Research article

A selective eradication of human nonhereditary breast cancer cells by phenanthridine-derived polyADP-ribose polymerase inhibitors

Dana Inbar-Rozensal¹ , Asher Castiel² , Leonid Visochek¹ , David Castel¹ , Françoise Dantzer³ , Shai Izraeli² and Malka Cohen-Armon¹

¹  The Neufeld Cardiac Research Institute and Dept. of Physiology and Pharmacology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel

²  Cancer Research Institute, Sheba Medical Center, Tel-Hashomer, Ramat-Gan 52621, Israel

³  Laboratory of Molecular and Structural Biology, Ecole Superieure de Biotechnologie de Strasbourg, F-67400, Illkrich-Graffenstaden, France

author email corresponding author email

Breast Cancer Research 2009, 11:R78doi:10.1186/bcr2445

Published:	9 November 2009

See related editorial by Frizzell and Kraus, http://breast-cancer-research.com/content/11/6/111

Abstract

Introduction

PARP-1 (polyADP-ribose polymerase-1) is known to be activated in response to DNA damage, and activated PARP-1 promotes DNA repair. However, a recently disclosed alternative mechanism of PARP-1 activation by phosphorylated externally regulated kinase (ERK) implicates PARP-1 in a vast number of signal-transduction networks in the cell. Here, PARP-1 activation was examined for its possible effects on cell proliferation in both normal and malignant cells.

Methods

In vitro (cell cultures) and in vivo (xenotransplants) experiments were performed.

Results

Phenanthridine-derived PARP inhibitors interfered with cell proliferation by causing G₂/M arrest in both normal (human epithelial cells MCF10A and mouse embryonic fibroblasts) and human breast cancer cells MCF-7 and MDA231. However, whereas the normal cells were only transiently arrested, G₂/M arrest in the malignant breast cancer cells was permanent and was accompanied by a massive cell death. In accordance, treatment with a phenanthridine-derived PARP inhibitor prevented the development of MCF-7 and MDA231 xenotransplants in female nude mice. Quiescent cells (neurons and cardiomyocytes) are not impaired by these PARP inhibitors.

Conclusions

These results outline a new therapeutic approach for a selective eradication of abundant nonhereditary human breast cancers.