Abstract 3437: P276, a cyclin-dependent kinase inhibitor with antitumor activity against high-risk human cervical cancer.

Abstract

Abstract Cervical cancer is the third most common cancer worldwide in women. While preventive vaccines have been approved for cervical cancer, treatment options are limited to chemotherapy drugs. An unmet need, thus, exists for the treatment of cervical cancer. High-risk human papilloma viruses (HPVs), type 16 and 18, account for 70% of the cervical cancer. Viral oncoproteins E6 and E7 bind and inhibit the p53 and Rb tumor suppressors, respectively. One attractive strategy for the treatment of cervical cancer is to attenuate the expression of E6 and E7 viral oncoproteins by a pharmacological inhibitor of cyclin-dependent kinases (CDKs). P276 is a CDKs inhibitor with potent activity against CDK4, CDK1 and CDK9 (Joshi et al, Mol. Cancer Ther. 2007; 6:918-25). The therapeutic potential and mechanism of action of P276 in cervical cancer was investigated using high-risk HPV type 16 (SiHa and Caski) and type 18 (HeLa) human cervical cancer cell line. P276 inhibited cell growth with sub-micromolar IC50 values (0.5-0.8 μM), induced cell cycle arrest and apoptosis in cervical cancer lines. E6 negatively regulates p53 protein stability in HPV-infected cervical cancer. P276 downregulated mRNA and protein expression of E6 in SiHa cells with concomitant upregulation of p53 protein and its downstream target p21, indicating activation of the p53 pathway. It also downregulated E7 mRNA expression in SiHa and HeLa cell lines. Further, it is known that hyperphosphorylation of Rb relieves its interaction with E2F, leading to Rb inactivation and E2F activation. Treatment with P276 dephosphorylated Rb at Ser780, indicating Rb activation. P276 demonstrated significant (p<0.01) in vivo efficacy in HPV type 16 SiHa human cervical cancer xenograft model when administered by i.p. route, Treatment with 25 mg/kg of P276 for 21 days induced 59% of tumor growth inhibition without body weight loss in this model. Conclusion: P276, a CDKs inhibitor, is efficacious against high-risk cervical cancer. Citation Format: Sanjeev Kumar Shangary, Gandhali Deshpande, Vinay Sonawane, Venkatesha Venkatasubbaiah, Archana Jalota-Badhwar, Asavari Joshi, Manoj Mayekar, Nitesh Shirsath, Prashant Pandey, Veena R. Agarwal. P276, a cyclin-dependent kinase inhibitor with antitumor activity against high-risk human cervical cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3437. doi:10.1158/1538-7445.AM2013-3437