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Oncotarget. 2016 Jun 21;7(25):38598-38611. doi: 10.18632/oncotarget.9560.

Selective antitumor activity of roscovitine in head and neck cancer.

Author information

1
Department of Surgery Division of Otolaryngology, Yale University, New Haven, CT USA.
2
Current address: Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Australia.
3
Department of Pathology, Yale University, New Haven, CT USA.
4
Department of Yale Cancer Center, Yale University, New Haven, CT USA.

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.

KEYWORDS:

DNA damage; HPV; head and neck cancer; roscovitine; toxicity

PMID:
27233076
PMCID:
PMC5122414
DOI:
10.18632/oncotarget.9560
[Indexed for MEDLINE]
Free PMC Article

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