Abstract
BackgroundCells 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'.MethodsWe used cell biology and biochemical methods, including flow cytometry, immunocytochemistry and live confocal imaging.ResultsWe 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.ConclusionWe 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.
Highlights
Cells of most human cancers have supernumerary centrosomes
We found that this molecule acts as a centrosomes de-clustering agent in cells with supernumerary centrosomes, which are most abundant in these mammary cancer cells and in most human cancers [4,5]
Given that MDA-231 cells have high occurrence of extra-centrosomes, and the interference with bipolar clustering of supernumerary centrosomes causes G2/M arrest [5,16,17], we examined the possibility that PJ-34 affects extra-centrosomes clustering in mitosis
Summary
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. We have recently reported the selective eradication of human triple negative mammary cancer cells MDA-231 by phenanthrene derivatives ( acting as potent inhibitors of polyADP-ribose polymerases) [1] These compounds included the phenanthridines PJ-34 and Phen and the isoquiniline Tiq-A. Bipolar centrosomes assembly during metaphase is crucial for bipolar spindle formation and accurate chromosomes segregation in cells undergoing mitosis [6,7] To accomplish these tasks, cells dividing with more than two centrosomes have developed a yet unresolved molecular mechanism, clustering their extra-centrosomes at two poles [4,5,8]. Cells dividing with more than two centrosomes have developed a yet unresolved molecular mechanism, clustering their extra-centrosomes at two poles [4,5,8] Failure of this bipolar centrosome assembly causes multipolar spindle structures and aberrant chromosomes segregation that prevent normal cell division [5]. Cell death induced by failure to accomplish mitosis has been well documented, the underlying molecular mechanisms are still poorly understood [5,10]
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