title: 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.affiliation: The Neufeld Cardiac Research Institute, Department of Physiology and Pharmacology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel.
authors.forename: Leonid
authors.initials: L
authors.lastname: Visochek
authors.affiliation: Cancer Research Center, Sheba Medical Center, Ramat Gan 53621, Israel.
authors.forename: Asher
authors.initials: A
authors.lastname: Castiel
authors.affiliation: The Imaging Unit, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel.
authors.forename: Leonid
authors.initials: L
authors.lastname: Mittelman
authors.affiliation: Sharett Oncology Institute, Hadassah Medical Center, Ein-Kerem, Jerusalem 91120, Israel.
authors.forename: Michael
authors.initials: M
authors.lastname: Elkin
authors.affiliation: Cancer Research Center, Sheba Medical Center, Ramat Gan 53621, Israel.
authors.forename: Dikla
authors.initials: D
authors.lastname: Atias
authors.affiliation: Cancer Research Center, Sheba Medical Center, Ramat Gan 53621, Israel.
authors.forename: Talia
authors.initials: T
authors.lastname: Golan
authors.affiliation: Cancer Research Center, Sheba Medical Center, Ramat Gan 53621, Israel.|The Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel.
authors.forename: Shai
authors.initials: S
authors.lastname: Izraeli
authors.affiliation: Sharett Oncology Institute, Hadassah Medical Center, Ein-Kerem, Jerusalem 91120, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Peretz
authors.affiliation: The Neufeld Cardiac Research Institute, Department of Physiology and Pharmacology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel.|Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv 69978, Israel.
authors.forename: Malka
authors.initials: M
authors.lastname: Cohen-Armon
mesh_terms: D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D016547:Kinesins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008938:Mitosis / Q000187:drug effects / Q000502:physiology*; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D034521:Nuclear Matrix-Associated Proteins / Q000235:genetics / Q000378:metabolism; D010616:Phenanthrenes / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D008941:Spindle Apparatus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D034961:Antigens, Nuclear; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C486566:KIFC1 protein, human; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; C050045:NUMA1 protein, human; D034521:Nuclear Matrix-Associated Proteins; D010616:Phenanthrenes; C502735:KIF18A protein, human; D016547:Kinesins
keywords: NuMA; human cancer cells; kinesins; mitotic spindles; phenanthrenes