Molecular mechanisms of anti-tumor properties of P276-00 in head and neck squamous cell carcinoma
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RESEARCH
Open Access
Molecular mechanisms of anti-tumor properties of P276-00 in head and neck squamous cell carcinoma Prabha B Mishra1,3*, Aurelio S Lobo1,3, Kalpana S Joshi2,3, Maggie J Rathos3, Gopinath A Kumar4 and Muralidhara Padigaru1
Abstract Background: Tumors of the head and neck present aggressive pathological behavior in patients due to high expression of CDK/CCND1 proteins. P276-00, a novel CDK inhibitor currently being tested in clinic, inhibits growth of several cancers in vitro and in vivo. The pre clinical activity of P276-00 in head and neck cancer and its potential mechanisms of action at molecular level are the focus of the current studies. Method: We have investigated the anti-cancer activity of P276-00 in head and neck tumors in vitro and in vivo. Candidate gene expression profiling and cell based proteomic approaches were taken to understand the pathways affected by P276-00 treatment. Results: It was observed that P276-00 is cytotoxic across various HNSCC cell lines with an IC50 ranging from 1.0-1.5 μmoles/L and culminated in significant cell-cycle arrest in G1/S phase followed by apoptosis. P276-00 treatment suppressed cell proliferation through inhibition of CCND1 expression, reduced phosphorylation of retinoblastoma protein and abrogative transcription of E2F1 gene targets. Further, we observed that apoptosis was mediated through P53 activation leading to higher BAX/BCL-2 ratio and cleaved caspase-3 levels. It was also seen that P276-00 treatment reduced expression of tumor micro-environment proteins such as IL-6, secreted EGFR and HSPA8. Finally, P276-00 treatment resulted in significant tumor growth inhibition in xenograft tumor models via lowered proliferative activity of E2F1 and aggravated P53 mediated apoptosis. Conclusion: In summary, we have observed that P276-00 inhibits cyclin-D/CDK4/P16/pRB/E2F axis and induces apoptosis by increased P53 phosphorylation in HNSCC cells. These results suggest a novel indication for P276-00 in head and neck cancer with a potential role for IL-6 and HSPA8 as candidate serum biomarkers. Keywords: FaDu, P276-00, Cyclin dependent kinase, Cyclin D, E2F1, HNSCC
Background Head and neck squamous cell carcinoma (HNSCC) is the 8th most common cause of morbidity and mortality due to cancer worldwide. Head and neck cancer refers to carcinoma arising in the mucosal surfaces of the oral cavity, oropharynx, larynx and hypopharynx of which 90% are HNSCC [1]. Current treatment options for * Correspondence: [email protected] 1 Biomarker Discovery Group, Department of Pharmacology, Piramal Healthcare Ltd, 1-Nirlon Complex, Goregaon (East), Mumbai 400063, Maharashtra, India 3 Department of Pharmacology, Piramal Healthcare Ltd, Mumbai 400063, Maharashtra, India Full list of author information is available at the end of the article
HNSCC include surgery, γ-irradiation, and chemotherapy depending on the site, size and the stage of lesions. Aberrant expression of P14, P16, P53, CCND1, RAS, EGFR, and MYC is known to initiate tumorigenesis and contribute toward
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