Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors

Huang, Xiumei; Motea, Edward A.; Moore, Zachary; Yao, Jun; Dong, Ying; Chakrabarti, Gaurab; Kilgore, Jessica A.; Silvers, Molly A.; Patidar, Praveen; Cholka, Agnieszka; Fattah, Farjana J.; Jin, Yoon; Anderson, Glenda G.; Kusko, Rebecca; Peyton, Michael; Yan, Jingsheng; Xie, Xian Jin; Sarode, Venetia; Williams, Noelle S.; Minna, John D.; Beg, Muhammad Shaalan; Gerber, David E.; Bey, Erik A.; Boothman, David A.

doi:10.1016/j.ccell.2016.11.006

Cited by 112 publications

(215 citation statements)

References 31 publications

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“…14,15 A majority (>90%) of pancreatic tumors have over-expressed NQO1 levels, believed mainly due to mutant K-Ras driven transcription. 5,16 We assessed NQO1 mRNA levels in 462 pancreatic adenocarcinoma tissues versus associated normal tissue, where uniformly elevated NQO1 levels were noted, consistent with our prior data. 17 As also noted in non-small cell lung cancer, head, and neck, prostate, and breast cancers, 6,8,12,18 we also demonstrated a reciprocal loss of expression of catalase in pancreatic adenocarcinoma tumors, with elevated catalase and low NQO1 levels in associated normal tissue.…”

Section: Introductionsupporting

confidence: 73%

Using a novel NQO1 bioactivatable drug, beta‐lapachone (ARQ761), to enhance chemotherapeutic effects by metabolic modulation in pancreatic cancer

Beg

Huang

Silvers

et al. 2017

Journal of Surgical Oncology

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Novel, tumor-selective therapies are needed to increase the survival rate of pancreatic cancer patients. K-Ras-mutant-driven NAD(P)H:quinone oxidoreductase 1 (NQO1) is over-expressed in pancreatic tumor vs associated normal tissue, while catalase expression is lowered compared to levels in associated normal pancreas tissue. ARQ761 undergoes a robust, futile redox cycle in NQO1+ cancer cells, producing massive hydrogen peroxide (H2O2) levels; normal tissues are spared by low NQO1 and high catalase expression. DNA damage created by ARQ761 in pancreatic cancer cells ‘hyperactivates’ PARP1, causing metabolic catastrophe and NAD+-keresis cell death. NQO1: catalase levels (high in tumor, low in normal tissue) are an attractive therapeutic window to treat pancreatic cancer. Based on a growing body of literature, we are leading a clinical trial to evaluate the combination of ARQ761 and chemotherapy in patients with pancreatic cancer.

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Section: Introductionsupporting

confidence: 73%

Using a novel NQO1 bioactivatable drug, beta‐lapachone (ARQ761), to enhance chemotherapeutic effects by metabolic modulation in pancreatic cancer

Beg

Huang

Silvers

et al. 2017

Journal of Surgical Oncology

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“…In addition to the inhibitory effect of CA on cell proliferation, its effect on cell migration and invasion may represent an attractive therapeutic option for highly metastatic malignant melanomas. Combined treatment with β-lap and poly(ADP-ribose) polymerase (PARP) inhibitors has been shown to exert a synergistic therapeutic effect in several tumor types by causing non-repairable DNA damage in the presence of NQO1 activity (45). It is possible that CA treatment may be able to further augment the combined effect of β-lap and PARP.…”

Section: Discussionmentioning

confidence: 99%

Carnosic acid, an inducer of NAD(P)H quinone oxidoreductase 1, enhances the cytotoxicity of β‑lapachone in melanoma cell lines

