A phenanthrene derived PARP inhibitor is an extra-centrosomes de-clustering agent exclusively eradicating human cancer cells.

Abstract

BACKGROUND:

Cells of most human cancers have supernumerary centrosomes. To enable an accurate chromosome segregation and cell division, these cells developed a yet unresolved molecular mechanism, clustering their extra centrosomes at two poles, thereby mimicking mitosis in normal cells. Failure of this bipolar centrosome clustering causes multipolar spindle structures and aberrant chromosomes segregation that prevent normal cell division and lead to 'mitotic catastrophe cell death'.

METHODS:

We used cell biology and biochemical methods, including flow cytometry, immunocytochemistry and live confocal imaging.

RESULTS:

We identified a phenanthrene derived PARP inhibitor, known for its activity in neuroprotection under stress conditions, which exclusively eradicated multi-centrosomal human cancer cells (mammary, colon, lung, pancreas, ovarian) while acting as extra-centrosomes de-clustering agent in mitosis. Normal human proliferating cells (endothelial, epithelial and mesenchymal cells) were not impaired. Despite acting as PARP inhibitor, the cytotoxic activity of this molecule in cancer cells was not attributed to PARP inhibition alone.

CONCLUSION:

We identified a water soluble phenanthridine that exclusively targets the unique dependence of most human cancer cells on their supernumerary centrosomes bi-polar clustering for their survival. This paves the way for a new selective cancer-targeting therapy, efficient in a wide range of human cancers.

• Authors: Asher Castiel, Leonid Visochek, Leonid Mittelman, Françoise Dantzer, Shai Izraeli, Malka Cohen-Armon
• Journal: BMC cancer (BMC Cancer) Vol. 11 Pg. 412 (Sep 26 2011) ISSN: 1471-2407 [Electronic] England
• PMID: 21943092 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride
• Phenanthrenes
• Poly(ADP-ribose) Polymerase Inhibitors

Topics

• Antineoplastic Agents (pharmacology)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Centrosome (drug effects)
• Chromosome Segregation (drug effects)
• Enzyme Inhibitors (pharmacology)
• Humans
• Mitosis (drug effects, genetics)
• Neoplasms (enzymology, genetics)
• Phenanthrenes (pharmacology)
• Poly(ADP-ribose) Polymerase Inhibitors
• Spindle Apparatus (drug effects)