title: Two 4N cell-cycle arrests contribute to cisplatin-resistance.
abstract: Cisplatin is a platinum-based drug that is used for the treatment of a wide-variety of primary human cancers. However, the therapeutic efficacy of cisplatin is often limited by intrinsic or acquired drug resistance. An important goal, therefore, is to identify mechanisms that lead to cisplatin resistance in cancer, and then use this information to more effectively target resistant cells. Cisplatin-resistant clones of the HCT116 cell line underwent a prolonged G2 arrest after cisplatin treatment while sensitive clones did not. The staurosporine analog UCN-01 abrogated this G2 arrest and sensitized the resistant clones to cisplatin. At later time points, 4N arrested cells assumed a tetraploid G1 state that was characterized by depletion of Cyclin A, Cyclin B, and CDC2, and increased expression of p53 and p21, in 4N cells. siRNA-mediated knockdown of p21 abrogated the tetraploid G1 arrest and induced killing that was dependent on p53. The results identify two targetable 4N arrests that can contribute to cisplatin resistance: First, a prolonged G2 arrest that can be targeted by UCN-01, and second, a tetraploid G1 arrest that can be targeted by siRNA against p21.
authors.affiliation: Department of Anatomy and Cell Biology, Rush University Medical Center, Chicago, IL, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Shen
authors.forename: Ricardo E
authors.initials: RE
authors.lastname: Perez
authors.forename: Batzaya
authors.initials: B
authors.lastname: Davaadelger
authors.forename: Carl G
authors.initials: CG
authors.lastname: Maki
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D016203:CDC2 Protein Kinase; D002945:Cisplatin / Q000494:pharmacology*; D019925:Cyclin A / Q000235:genetics / Q000378:metabolism; D019926:Cyclin B / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018844:Cyclin-Dependent Kinases; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D016193:G1 Phase / Q000187:drug effects* / Q000235:genetics; D016195:G2 Phase / Q000187:drug effects* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D045325:HCT116 Cells; D006801:Humans; D034741:RNA, Small Interfering / Q000235:genetics; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000494:pharmacology; D057891:Tetraploidy; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D019925:Cyclin A; D019926:Cyclin B; D050759:Cyclin-Dependent Kinase Inhibitor p21; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C054852:7-hydroxystaurosporine; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; D019311:Staurosporine; D002945:Cisplatin
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