Oncotarget

Research Papers:

Selective antitumor activity of roscovitine in head and neck cancer

Cyril Gary, Michael Hajek, Asel Biktasova, Gary Bellinger, Wendell G. Yarbrough and Natalia Issaeva _

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Oncotarget. 2016; 7:38598-38611. https://doi.org/10.18632/oncotarget.9560

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Abstract

Cyril Gary1,*, Michael Hajek1,*, Asel Biktasova1,4, Gary Bellinger1, Wendell G. Yarbrough1,2,3, Natalia Issaeva1,3

1Department of Surgery Division of Otolaryngology, Yale University, New Haven, CT USA

2Department of Pathology, Yale University, New Haven, CT USA

3Department of Yale Cancer Center, Yale University, New Haven, CT USA

4Current address: Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Australia

*These authors have contributed equally to this work

Correspondence to:

Natalia Issaeva, email: [email protected]

Keywords: roscovitine, head and neck cancer, HPV, DNA damage, toxicity

Received: September 28, 2015    Accepted: May 05, 2016    Published: May 23, 2016

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.


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