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

作者：Inbar Rozensal Dana; Castiel Asher; Visochek Leonid; Castel David; Dantzer Francoise; Izraeli Shai; Cohen Armon Malka^*

来源：Breast Cancer Research, 2009, 11(6): R78.

DOI：10.1186/bcr2445

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 G(2)/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, G(2)/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.

• 出版日期2009