et al. 2017

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Abstract. NAD(P)H quinone oxidoreductase 1 (NQO1)-dependent antitumor drugs such as β-lapachone (β-lap) are attractive candidates for cancer chemotherapy because several tumors exhibit higher expression of NQO1 than adjacent tissues. Although the association between NQO1 and β-lap has been elucidated, the effects of a NQO1-inducer and β-lap used in combination remain to be clarified. It has previously been reported that melanoma cell lines have detectable levels of NQO1 expression and are sensitive to NQO1-dependent drugs such as 17-allylamino-17-demethoxygeldanamycin. The present study was conducted to investigate the involvement of NQO1 in β-lap-mediated toxicity and the utility of combination treatment with a NQO1-inducer and β-lap in malignant melanoma cell lines. Decreased expression or inhibition of NQO1 caused these cell lines to become less sensitive to β-lap, indicating a requirement of NQO1 activity for β-lap-mediated toxicity. Of note was that carnosic acid (CA), a compound extracted from rosemary, was able to induce further expression of NQO1 through NF-E2 related factor 2 (NRF2) stabilization, thus significantly enhancing the cytotoxicity of β-lap in all of the melanoma cell lines tested. Taken together, the data presented in the current study indicated that the NRF2-NQO1 axis may have potential value as a therapeutic target in malignant melanoma to improve the rate of clinical response to NQO1-dependent antitumor drugs. IntroductionMalignant melanoma is one of the most aggressive forms of cancer, exhibiting resistance to various forms of chemotherapy.The global incidence and mortality rates of malignant melanoma are increasing (1-3). Novel targeted therapies designed to kill melanoma cells harboring mutations in B-Raf proto-oncogene, serine/threonine kinase (BRAF) have been developed using vemurafenib, which is a specific BRAF inhibitor (4,5). Missense mutations to the BRAF gene, most commonly a valine-to-glutamic acid substitution at codon 600, has been observed in ~80% of melanocytic nevi and ~50% of melanomas (6-9). In addition to this BRAF mutation, another therapeutic target has been investigated, as melanomas, including acral lentiginous melanoma, the most common type in ethnicities that produce high levels of melanin, have a low frequency of BRAF gene mutation (10,11). However, details of the mechanism responsible for the drug insensitivity of melanomas lacking BRAF mutations have been largely unclear. On the basis of the aforementioned background, a search for novel therapeutic strategies is justified.β-lapachone (β-lap), a lipophilic cytotoxic o-naphtoquinone derived from the bark of the South American Lapacho tree (Tabebuia avellanedae), has recently attracted attention as an antitumor drug (12,13). The mechanism of its antitumor effect is considered to involve the formation of reactive oxygen species (ROS) (13-15). ROS and other types of radicals are involved in a variety of biological phenomena, including tumorigenesis, degenerative disease and aging (16,17), and are also important medi...

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“…In a recent study, a bioactivatable drug targeting NAD(P)H:quinone oxidoreductase 1 (NQO1), β-lapachone, was used in conjunction with a PARPi to specifically target NQO1-overexpressing tumor cells (Huang et al 2016b). The synergistic effect of PARP inhibition in combination with β-lapachone-induced DNA damage specifically promoted tumor cell death and showed efficacy even in cancers with wild-type BRCA1/2 (Huang et al 2016b).…”

Section: Parpis In the Clinicmentioning

confidence: 99%

PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes

2017

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The discovery of poly(ADP-ribose) >50 years ago opened a new field, leading the way for the discovery of the poly(ADP-ribose) polymerase (PARP) family of enzymes and the ADP-ribosylation reactions that they catalyze. Although the field was initially focused primarily on the biochemistry and molecular biology of PARP-1 in DNA damage detection and repair, the mechanistic and functional understanding of the role of PARPs in different biological processes has grown considerably of late. This has been accompanied by a shift of focus from enzymology to a search for substrates as well as the first attempts to determine the functional consequences of site-specific ADP-ribosylation on those substrates. Supporting these advances is a host of methodological approaches from chemical biology, proteomics, genomics, cell biology, and genetics that have propelled new discoveries in the field. New findings on the diverse roles of PARPs in chromatin regulation, transcription, RNA biology, and DNA repair have been complemented by recent advances that link ADP-ribosylation to stress responses, metabolism, viral infections, and cancer. These studies have begun to reveal the promising ways in which PARPs may be targeted therapeutically for the treatment of disease. In this review, we discuss these topics and relate them to the future directions of the field.ADP-ribosylation is a reversible post-translational modification (PTM) of proteins resulting in the covalent attachment of a single ADP-ribose unit [i.e., mono(ADP-ribose) (MAR)] or polymers of ADP-ribose units [i.e., poly(ADP-ribose) (PAR)] on a variety of amino acid residues on target proteins (Gibson and Kraus 2012;Daniels et al. 2015a). This modification is mediated by a diverse group of ADPribosyl transferase (ADPRT) enzymes that use ADP-ribose units derived from β-NAD + to catalyze the ADP-ribosylation reaction. These enzymes include bacterial ADPRTs (e.g., cholera toxin and diphtheria toxin) as well as members of three different protein families in yeast and animals: (1) arginine-specific ecto-enzymes (ARTCs), (2) sirtuins, and (3) PAR polymerases (PARPs) . Surprisingly, a recent study showed that the bacterial toxin DarTG can ADP-ribosylate DNA . How this fits into the broader picture of cellular ADP-ribosylation has yet to be determined.In this review, we focus on the mono(ADP-ribosyl)ation (MARylation) and poly(ADP-ribosyl)ation (PARylation) of glutamate, aspartate, and lysine residues by PARP family members. While many reviews have been written on PARPs in the past decade, we highlight the current trends and ideas in the field, in particular those discoveries that have been published in the past 2-3 years.

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Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors

Cited by 112 publications

References 31 publications

Using a novel NQO1 bioactivatable drug, beta‐lapachone (ARQ761), to enhance chemotherapeutic effects by metabolic modulation in pancreatic cancer

Using a novel NQO1 bioactivatable drug, beta‐lapachone (ARQ761), to enhance chemotherapeutic effects by metabolic modulation in pancreatic cancer

Carnosic acid, an inducer of NAD(P)H quinone oxidoreductase 1, enhances the cytotoxicity of β‑lapachone in melanoma cell lines

PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes

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