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

Dana Inbar-Rozensal email, Asher Castiel email, Leonid Visochek email, David Castel email, Francoise Dantzer email, Shai Izraeli email and Malka Cohen-Armon email

Breast Cancer Research 2009, 11:R78doi:10.1186/bcr2445
Published: 5 November 2009
Abstract (provisional)

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

PARP inhibition by 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 non-hereditary breast cancer cells MCF-7 and MDA231. However, while 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 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