Research article
A selective eradication of human non-hereditary breast cancer cells by phenanthridine derived polyADP-ribose polymerase inhibitors
Dana Inbar-Rozensal,
Asher Castiel,
Leonid Visochek,
David Castel,
Francoise Dantzer,
Shai Izraeli and
Malka Cohen-Armon
Breast Cancer Research 2009,
11:R78doi:10.1186/bcr2445
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| 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
These results outline a new therapeutic approach for a selective eradication of abundant non-hereditary human breast cancers.
Selective Eradication Of Malignant Cells
05 Nov 2009
The ultimate goal in cancer research, a treatment that kills cancer cells whilst leaving healthy cells untouched, is brought nearer by the success of a new therapeutic approach. The potential therapy, published in BioMed Central's open access journal
Breast Cancer Research, targets proliferation of cancer, but not normal, cells.
An international research team led by Professor Cohen-Armon of Tel-Aviv University found that potent
phenanthridine derived polyADP-ribose polymerase (PARP) inhibitors that were originally designed to protect cells from cell-death under stress conditions (e.g. stroke or inflammation), efficiently eradicate MCF-7 and MDA231 breast cancer cells without impairing normal proliferating cells, such as human epithelial cells (MCF-10A), nor normal non-proliferating cells, such as neurons and cardiomyocytes.
Human cancers depending on a constitutive activity of externally regulated kinase (ERK) were examined. The rationale for testing PARP inhibitors in these cancers was the recently disclosed up-regulation of ERK signals in the nucleus by activated PARP-1. However, other mechanisms are apparently involved.
The phenanthridine PJ-34 caused a permanent G2/M cell-cycle arrest and cell death within 48-72 hours in breast cancer MCF-7 and MDA231 cells. In contrast,
normal proliferating cells overcame the imposed G2/M cell-cycle arrest within 12 hours, survived and continued to proliferate.
In vivo,
PJ-34 prevented the development of MCF-7 and MDA231 xenotransplants in nude mice without affecting their growth, development or behaviour.
Other PARP inhibitors were recently proved efficient only for treating relatively rare hereditary human cancers developed in individuals with an impaired DNA repair (BRCA gene mutation). However, in the current research, breast cancer cells lacking the BRCA mutation were efficiently eradicated.
According to Professor Cohen-Armon, "This research provides a new therapeutic approach for a selective eradication of abundant human cancers."
Notes:
A selective eradication of human non-hereditary breast cancer cells by phenanthridine derived polyADP-ribose polymerase inhibitors
Dana Inbar-Rozensal, Asher Castiel, Leonid Visochek, David Castel, Francoise Dantzer, Shai Izraeli and Malka Cohen-Armon
Breast Cancer Research (in press)
http://breast-cancer-research.com/
Article on expanding PARP uses including short video clip discussing efficacy against "hypoxic" tumors. CSCs are thought to be hypoxic