Cancer Chemotherapy and Pharmacology

, Volume 62, Issue 2, pp 305–313

Antiproliferative effects of rapamycin as a single agent and in combination with carboplatin and paclitaxel in head and neck cancer cell lines

  • Nasredine Aissat
  • Christophe Le Tourneau
  • Aïda Ghoul
  • Maria Serova
  • Ivan Bieche
  • François Lokiec
  • Eric Raymond
  • Sandrine Faivre
Original Article

DOI: 10.1007/s00280-007-0609-2

Cite this article as:
Aissat, N., Le Tourneau, C., Ghoul, A. et al. Cancer Chemother Pharmacol (2008) 62: 305. doi:10.1007/s00280-007-0609-2

Abstract

Purpose

Recent data suggested that combining targeted therapies with chemotherapy may counteract drug resistance. Activation of the PI3K/AKT/mTOR pathway downstream to kinase receptors, such as EGFR, was found in 57–81% of head and neck squamous cell carcinoma (HNSCC), and was eventually associated with a loss of PTEN function. mTOR was shown to modulate cell proliferation, apoptosis, invasion, and angiogenesis. This study aimed to evaluate molecular and cellular effects of rapamycin in a panel of cell lines either as single agent or in combination with cytotoxics commonly used in HNSCC.

Methods

Antiproliferative effects of rapamycin, carboplatin, and paclitaxel were evaluated in a panel of three HNSCC cell lines (SCC61, SQ20B and HEP2). Cells were exposed to rapamycin for 48 h, to carboplatin for 48 h, or to paclitaxel for 24 h. Antiproliferative effects of simultaneous and sequential rapamycin-based combinations were studied using MTT assay and median effect plot analysis. Cell cycle effects were analysed using flow cytometry.

Results

Rapamycin induced concentration dependent antiproliferative effects in HNSCC cell lines with IC50 of 5 ± 1, 12 ± 2 and 20 ± 2 μM in SCC61, SQ20B, and HEP2 cells, respectively. Higher antiproliferative effects were observed in SCC61 cells overexpressing NOXA and cyclin D1 than in HEP2 that overexpressed MDR1 and BCL2. In our panel, antiproliferative effects of rapamycin were associated with G0/G1 cell cycle accumulation and apoptosis induction, at concentrations ranging 3–30 μM. Combinations of rapamycin with paclitaxel and carboplatin displayed synergistic and additive effects. Synergistic effects were observed with paclitaxel in SQ20B and HEP2 cells and with carboplatin in SQ20B cells, when cells were exposed to cytotoxics prior to rapamycin.

Conclusion

Our results show that rapamycin displays antiproliferative effects and induces apoptosis in HNSCC cell lines, cellular effects being more potent in cells that do not express BCL2 and MDR1. Additive and synergistic effects were observed when rapamycin was combined with carboplatin and paclitaxel.

Keywords

mTOR PI3K/AKT pathway Cytotoxicity Apoptosis 

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Nasredine Aissat
    • 1
  • Christophe Le Tourneau
    • 1
  • Aïda Ghoul
    • 1
  • Maria Serova
    • 1
  • Ivan Bieche
    • 2
  • François Lokiec
    • 3
  • Eric Raymond
    • 1
  • Sandrine Faivre
    • 1
    • 4
  1. 1.Department of Experimental Pharmacology (RayLab) and Medical OncologyBeaujon University HospitalClichyFrance
  2. 2.Laboratory of Molecular GeneticsBeaujon University HospitalClichyFrance
  3. 3.Department of Clinical PharmacologyCentre René HugueninSaint-CloudFrance
  4. 4.Service Inter-Hospitalier de Cancérologie Bichat-BeaujonClichyFrance

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