PARP Inhibitors in Cancer Therapy: Promise, Progress, and Puzzles

Ellisen, Leif W.

doi:10.1016/j.ccr.2011.01.047

Cited by 56 publications

(52 citation statements)

References 11 publications

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“…Indeed, iniparib has been hypothesized to interact with targets beyond PARP that may account for the reported activity of this compound (42)(43)(44)(45). The reactive nature of the iniparib-met molecule indicates that nonspecific modification of cysteine-containing proteins is likely to occur with this compound.…”

Section: Discussionmentioning

confidence: 99%

Iniparib Nonselectively Modifies Cysteine-Containing Proteins in Tumor Cells and Is Not a Bona Fide PARP Inhibitor

Liu

Shi

Maag

et al. 2012

Clinical Cancer Research

167

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Purpose: PARP inhibitors are being developed as therapeutic agents for cancer. More than six compounds have entered clinical trials. The majority of these compounds are b-nicotinamide adenine dinucleotide (NAD þ )-competitive inhibitors. One exception is iniparib, which has been proposed to be a noncompetitive PARP inhibitor. In this study, we compare the biologic activities of two different structural classes of NAD þ -competitive compounds with iniparib and its C-nitroso metabolite.Experimental Design: Two chemical series of NAD þ -competitive PARP inhibitors, iniparib and its C-nitroso metabolite, were analyzed in enzymatic and cellular assays. Viability assays were carried out in MDA-MB-436 (BRCA1-deficient) and DLD1À/À (BRCA2-deficient) cells together with BRCA-proficient MDA-MB-231 and DLD1 þ/þ cells. Capan-1 and B16F10 xenograft models were used to compare iniparib and veliparib in vivo. Mass spectrometry and the 3 H-labeling method were used to monitor the covalent modification of proteins.Results: All NAD þ -competitive inhibitors show robust activity in a PARP cellular assay, strongly potentiate the activity of temozolomide, and elicit robust cell killing in BRCA-deficient tumor cells in vitro and in vivo. Cell killing was associated with an induction of DNA damage. In contrast, neither iniparib nor its C-nitroso metabolite inhibited PARP enzymatic or cellular activity, potentiated temozolomide, or showed activity in a BRCA-deficient setting. We find that the nitroso metabolite of iniparib forms adducts with many cysteine-containing proteins. Furthermore, both iniparib and its nitroso metabolite form protein adducts nonspecifically in tumor cells. Conclusions: Iniparib nonselectively modifies cysteine-containing proteins in tumor cells, and the primary mechanism of action for iniparib is likely not via inhibition of PARP activity. Clin Cancer Res; 18(2); 510-23. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 99%

Iniparib Nonselectively Modifies Cysteine-Containing Proteins in Tumor Cells and Is Not a Bona Fide PARP Inhibitor

Liu

Shi

Maag

et al. 2012

Clinical Cancer Research

167

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“…Recent studies have highlighted the utility of combining DNAdamaging chemotherapy with PARP inhibition (30)(31)(32). PARP inhibitors were initially evaluated in BRCA-deficient breast cancers based on the predicted "synthetic lethality" between PARPdependent largely single-strand break repair and BRCA-associated DSB repair (31).…”

Section: Discussionmentioning

confidence: 99%

BAL1 and Its Partner E3 Ligase, BBAP, Link Poly(ADP-Ribose) Activation, Ubiquitylation, and Double-Strand DNA Repair Independent of ATM, MDC1, and RNF8

