Molecular mechanisms of anti-tumor properties of P276-00 in head and neck squamous cell carcinoma.

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.

• Authors: Prabha B Mishra, Aurelio S Lobo, Kalpana S Joshi, Maggie J Rathos, Gopinath A Kumar, Muralidhara Padigaru
• Journal: Journal of translational medicine (J Transl Med) Vol. 11 Pg. 42 (Feb 18 2013) ISSN: 1479-5876 [Electronic] England
• PMID: 23414419 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Cyclin D
• E2F1 Transcription Factor
• Flavones
• HSC70 Heat-Shock Proteins
• HSPA8 protein, human
• Interleukin-6
• P276-00
• Protein Kinase Inhibitors
• Retinoblastoma Protein
• Cyclin D1
• ErbB Receptors
• Cyclin-Dependent Kinases

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Carcinoma, Squamous Cell (drug therapy)
• Cell Line, Tumor
• Cell Proliferation
• Cyclin D (metabolism)
• Cyclin D1 (metabolism)
• Cyclin-Dependent Kinases (antagonists & inhibitors)
• E2F1 Transcription Factor (metabolism)
• ErbB Receptors (metabolism)
• Flavones (pharmacology)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• HSC70 Heat-Shock Proteins (metabolism)
• Head and Neck Neoplasms (drug therapy)
• Humans
• Inhibitory Concentration 50
• Interleukin-6 (metabolism)
• Mice
• Mice, SCID
• Neoplasm Transplantation
• Phosphorylation
• Protein Kinase Inhibitors (pharmacology)
• Retinoblastoma Protein (metabolism)
• Xenograft Model Antitumor Assays