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

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...

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Autores principales: Mishra, Prabha B, Lobo, Aurelio S, Joshi, Kalpana S, Rathos, Maggie J, Kumar, Gopinath A, Padigaru, Muralidhara
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3672051/
https://www.ncbi.nlm.nih.gov/pubmed/23414419
http://dx.doi.org/10.1186/1479-5876-11-42
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author Mishra, Prabha B
Lobo, Aurelio S
Joshi, Kalpana S
Rathos, Maggie J
Kumar, Gopinath A
Padigaru, Muralidhara
author_facet Mishra, Prabha B
Lobo, Aurelio S
Joshi, Kalpana S
Rathos, Maggie J
Kumar, Gopinath A
Padigaru, Muralidhara
author_sort Mishra, Prabha B
collection PubMed
description 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 IC(50) 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.
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spelling pubmed-36720512013-06-05 Molecular mechanisms of anti-tumor properties of P276-00 in head and neck squamous cell carcinoma Mishra, Prabha B Lobo, Aurelio S Joshi, Kalpana S Rathos, Maggie J Kumar, Gopinath A Padigaru, Muralidhara J Transl Med Research 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 IC(50) 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. BioMed Central 2013-02-18 /pmc/articles/PMC3672051/ /pubmed/23414419 http://dx.doi.org/10.1186/1479-5876-11-42 Text en Copyright © 2013 Mishra et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Mishra, Prabha B
Lobo, Aurelio S
Joshi, Kalpana S
Rathos, Maggie J
Kumar, Gopinath A
Padigaru, Muralidhara
Molecular mechanisms of anti-tumor properties of P276-00 in head and neck squamous cell carcinoma
title Molecular mechanisms of anti-tumor properties of P276-00 in head and neck squamous cell carcinoma
title_full Molecular mechanisms of anti-tumor properties of P276-00 in head and neck squamous cell carcinoma
title_fullStr Molecular mechanisms of anti-tumor properties of P276-00 in head and neck squamous cell carcinoma
title_full_unstemmed Molecular mechanisms of anti-tumor properties of P276-00 in head and neck squamous cell carcinoma
title_short Molecular mechanisms of anti-tumor properties of P276-00 in head and neck squamous cell carcinoma
title_sort molecular mechanisms of anti-tumor properties of p276-00 in head and neck squamous cell carcinoma
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3672051/
https://www.ncbi.nlm.nih.gov/pubmed/23414419
http://dx.doi.org/10.1186/1479-5876-11-42
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