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Targeting poly(ADP-ribose) polymerase activity for cancer therapy.

ABSTRACT: Poly(ADP-ribosyl)ation is a ubiquitous protein modification found in mammalian cells that modulates many cellular responses, including DNA repair. The poly(ADP-ribose) polymerase (PARP) family catalyze the formation and addition onto proteins of negatively charged ADP-ribose polymers synthesized from NAD(+). The absence of PARP-1 and PARP-2, both of which are activated by DNA damage, results in hypersensitivity to ionizing radiation and alkylating agents. PARP inhibitors that compete with NAD(+) at the enzyme's activity site are effective chemo- and radiopotentiation agents and, in BRCA-deficient tumors, can be used as single-agent therapies acting through the principle of synthetic lethality. Through extensive drug-development programs, third-generation inhibitors have now entered clinical trials and are showing great promise. However, both PARP-1 and PARP-2 are not only involved in DNA repair but also in transcription regulation, chromatin modification, and cellular homeostasis. The impact on these processes of PARP inhibition on long-term therapeutic responses needs to be investigated.

SUBMITTER: Megnin-Chanet F

PROVIDER: S-EPMC2955921 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Targeting poly(ADP-ribose) polymerase activity for cancer therapy.

Mégnin-Chanet Frédérique F Bollet Marc A MA Hall Janet J

Cellular and molecular life sciences : CMLS 20100820 21

Poly(ADP-ribosyl)ation is a ubiquitous protein modification found in mammalian cells that modulates many cellular responses, including DNA repair. The poly(ADP-ribose) polymerase (PARP) family catalyze the formation and addition onto proteins of negatively charged ADP-ribose polymers synthesized from NAD(+). The absence of PARP-1 and PARP-2, both of which are activated by DNA damage, results in hypersensitivity to ionizing radiation and alkylating agents. PARP inhibitors that compete with NAD(+) ...[more]

PMID: 20725763

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Project description:Poly(ADP-ribose) polymerases (PARPs) are involved in many aspects of the cellular response to various forms of damage. PARP-1 and PARP-2, the most abundant PARPs, are central to the response to specific types of DNA damage, especially single-strand breaks. Inhibition of PARP activity may sensitize the cell to exogenous agents such as chemotherapy and radiation. In circumstances where rescue pathways are deficient, particularly the homologous recombination (HR)-directed DNA repair pathway, inhibition of PARP may result in "synthetic lethality." BRCA mutation-associated breast cancers are a paradigm of HR-directed repair deficient tumors. Early clinical trials have demonstrated significant activity of single-agent PARP inhibitors in BRCA-deficient breast and ovarian cancer. Because of phenotypic similarities between some "triple-negative" breast cancers (TNBC) and the most prevalent type of breast cancer seen in BRCA1 mutation carriers, some have hypothesized that TNBC might also be specifically sensitive to PARP inhibition. The activity of single-agent PARP inhibitors in TNBC has not been reported. One trial did suggest significant enhancement of the activity of platinum-based combination chemotherapy, without incremental toxicity. These studies indicate that PARP inhibition is an exciting new approach to the treatment of breast cancers in women with underlying BRCA mutations and possibly in sporadic cancers with defects in HR-directed repair. Future studies will be necessary to determine whether the effectiveness of PARP inhibitors in nonhereditary cancer requires an underlying HR defect or whether these agents may improve the activity of conventional chemotherapy by other means. In addition, studies will be required to determine whether PARP inhibitors may induce synthetic lethality in tumors with defects in pathways other than the BRCA-dependent DNA repair pathway. If either or both of these prove to be the case, then PARP inhibition may benefit a wide spectrum of cancer patients.

Dataset Information

Targeting poly(ADP-ribose) polymerase activity for cancer therapy.

Publications

Targeting poly(ADP-ribose) polymerase activity for cancer therapy.

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