Exclusive destruction of mitotic spindles in human cancer cells

Abstract

We identified target proteins modified by phenanthrenes that cause exclusive eradication of human cancer cells. The cytotoxic activity of the phenanthrenes in a variety of human cancer cells is attributed by these findings to post translational modifications of NuMA and kinesins HSET/kifC1 and kif18A. Their activity prevented the binding of NuMA to α-tubulin and kinesins in human cancer cells, and caused aberrant spindles. The most efficient cytotoxic activity of the phenanthridine PJ34, caused significantly smaller aberrant spindles with disrupted spindle poles and scattered extra-centrosomes and chromosomes. Concomitantly, PJ34 induced tumor growth arrest of human malignant tumors developed in athymic nude mice, indicating the relevance of its activity for cancer therapy.

The Modified Phenanthridine PJ34 Unveils an Exclusive Cell-Death Mechanism in Human Cancer Cells

“…In these experiments PJ34 (60 mg/kg) was injected IP after the tumors reached a volume >100 mm 3 . PJ34 injected daily for 14 days efficiently suppressed tumor growth [31].…”

“…It was observed that apart from PARP inhibition, some of these molecules target a variety of kinases implicated in signal transduction pathways in both healthy and malignant cells [27]. Unexpectedly, this research also disclosed that a group of phenanthrene derivatives acting as PARP inhibitors, exclusively kill human cancer cells without affecting benign cells [28][29][30][31][32]. Unlike other PARP inhibitors, these small molecules exclusively eradicated a variety of human cancer cells without affecting proliferating and non-proliferating healthy somatic cells.…”

“…In view of the decreased expression of PARP1 and NFkappaB in several cancer cell types eradicated by PJ34, it has been suggested that eradication by PJ34 can be attributed to the attenuation of PARP1-dependent NF-kappaB activity that promotes proliferation [45]. However, the suggested mechanisms of PARP1-dependent activity of PJ34 in cancer cells are inconsistent with its exclusive PARP1 independent cytotoxic activity in human cancer cells at a higher concentration range than that causing PARP1 inhibition [29][30][31]35]. Its exclusive cytotoxic activity in human cancer cells was not shared by other potent PARP inhibitors [29][30][31]61].…”

“…On the other hand, their exclusive cytotoxic activity in human cancer cells resembles the cytotoxic activity of other phenanthridines [36][37][38]. The modified phenanthridine PJ34, one of the molecules in this group, was the most potent in a variety of human cancer cells, including cells that are resistant to currently offered therapies [28][29][30][31][32]. Its specific cytotoxic activity in human cancer cells is summarized in this overview.…”

Clinically Applicable Inhibitors Impacting Genome Stability

“…PolyADP-ribosylation of TNKS1 may contribute to spindle bipolarity by providing a static matrix, anchoring microtubule-associated motor and spindle proteins [ 124 ]. A second PARP inhibitor, PJ-34, is currently undergoing pre-clinical trials and is known to induce distorted multipolar spindles and to disrupt bipolar clustering of extra centrosomes resulting in mitotic catastrophe and cell death, an effect exclusively eradicating cancer cells harbouring CA without affecting normal cell proliferation [ 124 , 132 , 150 ]. AZ0108 and PJ-34 showed better centrosome de-clustering abilities, compared to isoquinolinone-derived PARP inhibitors Tiq-A and Phen (phenanthrene) [ 124 , 151 ] ( Table 3 ).…”