Investigational New Drugs

, Volume 28, Issue 4, pp 413–420

The activity of mTOR inhibitor RAD001 (everolimus) in nasopharyngeal carcinoma and cisplatin-resistant cell lines

  • Brigette B. Y. Ma
  • Vivian W. Y. Lui
  • Edwin P. Hui
  • Cecilia P. Y. Lau
  • Kakiu Ho
  • Margaret H. L. Ng
  • S. H. Cheng
  • Sai-Wah Tsao
  • Anthony T. C. Chan
PRECLINICAL STUDIES

DOI: 10.1007/s10637-009-9269-x

Cite this article as:
Ma, B.B.Y., Lui, V.W.Y., Hui, E.P. et al. Invest New Drugs (2010) 28: 413. doi:10.1007/s10637-009-9269-x
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Summary

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 (IC50 = 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.

Keywords

Nasopharyngeal carcinoma RAD001 (everolimus) AKT mTOR 

Supplementary material

10637_2009_9269_MOESM1_ESM.ppt (9.9 mb)
ESM 1Supplementary Figures to Figure 2b (PPT 9.86 MB)

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Brigette B. Y. Ma
    • 1
    • 4
  • Vivian W. Y. Lui
    • 1
  • Edwin P. Hui
    • 1
  • Cecilia P. Y. Lau
    • 1
  • Kakiu Ho
    • 1
  • Margaret H. L. Ng
    • 2
  • S. H. Cheng
    • 2
  • Sai-Wah Tsao
    • 3
  • Anthony T. C. Chan
    • 1
  1. 1.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 and Li Ka Shing Institute of Health SciencesChinese University of Hong KongShatinHong Kong
  2. 2.Department of Anatomical and Cellular PathologyChinese University of Hong KongShatinHong Kong
  3. 3.Department of AnatomyUniversity of Hong KongShatinHong Kong
  4. 4.Department of Clinical OncologyChinese University of Hong KongShatin, New TerritoriesChina

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