title: Selective antitumor activity of roscovitine in head and neck cancer.
abstract: Radiation and chemotherapy that are commonly used to treat human cancers damage cellular DNA. DNA damage appears to be more toxic to cancer cells than normal cells, most likely due to deregulated checkpoint activation and/or deficiency in DNA repair pathways that are characteristics of many tumors. However, unwanted side effects arise as a result of DNA damage to normal cells during the treatment.Here, we show that roscovitine, a cyclin-dependent kinase (CDK) inhibitor that inhibits CDK-1, CDK-2, CDK-5, CDK-7, and CDK-9 due to competitive binding to the ATP site on the kinases, causes significant DNA damage followed by p53-dependent cell death in human papilloma virus (HPV)-positive, but not in HPV-negative, head and neck cancer cells. Since HPV positivity was a molecular marker for increased sensitivity of cells to roscovitine, we reasoned that systemic roscovitine administration would not be toxic to healthy HPV-negative tissue. Indeed, low roscovitine doses significantly inhibited the growth of HPV-associated xenografted tumors in mice without causing any detectable side effects.Given that inhibition of CDKs has been shown to inhibit replication of several viruses, we suggest that roscovitine treatment may represent a selective and safe targeted therapeutic option against HPV-positive head and neck cancer.
authors.affiliation: Department of Surgery Division of Otolaryngology, Yale University, New Haven, CT USA.
authors.forename: Cyril
authors.initials: C
authors.lastname: Gary
authors.affiliation: Department of Surgery Division of Otolaryngology, Yale University, New Haven, CT USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Hajek
authors.affiliation: Department of Surgery Division of Otolaryngology, Yale University, New Haven, CT USA.|Current address: Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Australia.
authors.forename: Asel
authors.initials: A
authors.lastname: Biktasova
authors.affiliation: Department of Surgery Division of Otolaryngology, Yale University, New Haven, CT USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Bellinger
authors.affiliation: Department of Surgery Division of Otolaryngology, Yale University, New Haven, CT USA.|Department of Pathology, Yale University, New Haven, CT USA.|Department of Yale Cancer Center, Yale University, New Haven, CT USA.
authors.forename: Wendell G
authors.initials: WG
authors.lastname: Yarbrough
authors.affiliation: Department of Surgery Division of Otolaryngology, Yale University, New Haven, CT USA.|Department of Yale Cancer Center, Yale University, New Haven, CT USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Issaeva
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D027383:Papillomaviridae / Q000302:isolation & purification; D030361:Papillomavirus Infections / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology*; D000077546:Roscovitine; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011687:Purines; D000077546:Roscovitine
keywords: DNA damage; HPV; head and neck cancer; roscovitine; toxicity