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

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.

KIFC1 is a novel potential therapeutic target for breast cancer

“…It has been demonstrated that PJ34 was able to prevent the clustering of extra centrosomes in mitosis and exclusively eradicate human cancer cells with supernumerary centrosomes without impairing normal proliferating cells. 11 In the present study, we demonstrated that KIFC1 is upregulated in breast cancer tissues and breast cancer cell lines, and that KIFC1 silencing in breast cancer cells significantly reduced cell viability. Furthermore, we found that PJ34 acts as a small molecule KIFC1 inhibitor by suppressing KIFC1 expression in breast cancer cells.…”

“…12 Recently, it has been found that PJ34 is a centrosome declustering agent exclusively eradicating human cancer cells. 11 However the molecular mechanism underlying PJ34-induced centrosome declustering was unclear. Interestingly, we found that PJ34 at 7-56 mM was able to markedly suppress KIFC1 expression in breast cancer MDA-MB-231, HS578T and BT549 cells (Fig.…”

Causes and consequences of centrosome abnormalities in cancer

“…The recent development of inhibitors that compromise centrosome clustering could be the beginning of the validation of this idea in vivo. Several inhibitors have been developed that induce multipolar mitosis preferentially in cancer cells, such as a phenanthrene-derived PARP inhibitor, GF-15, a derivative of griseofulvin and taxol [140][141][142]. There is interest in the clinical use of these compounds, such as for example GF-15 which decreases tumour growth in xenograft mouse models [141].…”

Let's huddle to prevent a muddle: centrosome declustering as an attractive anticancer strategy

“…Treatment of tumors exhibiting centrosome amplification with the phenanthrene-derived PARP-1 inhibitor, PJ-34, results in clustering inhibition, spindle multipolarity, and death by mitotic catastrophe. 134 By contrast, treatment of normal proliferating cells with high drug concentration (i.e., 2-3 times greater than necessary for complete PARP-1 inhibition) for several days has no discernible effect on spindle morphology, centrosome integrity, mitosis, or cell viability. PARP-1 is involved in detection and base-excision repair of DNA strand breaks, initiation of the DNA damage checkpoint, and apoptosis, 135 activities not plainly related to clustering.…”

“…Some phenanthrene-derived poly-ADP-ribose polymerase (PARP) inhibitors also exhibit cancer cell-specific declustering. 134 PARP-1 expression is upregulated in various human cancers 135 but downregulated in others, 136 suggesting a complex role for this protein in tumorigenesis. Treatment of tumors exhibiting centrosome amplification with the phenanthrene-derived PARP-1 inhibitor, PJ-34, results in clustering inhibition, spindle multipolarity, and death by mitotic catastrophe.…”