Yan

Zhu

et al. 2013

Molecular and Cellular Biology

100

115

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The BAL1 macrodomain-containing protein and its partner E3 ligase, BBAP, are overexpressed in chemotherapy-resistant lymphomas. BBAP selectively ubiquitylates histone H4 and indirectly promotes early 53BP1 recruitment to DNA damage sites. However, neither BBAP nor BAL1 has been directly associated with a DNA damage response (DDR), and the function of BAL1 remains undefined. Herein, we describe a direct link between rapid and short-lived poly(ADP-ribose) (PAR) polymerase 1 (PARP1) activation and PARylation at DNA damage sites, PAR-dependent recruitment of the BAL1 macrodomain-containing protein and its partner E3 ligase, local BBAP-mediated ubiquitylation, and subsequent recruitment of the checkpoint mediators 53BP1 and BRCA1. The PARP1-dependent localization of BAL1-BBAP functionally limits both early and delayed DNA damage and enhances cellular viability independent of ATM, MDC1, and RNF8. These data establish that BAL1 and BBAP are bona fide members of a DNA damage response pathway and are directly associated with PARP1 activation, BRCA1 recruitment, and double-strand break repair.

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“…PARP inhibitors induced therapeutic synthetic lethality in BRCA mutation carriers with advanced breast (26) and ovarian cancer and have since moved into early clinical testing for breast cancer interception (27). The development of this approach includes a phase II therapy trial of the PARP inhibitor olaparib (competitive inhibitor of PARP1 and PARP2), which produced a response rate of 41% in advanced breast cancer patients with germ line BRCA1 or BRCA2 mutations.…”

Section: Cancer/ Therapymentioning

confidence: 99%

Cancer Interception

Blackburn

2011

Cancer Prevention Research

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A common perception is that cancer risk reduction is passive, such as not smoking. However, advances in the understanding of cancer biology and in cancer treatment modalities suggest that it is now timely to consider anew cancer risk reduction by active, including pharmacologic, approaches. Risk avoidance approaches are certainly important, but other approaches are important as well, as exemplified by the irony that most new lung cancers occur in former smokers, or current avoiders. Cancer interception is the active way of combating cancer and carcinogenesis at earlier and earlier stages. A great challenge is to educate people that the development of cancers, like heart disease, typically takes years and accordingly can potentially be intercepted with risk-reducing agents in the same way that advanced cancers can be treated with drugs or that cardiovascular disease can be intercepted with antihypertensive and other risk-reducing drugs. The cancer biology behind cancer interception is increasingly solid. For example, hedgehog pathway studies of mutations in the patched homolog 1 (PTCH1) gene, which constitutively activates Smoothened (SMO), led to development of an oral SMO inhibitor active in advanced basal cell carcinoma and which, in very high-risk Gorlin syndrome patients (germ line PTCH1 mutation), is nearly completely clinically effective in intercepting basal cell neoplasia. Also, the oral immunomodulator lenalidomide, first found to be active in advanced, relapsed multiple myeloma, was highly effective in intercepting the precursor stage, high-risk smoldering multiple myeloma from progressing. These are but two exciting, recent examples of the many advances in cancer research that have created an optimal time to discover and implement cancer interception. The multifaceted roles of telomere maintenance in both fueling advanced cancers and, at early stages, keeping them at bay, also highlight how the growing knowledge of cancer biology opens avenues for cancer interception. Emerging molecular techniques, including next-generation sequencing platforms, that account for a large part of the remarkable recent advances in cancer biology are now being applied to interception of premalignancy. Keeping the medical community and public at large informed about possibilities for actively intercepting cancer will be important for gaining acceptance of this increasingly powerful approach to lessening the cancer burden. Cancer Prev Res; 4(6); 787-92. Ó2011 AACR.

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PARP Inhibitors in Cancer Therapy: Promise, Progress, and Puzzles

Cited by 56 publications

References 11 publications

Iniparib Nonselectively Modifies Cysteine-Containing Proteins in Tumor Cells and Is Not a Bona Fide PARP Inhibitor

Iniparib Nonselectively Modifies Cysteine-Containing Proteins in Tumor Cells and Is Not a Bona Fide PARP Inhibitor

BAL1 and Its Partner E3 Ligase, BBAP, Link Poly(ADP-Ribose) Activation, Ubiquitylation, and Double-Strand DNA Repair Independent of ATM, MDC1, and RNF8

Cancer Interception

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