fluorouracil (5-FU) and Trifluridine (FTD), are frequently incorporated into DNA by the replicative DNA polymerases. However, it remains unclear how this incorporation kills cycling cells. There are two possibilities: Nucleoside analog triphosphates inhibit the replicative DNA polymerases, and/or nucleotide analogs mis-incorporated into genomic DNA interfere with the next round of DNA synthesis as replicative DNA polymerases recognize them as template DNA lesions, arresting synthesis. To address the first possibility, we selectively disrupted the proofreading exonuclease activity of DNA polymerase ε (Polε), the leading-strand replicative polymerase in avian DT40 and human TK6 cell lines. To address the second, we disrupted RAD18, a gene involved in translesion DNA synthesis, a mechanism that relieves stalled replication. Strikingly, POLE1exo−/− cells, but not RAD18−/− cells, were hypersensitive to Ara-C, while RAD18−/− cells were hypersensitive to FTD. gH2AX focus formation following a pulse of Ara-C was immediate and did not progress into the next round of replication, while gH2AX focus formation following a pulse of 5-FU and FTD was delayed to the next round of replication. Biochemical studies indicate that human proofreading-deficient Polε-exo− holoenzyme incorporates Ara-CTP, but subsequently extend from this base several times less efficiently than from intact nucleotides. Together our results suggest that Ara-C acts by blocking extension of the nascent DNA strand and is counteracted by the proofreading activity of Polε, while 5-FU and FTD are efficiently incorporated but act as replication fork blocks in the subsequent S phase, which is counteracted by translesion synthesis.

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“…Like MMS, ABC sensitizes cells deficient in base excision repair, HR and TLS, as reported previously [ 17 ] (Figure 4 ). AZT also sensitizes isogenic mutants of the three pathways.…”

Section: Resultssupporting

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The dominant role of proofreading exonuclease activity of replicative polymerase ε in cellular tolerance to cytarabine (Ara-C)

et al. 2017

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“…39 2.9 | Preparation of mouse ATL model Rapid tumor formation by the ATL-cell line in NOD/SCID mice has been previously established. 35,40,41 In brief, 5-week-old NOD/SCID mice were purchased from CLEA Japan (Tokyo, Japan). Mice were anesthetized with isoflurane, and 3 9 10 7 of ED-40515(À) cells were s.c. inoculated into the posterior cervical lesion.…”

Section: Immunoblottingmentioning

confidence: 99%

Dual inhibition of the mTORC1 and mTORC2 signaling pathways is a promising therapeutic target for adult T‐cell leukemia

et al. 2017

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Adult T‐cell leukemia (ATL) has a poor prognosis as a result of severe immunosuppression and rapid tumor progression with resistance to conventional chemotherapy. Recent integrated‐genome analysis has revealed mutations in many genes involved in the T‐cell signaling pathway, suggesting that the aberration of this pathway is an important factor in ATL pathogenesis and ATL‐cell proliferation. We screened a siRNA library to examine signaling‐pathway functionality and found that the PI3K/Akt/mTOR pathway is critical to ATL‐cell proliferation. We therefore investigated the effect of mammalian target of rapamycin (mTOR) inhibitors, including the dual inhibitors PP242 and AZD8055 and the mTORC1 inhibitors rapamycin and everolimus, on human T‐cell leukemia virus type 1 (HTLV‐1)‐infected‐cell and ATL‐cell lines. Both dual inhibitors inhibited the proliferation of all tested cell lines by inducing G1‐phase cell‐cycle arrest and subsequent cell apoptosis, whereas the effects of the 2 mTORC1 inhibitors were limited, as they did not induce cell apoptosis. In the ATL‐cell lines and in the primary ATL samples, both dual inhibitors inhibited phosphorylation of AKT at serine‐473, a target of mTORC2, as well as that of S6K, whereas the mTORC1 inhibitors only inhibited mTORC1. Furthermore, AZD8055 more significantly inhibited the in vivo growth of the ATL‐cell xenografts than did everolimus. These results indicate that the PI3K/mTOR pathway is critical to ATL‐cell proliferation and might thus be a new therapeutic target in ATL.

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“…Consistently, TDP1−/− cells are hypersensitive to the TOP1 poisoning anticancer drugs, camptothecin (CPT) and its clinical derivatives topotecan and irinotecan (9–12). TDP1 is also critical for the repair of DNA damage induced by chain terminating anticancer and antiviral drugs, such as AraC, acyclovir, zidovudine (AZT) and abacavir (11,13,14) and by DNA alkylating agents (11) owing to its 3’-nucleosidase activity (15,16). …”

Section: Introductionmentioning

confidence: 99%

TDP1 is Critical for the Repair of DNA Breaks Induced by Sapacitabine, a Nucleoside also Targeting ATM- and BRCA-Deficient Tumors

Abo

Sasanuma

Liu

et al. 2017

Molecular Cancer Therapeutics

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2'-C-cyano-2'-deoxy-1-β-D-arabino-pentofuranosylcytosine (CNDAC) is the active metabolite of the anticancer drug, sapacitabine. CNDAC is incorporated into the genome during DNA replication and subsequently undergoes beta-elimination that generates single-strand breaks with abnormal 3’-ends. Because tyrosyl-DNA phosphodiesterase 1 (TDP1) selectively hydrolyzes non-phosphorylated 3’-blocking ends, we tested its role in the repair of CNDAC-induced DNA damage. We show that cells lacking TDP1 (avian TDP1−/− DT40 cells and human TDP1 KO TSCER2 and HCT116 cells) exhibit marked hypersensitivity to CNDAC. We also identified BRCA1, FANCD2 and PCNA in the DNA repair pathways to CNDAC. Comparing CNDAC with the chemically related arabinosyl nucleoside analog, cytosine arabinoside (cytarabine, AraC) and the topoisomerase I inhibitor camptothecin (CPT), which both generate 3’-end blocking DNA lesions that are also repaired by TDP1, we found that inactivation of BRCA2 renders cells hypersensitive to CNDAC and CPT but not to AraC. By contrast, cells lacking PARP1 were only hypersensitive to CPT but not to CNDAC or AraC. Examination of TDP1 expression in the cancer cell line databases (CCLE, GDSC, NCI-60) and human cancers (TCGA) revealed a broad range of expression of TDP1, which was correlated with PARP1 expression, TDP1 gene copy number and promoter methylation. Thus, the present study identifies the importance of TDP1 as a novel determinant of response to CNDAC across various cancer types (especially non-small cell lung cancers), and demonstrates the differential involvement of BRCA2, PARP1 and TDP1 in the cellular responses to CNDAC, AraC and CPT.

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

Abstract: An anti–HIV-1 drug is found to destroy leukemia cells in adults.

Cited by 35 publications

References 83 publications

The dominant role of proofreading exonuclease activity of replicative polymerase ε in cellular tolerance to cytarabine (Ara-C)

The dominant role of proofreading exonuclease activity of replicative polymerase ε in cellular tolerance to cytarabine (Ara-C)

Dual inhibition of the mTORC1 and mTORC2 signaling pathways is a promising therapeutic target for adult T‐cell leukemia

TDP1 is Critical for the Repair of DNA Breaks Induced by Sapacitabine, a Nucleoside also Targeting ATM- and BRCA-Deficient Tumors

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