Pharmacological modulation of Poly(ADP-ribose) polymerase-mediated cell death: exploitation in cancer chemotherapy.

Poly(ADP-ribose) polymerases (PARPs) are defined as a family of cell-signaling enzymes present in eukaryotes, which are involved in poly(ADP-ribosylation) of DNA-binding proteins. PARP enzymes are activated in response to DNA damage induced by ionizing radiation, oxidative stress, and DNAbinding antitumor drugs (Lindahl et al., 1995; D’Amours et al., 1999). Poly(ADP-ribose) polymerase-1 (PARP-1; EC 2.4.2.30), also known as poly(ADP-ribose) synthetase and poly(ADP-ribose) transferase, is the main member of the PARP enzyme family. PARP-1 is an abundant and highly conserved chromatin-bound enzyme that binds to nicked DNA as a homodimer [molecular weight 2 113 kDa] and mediates protection against DNA damage. Upon binding to DNA breaks, activated PARP-1 cleaves NAD into nicotinamide and ADP-ribose moieties and polymerizes the latter onto nuclear acceptor proteins and PARP-1 itself. When DNA is moderately damaged, PARP-1 participates in the DNA repair process and the cell survives. However, in the case of extensive DNA damage, PARP-1 overactivation induces a decrease of NAD and ATP levels, leading to cell dysfunction or even to necrotic cell death (Martin et al., 2000). PARP-1 and other poly(ADP-ribosyl) transferases are localized not only in the nucleus but also in the mitochondria. In fact, it has been recently reported that intramitochondrial poly(ADP-ribosylation) contributes to NAD depletion and cell death induced by oxidative stress in neurons (Du et al., 2003). Overactivation of PARP-1 have been implicated in the pathogenesis of several diseases, including stroke, myocardial infarction, diabetes, shock, neurodegenerative disorder, allergy, and several other inflammatory processes (Tentori et al., 2002). Therefore, PARP-1 may be considered a potential target for pharmacological intervention against various pathophysiological states. In addition, because of PARP-1 involvement in cell death, pharmacological modulation of PARP activity may constitute a suitable target to enhance the activity of antitumor drugs. In fact, several adjuvant strategies directed to modulate PARP activity, such as the use of PARP-1 inhibitors (Southan and Szabó, 2003) or ATPdepleting agents (Martin et al., 2000), have been recently reported. The present review gives an update of the pharmacological modulation of PARP activity in cancer therapy and tries to shed further light on this important subject.