Inhibition of radiation-induced neoplastic transformation by beta-lapachone.

Boothman, David A.; Pardee, Arthur B.

doi:10.1073/pnas.86.13.4963

Cited by 61 publications

(50 citation statements)

References 28 publications

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“…NQO1-dependent DNA Damage after ␤-lap Treatment-To date, there is little direct evidence that ␤-lap treatment causes DNA damage as assessed by alkaline or neutral filter elution, p53 induction, or covalent complex protein-DNA formation (8,32,33). However, many of these prior studies were performed in cells expressing little to no NQO1 (34).…”

Section: Parp-1 Hyperactivation After ␤-Lapmentioning

confidence: 99%

Calcium-dependent Modulation of Poly(ADP-ribose) Polymerase-1 Alters Cellular Metabolism and DNA Repair

Bentle

Reinicke

Bey

et al. 2006

Journal of Biological Chemistry

117

179

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Alterations in the initiation and regulation of caspase-mediated apoptosis are associated with an array of pathological disease states, including chemotherapy resistance in cancer (1). Therefore, elucidating mechanisms that initiate non-caspasemediated cell death are crucial for the development and use of novel anticancer agents.A growing number of chemotherapeutic approaches focus on targeting specific DNA repair enzymes. In particular, inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) 2 that sensitize cells to DNA-damaging agents are under extensive investigation (2). PARP-1 functions as a DNA damage sensor that responds to both single-and/or double-strand DNA breaks (SSBs, DSBs), facilitating DNA repair and cell survival. After binding to DNA breaks, PARP-1 converts ␤-NAD ϩ (NAD ϩ ) into polymers of branched or linear poly(ADP-ribose) units (PAR) and attaches them to various nuclear acceptor proteins, including XRCC1, histones, and PARP-1 for its autoregulation (3). However, in response to extensive DNA damage, PARP-1 can be hyperactivated, eliciting rapid cellular NAD ϩ and ATP pool depletion. PARP-1-mediated NAD ϩ and ATP losses have affects on mitochondrial function by decreasing the levels of pyruvate and NADH. Loss of mitochondrial membrane potential (MMP) ensues, causing caspase-independent cell death by as yet unknown mechanisms (3). PARP-1 hyperactivation was documented in the cellular response to trauma, such as ischemia-reperfusion, myocardial infarction, and reactive oxygen species (ROS)-induced injury (3). In each case, inhibition of PARP-1 was necessary for the long-term survival of damaged cells (4).␤-lapachone (␤-lap) elicits a unique cell death process in various human breast, lung, and prostate cancers that have elevated levels of the two-electron oxidoreductase, NAD(P)H: quinone oxidoreductase 1 (NQO1) (EC 1.6.99.2) (5). ␤-lap induces an NQO1-dependent form of cell death wherein PARP-1 and p53 proteolytic cleavage fragments were noted (6), concomitant with -calpain activation (7). ␤-lap-induced lethality and proteolysis were abrogated by dicoumarol (an NQO1 inhibitor), and were muted in cells deficient in NQO1

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Section: Parp-1 Hyperactivation After ␤-Lapmentioning

confidence: 99%

Calcium-dependent Modulation of Poly(ADP-ribose) Polymerase-1 Alters Cellular Metabolism and DNA Repair

Bentle

Reinicke

Bey

et al. 2006

Journal of Biological Chemistry

117

179

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“…4 h-Lap is a novel antitumor agent that is bioactivated by the two-electron oxidoreductase, NAD(P)H quinone oxidoreductase-1 (NQO1; EC 1.6.99.2). Because NQO1 is highly expressed in many human cancers (e.g., pancreatic, breast, lung, and prostate cancers), it is an attractive target for selective cancer chemotherapy by h-lap alone or with IR (14)(15)(16). h-Lap-induced cell death is triggered by the NQO1-dependent oxidoreduction of h-lap (14), resulting in a futile cycling wherein h-lap is reduced to an unstable hydroquinone that spontaneously reverts to its parent structure using two oxygen molecules (17).…”

