PMID- 19471857 OWN - NLM STAT- MEDLINE DCOM- 20100914 LR - 20211203 IS - 1573-0646 (Electronic) IS - 0167-6997 (Linking) VI - 28 IP - 4 DP - 2010 Aug TI - The activity of mTOR inhibitor RAD001 (everolimus) in nasopharyngeal carcinoma and cisplatin-resistant cell lines. PG - 413-20 LID - 10.1007/s10637-009-9269-x [doi] AB - Phosphorylated (pi-) protein kinase B (AKT) is commonly expressed in nasopharyngeal carcinoma (NPC) cell lines and tissues, suggesting the involvement of AKT-mammalian target of rapamycin (mTOR) signaling in NPC carcinogenesis. This study evaluated the activity of an mTOR inhibitor, RAD001 (Everolimus, Novartis Pharma AG, Switzerland), in 5 NPC cell lines (HK1, HONE-1, CNE-1, CNE-2, C666-1), 2 cisplatin-resistant NPC cell lines and their respective parental cell lines (HK1-LMP1, HONE-1-EBV). RAD001 inhibited cell growth in a dose-dependent manner at nanomolar concentrations in all cell lines. HONE-1 was most sensitive to RAD001 (IC(50) = 0.63 nM, 60% maximal inhibition), while Het-1A (a normal esophageal epithelial cell line) was relatively resistant. No consistent relationship between sensitivity to RAD001 and basal expression of pi-mTOR and pi-p70S6 Kinase-1 (p70S6K) was found. Exposure to RAD001 at picomolar concentrations for 48 h resulted in reduction of pi-mTOR and pi-p70S6K1 expression, but increase in pi-AKT (Ser473) expression in HONE-1 and CNE-1 cell lines. RAD001 significantly induced apoptosis in HONE-1 cells, but has no effect on cell cycle progression. RAD001 exerted an additive to synergistic effect on cisplatin-induced growth inhibition in CNE-1 and HONE-1 cells, and could inhibit the growth of both cisplatin-resistant and cisplatin-sensitive NPC cell lines. In summary, combination of RAD001 and cisplatin maybe a useful therapeutic strategy in NPC. AKT upregulation following RAD001 treatment suggests the presence of a feedback loop on AKT signaling in NPC which warrants further investigation. FAU - Ma, Brigette B Y AU - Ma BB AD - State Key Laboratory in Oncology in South China, Sir Y.K. Pao Centre for Cancer, Department of Clinical Oncology, Cancer Drug Testing Unit, Hong Kong Cancer Institute, Chinese University of Hong Kong, Shatin, Hong Kong. brigette@clo.cuhk.edu.hk FAU - Lui, Vivian W Y AU - Lui VW FAU - Hui, Edwin P AU - Hui EP FAU - Lau, Cecilia P Y AU - Lau CP FAU - Ho, Kakiu AU - Ho K FAU - Ng, Margaret H L AU - Ng MH FAU - Cheng, S H AU - Cheng SH FAU - Tsao, Sai-Wah AU - Tsao SW FAU - Chan, Anthony T C AU - Chan AT LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20090527 PL - United States TA - Invest New Drugs JT - Investigational new drugs JID - 8309330 RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 9HW64Q8G6G (Everolimus) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - Q20Q21Q62J (Cisplatin) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Antineoplastic Combined Chemotherapy Protocols/*pharmacology MH - Apoptosis/drug effects MH - Cell Cycle/drug effects MH - Cell Line, Tumor MH - Cell Survival/drug effects MH - Cisplatin/*pharmacology/therapeutic use MH - Dose-Response Relationship, Drug MH - Drug Resistance, Neoplasm/*drug effects MH - Drug Screening Assays, Antitumor/methods MH - Drug Synergism MH - Everolimus MH - Humans MH - Intracellular Signaling Peptides and Proteins/*antagonists & inhibitors MH - Nasopharyngeal Neoplasms/*drug therapy MH - Phosphatidylinositol 3-Kinases/metabolism MH - Protein Serine-Threonine Kinases/*antagonists & inhibitors MH - Proto-Oncogene Proteins c-akt/metabolism MH - Ribosomal Protein S6 Kinases, 70-kDa/metabolism MH - Sirolimus/*analogs & derivatives/pharmacology/therapeutic use MH - TOR Serine-Threonine Kinases EDAT- 2009/05/28 09:00 MHDA- 2010/09/15 06:00 CRDT- 2009/05/28 09:00 PHST- 2009/03/15 00:00 [received] PHST- 2009/05/13 00:00 [accepted] PHST- 2009/05/28 09:00 [entrez] PHST- 2009/05/28 09:00 [pubmed] PHST- 2010/09/15 06:00 [medline] AID - 10.1007/s10637-009-9269-x [doi] PST - ppublish SO - Invest New Drugs. 2010 Aug;28(4):413-20. doi: 10.1007/s10637-009-9269-x. Epub 2009 May 27.