title: Protein kinase C β inhibition by enzastaurin leads to mitotic missegregation and preferential cytotoxicity toward colorectal cancer cells with chromosomal instability (CIN).
abstract: Enzastaurin is a selective inhibitor of protein kinase C β and a potent inhibitor of tumor angiogenesis. In addition, enzastaurin shows direct cytotoxic activity toward a subset of tumor cells including colorectal cancer cells (CRC). In spite of promising results in animal models, the clinical activity of enzastaurin in CRC patients has been disappointing although a subset of patients seems to derive benefit. In the present study we investigated the biological and cytotoxic activities of enzastaurin toward a panel of well-characterized CRC cell lines in order to clarify the mechanistic basis for the cytotoxic activity. Our results show that enzastaurin is significantly more cytotoxic toward CRC cells with chromosome instability (CIN) compared to cells with microsatellite instability (MSI). Since CIN is usually attributed to mitotic dysfunction, the influence of enzastaurin on cell cycle progression and mitotic transit was characterized for representative CIN and MSI cell lines. Enzastaurin exposure was accompanied by prolonged metaphase arrest in CIN cells followed by the appearance of tetraploid and micronuclei-containing cells as well as by increased apoptosis, whereas no detectable mitotic dysfunctions were observed in MSI cells exposed to isotoxic doses of enzastaurin. Our study identifies enzastaurin as a new, context dependent member of a heterogeneous group of anticancer compounds that induce "mitotic catastrophe," that is mitotic dysfunction accompanied by cell death. These data provide novel insight into the mechanism of action of enzastaurin and may allow the identification of biomarkers useful to identify CRC patients particularly likely, or not, to benefit from treatment with enzastaurin.
authors.affiliation: a Laboratory of Cancer Biology and Therapeutics; Center de Recherche Saint-Antoine ; Paris , France.
authors.forename: Djamila
authors.initials: D
authors.lastname: Ouaret
authors.forename: Annette K
authors.initials: AK
authors.lastname: Larsen
mesh_terms: D059447:Cell Cycle Checkpoints / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D018385:Centrosome / Q000187:drug effects / Q000378:metabolism; D043171:Chromosomal Instability / Q000187:drug effects*; D020090:Chromosome Segregation / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000473:pathology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008677:Metaphase / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects*; D011123:Polyploidy; D064546:Protein Kinase C beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D007211:Indoles; D016159:Tumor Suppressor Protein p53; D064546:Protein Kinase C beta; C504878:enzastaurin
keywords: CIN, chromosome instability; CRC, colorectal cancer; DMSO, Dimethyl sulfoxide; MAP, mitogen-activated protein; MEK, mitogen-activated protein kinase kinase; MMC, mitomycin C; MN, micronuclei; MSI, microsatellite instability; PKC, protein kinase C; RACK, receptor of activated protein kinase C; TP53, tumor protein p53; VEGF, vascular endothelial cell growth factor; VEGFR, vascular endothelial cell growth factor receptor; chromosome instability (CIN); colorectal cancer (CRC); enzastaurin; mitotic catastrophe; protein kinase C (PKC) β inhibition