Section: Introductionmentioning

confidence: 99%

Nonhomologous End Joining Is Essential for Cellular Resistance to the Novel Antitumor Agent, β-Lapachone

Bentle¹,

Reinicke

Dong

et al. 2007

Cancer Research

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Commonly used antitumor agents, such as DNA topoisomerase I/II poisons, kill cancer cells by creating nonrepairable DNA double-strand breaks (DSBs). To repair DSBs, error-free homologous recombination (HR), and/or error-prone nonhomologous end joining (NHEJ) are activated. These processes involve the phosphatidylinositol 3 ¶-kinase-related kinase family of serine/threonine enzymes: ataxia telangiectasia mutated (ATM), ATM-and Rad3-related for HR, and DNAdependent protein kinase catalytic subunit (DNA-PKcs) for NHEJ. Alterations in these repair processes can cause drug/ radiation resistance and increased genomic instability. BLapachone (B-lap; also known as ARQ 501), currently in phase II clinical trials for the treatment of pancreatic cancer, causes a novel caspase-and p53-independent cell death in cancer cells overexpressing NAD(P)H:quinone oxidoreductase-1 (NQO1). NQO1 catalyzes a futile oxidoreduction of B-lap leading to reactive oxygen species generation, DNA breaks, ;-H2AX foci formation, and hyperactivation of poly(ADP-ribose) polymerase-1, which is required for cell death. Here, we report that B-lap exposure results in NQO1-dependent activation of the MRE11-Rad50-Nbs-1 complex. In addition, ATM serine 1981, DNA-PKcs threonine 2609, and Chk1 serine 345 phosphorylation were noted; indicative of simultaneous HR and NHEJ activation. However, inhibition of NHEJ, but not HR, by genetic or chemical means potentiated B-lap lethality. These studies give insight into the mechanism by which B-lap radiosensitizes cancer cells and suggest that NHEJ is a potent target for enhancing the therapeutic efficacy of B-lap alone or in combination with other agents in cancer cells that express elevated NQO1 levels. [Cancer Res 2007;67(14):6936-45]

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“…l3-Lapachone, which is isolated from plant extracts (9), has a variety of pharmacological effects (10,11). Toxicity data in humans are not available for (3-lapachone; it is well tolerated in mice at <40 mg/kg given i.v.…”

mentioning

confidence: 99%

Three inhibitors of type 1 human immunodeficiency virus long terminal repeat-directed gene expression and virus replication.

Zhang

Dezube

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

203

109

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Transcription of type 1 human immunodeficiency virus (HIV-1) provirus is governed by the viral long terminal repeat (LTR). Drugs can block HIV-1 replication by inhibiting activity of its LTR. We report that topotecan, beta-lapachone, and curcumin are potent and selective inhibitors of HIV-1 LTR-directed gene expression, at concentrations that have minor effects on cells. At these concentrations, each drug inhibited p24 antigen production in cells either acutely or chronically infected with HIV-1. Their target is transcriptional function of the LTR.

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Inhibition of radiation-induced neoplastic transformation by beta-lapachone.

Abstract: ABSTRACT13-Lapachone is a potent inhibitor of DNA repair in mammalian cells and activates topoisomerase I. We show that fi-lapachone can prevent the oncogenic

Cited by 61 publications

References 28 publications

Calcium-dependent Modulation of Poly(ADP-ribose) Polymerase-1 Alters Cellular Metabolism and DNA Repair

Calcium-dependent Modulation of Poly(ADP-ribose) Polymerase-1 Alters Cellular Metabolism and DNA Repair

Nonhomologous End Joining Is Essential for Cellular Resistance to the Novel Antitumor Agent, β-Lapachone

Three inhibitors of type 1 human immunodeficiency virus long terminal repeat-directed gene expression and virus replication.

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