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.

• Authors: Leonid Visochek, Asher Castiel, Leonid Mittelman, Michael Elkin, Dikla Atias, Talia Golan, Shai Izraeli, Tamar Peretz, Malka Cohen-Armon
• Journal: Oncotarget (Oncotarget) Vol. 8 Issue 13 Pg. 20813-20824 (Mar 28 2017) ISSN: 1949-2553 [Electronic] United States
• PMID: 28209915 (Publication Type: Journal Article)

Chemical References

• Antigens, Nuclear
• Biomarkers, Tumor
• Cell Cycle Proteins
• KIFC1 protein, human
• N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride
• NUMA1 protein, human
• Nuclear Matrix-Associated Proteins
• Phenanthrenes
• KIF18A protein, human
• Kinesins

Topics

• Animals
• Antigens, Nuclear (genetics, metabolism)
• Apoptosis (drug effects)
• Biomarkers, Tumor (genetics, metabolism)
• Cell Cycle Proteins
• Cell Proliferation (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Kinesins (genetics, metabolism)
• Mice
• Mitosis (drug effects, physiology)
• Neoplasms (drug therapy, genetics, metabolism, pathology)
• Nuclear Matrix-Associated Proteins (genetics, metabolism)
• Phenanthrenes (pharmacology)
• Protein Processing, Post-Translational (drug effects)
• Spindle Apparatus (drug effects, genetics, metabolism, pathology)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays