Enzastaurin inhibits tumours sensitive and resistant to anti-EGFR drugs
| Autor: | Teresa Gelardi, Roberto Bianco, Vincenzo Damiano, Stefano Pepe, Fortunato Ciardiello, Gennaro Daniele, Michael Lahn, Giampaolo Tortora, Rosa Caputo |
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| Přispěvatelé: | Gelardi, T, Caputo, R, Damiano, V, Daniele, G, Pepe, S, Ciardiello, Fortunato, Lahn, M, Bianco, R, Tortora, G. |
| Rok vydání: | 2008 |
| Předmět: |
Vascular Endothelial Growth Factor A
Cancer Research Indoles medicine.medical_treatment Mice Nude Antineoplastic Agents Apoptosis Enzyme-Linked Immunosorbent Assay Pharmacology Targeted therapy Mice Phosphatidylinositol 3-Kinases chemistry.chemical_compound Enzastaurin Gefitinib In vivo Cell Line Tumor Animals Humans Medicine Epidermal growth factor receptor neoplasms EGFR inhibitors drug resistance biology business.industry Cell Cycle Cell cycle targeted therapy respiratory tract diseases ErbB Receptors Oncology chemistry Culture Media Conditioned Quinazolines biology.protein Drug Screening Assays Antitumor Translational Therapeutics business medicine.drug |
| Zdroj: | British Journal of Cancer |
| ISSN: | 1532-1827 0007-0920 |
| DOI: | 10.1038/sj.bjc.6604493 |
| Popis: | We investigated the antitumour effect and ability to overcome the resistance to anti-EGFR drugs of enzastaurin, an inhibitor of VEGFR-dependent PKCbeta signalling. Enzastaurin was evaluated alone and in combination with the EGFR inhibitor gefitinib, on growth and signalling protein expression in human cancer cells sensitive and resistant to anti-EGFR drugs, both in vitro and in nude mice. We demonstrated the marked inhibitory activity of enzastaurin against GEO colon and PC3 prostate cancer cells and their gefitinib-resistant counterparts GEO-GR and PC3-GR, accompanied by inhibition of pAkt and its effector pp70S6K, pGSK3beta and VEGF expression and secretion. Moreover, enzastaurin showed a cooperative effect with gefitinib in parental and in gefitinib-resistant cells. Remarkably, these results were confirmed in vivo, where enzastaurin showed antitumour activity and cooperativity with gefitinib in mice grafted with GEO and GEO-GR tumours, incrementing their median survival and inhibiting the aforesaid protein expression and secretion in tumour specimens. In conclusion, enzastaurin by interfering with signalling proteins implicated in EGFR drug resistance markedly cooperates with gefitinib in sensitive and gefitinib-resistant tumours, thus overcoming and reverting such resistance and providing a rational basis for its development in patients resistant to anti-EGFR drugs. |
| Databáze: | OpenAIRE |
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