Poly(ADP‐ribosyl)ation inhibitors: Promising drug candidates for a wide variety of pathophysiologic conditions

Abstract

Poly(ADP-ribose) polymerases are involved in many aspects of regulation of cellular functions. Using NAD ؉ as a substrate, they catalyse the covalent transfer of ADP-ribose units onto several acceptor proteins to form a branched ADP-ribose polymer. The best characterised and first discovered member of this multiprotein family is PARP-1. Its catalytic activity is markedly stimulated upon binding to DNA strand interruptions, and the resulting polymer is thought to function in chromatin relaxation as well as in signalling the presence of damage to DNA repair complexes and in regulating enzyme activities. Moderate activation of PARP-1 facilitates the efficient repair of DNA damage arising from monofunctional alkylating agents, reactive oxygen species or ionising radiation, but severe genotoxic stress leads to rapid energy consumption and subsequently to necrotic cell death. The latter aspect of PARP-1 activity has been implicated in the pathogenesis of various clinical conditions such as shock, ischaemia-reperfusion and diabetes. Inhibition of ADP-ribose polymer formation has been shown to be effective, on the one hand, in the treatment of cancer in combination with alkylating agents by suppressing DNA repair and thus driving tumour cells into apoptosis, and on the other hand it appears to be a promising drug target for the treatment of pathologic conditions involving oxidative stress. In view of the existence of several members of the PARP family in mammalian cells, one has to be aware of possible side effects but also of a wide spectrum of potential clinical applications, which calls for the development of more specific inhibitors. © 2004 Wiley-Liss, Inc. Key words: DNA damage; PARP; cancer chemotherapy; radiotherapy; ischaemia-reperfusion damage; diabetes; shock; Parkinson syndromePoly(ADP-ribosyl)ation is a posttranslational modification of proteins in eukaryotic cells performed by a family of NAD ϩ ADP-ribosyl transferases, the poly(ADP-ribose) polymerases (PARPs). NAD ϩ molecules as precursor are cleaved into nicotinamide and ADP-ribose moieties, and the latter are covalently attached to glutamic or aspartic acid residues of proteins, with PARP itself being the major acceptor. Poly(ADP-ribosyl)ation may alter the activity of acceptor protein, leading to inactivation due to the attachment of a highly complex, branched polymer carrying large numbers of negative charges (Fig. 1). The polymer is rapidly degraded by the enzyme poly(ADP-ribose) glycohydrolase (PARG), limiting the half-life of the polymer to approximately 1 min under conditions of DNA breakage. Poly(ADPribosyl)ation was originally discovered as an immediate response of cells to DNA strand-break-inducing agents, i.e., ionising radiation, alkylating agents and oxidants. Polymer formation in living cells after genotoxic stresses is mainly dependent on PARP-1 (encoded by the ADPRT gene), the first-discovered and best-investigated member of the PARP family. After binding of PARP-1 with its 2 zinc-fingers within the N-terminal DNA-binding domain to double...

The selective poly(ADP-ribose) polymerase-1(2) inhibitor, CEP-8983, increases the sensitivity of chemoresistant tumor cells to temozolomide and irinotecan but does not potentiate myelotoxicity

“…PARP-1 inhibition has been the focus of extensive research as a radiosensitizer/ chemosensitizer based on evidence implicating a role for PARP-1 (and PARP-2) in DNA damage repair and survival of cells under genotoxic stress (3,9). The potential application and preclinical development of PARP inhibitors as radiosensitizers/chemosensitizers, until recently, was limited by their potency, selectivity, and pharmaceutical properties.…”

“…Poly(ADP-ribose) (PAR) polymerase (PARP)-1 belongs to the PARP enzyme family that currently includes 18 members; of these members, only PARP-1 and PARP-2 play a role in DNA damage and repair (3,4). PARP-1 is activated by, and implicated in, base excision repair of DNA strand breaks caused by ionizing radiation, or following enzymatic repair of DNA lesions induced by methylating agents, topoisomerase I inhibitors, and other chemotherapeutic agents, such as cisplatin and bleomycin (5,6).…”

Mechanisms of Chemoresistance to Alkylating Agents in Malignant Glioma

“…Potential applications in the nonmalignant setting have recently been reviewed (56,57). In the realm of cancer therapy, preclinical models have shown that inhibition of PARP-1 can potentiate the activity of both radiotherapy and a variety of chemotherapeutic agents (58 -64), and PARP-1 inhibitors have also shown single-agent activity against certain tumor cell lines (65,66).…”

Two small enzyme isoforms mediate mammalian mitochondrial poly(ADP-ribose) glycohydrolase (PARG) activity

“…Alterations of PAR metabolism are causally involved in the pathogenesis of inflammatory [18] and autoimmune disease [19] , ischemia reperfusion injury in brain [20] , heart and intestine [21][22][23] , neuronal degeneration and neurotoxicity [24] , genetic and genomic instability (reviewed in [25]) and cancer (reviewed in [26,27] ). Targeting of the poly(ADP-ribose) metabolic pathway has therefore become an important focus in research on cancer therapy (recent reviews in [28][29][30]), cardiovascular disease intervention [31][32][33][34] and a number of other pathophysiological conditions [35,36] . Because of the potential of PAR metabolism as a drug target, identification of the key players appears to be crucial.…”