title: Small-molecule inducer of cancer cell polyploidy promotes apoptosis or senescence: Implications for therapy.
abstract: Polyploidy results from deregulated cell division and has been considered an undesirable event leading to increased mutation rate and cancer development. However, polyploidy may also render cancer cells more vulnerable to chemotherapy. Here, we identify a small-molecule inducer of polyploidy, R1530, which interferes with tubulin polymerization and mitotic checkpoint function in cancer cells, leading to abortive mitosis, endoreduplication and polyploidy. In the presence of R1530, polyploid cancer cells underwent apoptosis or became senescent which translated into potent in vitro and in vivo efficacy. Normal proliferating cells were resistant to R1530-induced polyploidy thus supporting the rationale for cancer therapy by induced polyploidy. Mitotic checkpoint kinase BubR1 was found downregulated during R1530-induced exit from mitosis, a likely consequence of PLK4 inhibition. BubR1 knockdown in the presence of nocodazole induced an R1530-like phenotype, suggesting that BubR1 plays a key role in polyploidy induction by R1530 and could be exploited as a target for designing more specific polyploidy inducers.
authors.affiliation: Discovery Oncology, Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Tovar
authors.forename: Brian
authors.initials: B
authors.lastname: Higgins
authors.forename: Dayanand
authors.initials: D
authors.lastname: Deo
authors.forename: Kenneth
authors.initials: K
authors.lastname: Kolinsky
authors.forename: Jin-Jun
authors.initials: JJ
authors.lastname: Liu
authors.forename: David C
authors.initials: DC
authors.lastname: Heimbrook
authors.forename: Lyubomir T
authors.initials: LT
authors.lastname: Vassilev
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis; D001569:Benzodiazepines / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D006801:Humans; D008938:Mitosis; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D015739:Nocodazole / Q000494:pharmacology; D011123:Polyploidy; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism
chemical_list: C555028:5-(2-chlorophenyl)-7-fluoro-1,2-dihydro-8-methoxy-3-methylpyrazol(3,4b)(1,4)benzodiazepine; D000970:Antineoplastic Agents; D011720:Pyrazoles; D034741:RNA, Small Interfering; D014404:Tubulin; D001569:Benzodiazepines; C490219:PLK4 protein, human; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases; D015739:Nocodazole