The role of poly (ADP-ribose) polymerase-1 in the celluar response to several marine-derived compounds:

PARP-1 is a multi-functional protein that is involved in many DNA-dependent genomic processes under normal and pathophysiological conditions. It is well characterized as a DNA damage detector and responds by catalytic production and attachment of polymers of ADP-ribose (PAR) to nuclear protein targets, facilitating the chromatin changes that are a prerequisite to DNA repair. In this study, we tested whether PARP-1 is involved in the cellular response to Yondelis®, Zalypsis®, PSL1, and PSL2, novel chemotherapeutic agents with putative DNA damage- and transcription-targeted activities. We observed a dose-dependent activation of PARP-1 catalytic activity following treatment with all four compounds, while PARP-1 protein levels remained unchanged. Interestingly, cells derived from PARP-1 null mice were significantly sensitized to the agents, yet, with respect to Yondelis®, only moderate DNA damage was observed which was repaired with equal efficiency by both PARP-1 wildtype and PARP-1 null cells. While the mechanism of sensitization is unclear, it is of interest to determine whether inhibition of PARP in human cells could sensitize cells to the four agents. Initial in vivo experiments testing this prediction using MX-1 breast carcinoma xenografts treated with Yondelis® alone or in combination with the PARP-1 inhibitor DIQ, demonstrate an additive effect between these two compounds with regard to tumor volume inhibition and tumor growth delay. However, corresponding in vitro experiments failed to corroborate this observation. The effects of PARP-1 on the transcription of genes impacting drug sensitivity, as well as the cyto-protective role of PARP-1 independent of its catalytic function are of interest to direct future efforts to clarify the mechanism of PARP-1-mediated sensitivity to the four agents. Taken together, these data suggest that PARP-1 plays an important role in the protection of cells to Yondelis®, Zalypsis®, PSL1, and PSL2, and suggest that PARP-1 status may determine the sensitivity or resistance of cells treated with these agents.M.S.Includes bibliographical references (p. 45-53)by Brijesh B. Pate