A phenanthrene derived PARP inhibitor is an extra-centrosomes de-clustering agent exclusively eradicating human cancer cells
- Equal contributors
1 The Neufeld Cardiac Research Institute, Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv University, 69978, Tel-Aviv, Israel
2 Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel-Aviv University, 69978, Tel-Aviv, Israel
3 Imaging Unit, Sackler Faculty of Medicine, Tel-Aviv University, 69978, Tel-Aviv, Israel
4 Cancer Research Center, Sheba Medical Center, Tel-Hashomer, 52621 Ramat-Gan, Israel
5 Biotechnology and Cell Signaling, UMR7242, Ecole Superieure de Biotechnologie Strasbourg, F-67400, Illkrich-Graffenstaden, France
BMC Cancer 2011, 11:412 doi:10.1186/1471-2407-11-412Published: 26 September 2011
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'.
We used cell biology and biochemical methods, including flow cytometry, immunocytochemistry and live confocal imaging.
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.
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.