The first 2 authors contributed equally to this article.
Synergistic effect of rapamycin and cisplatin in endometrial cancer cells
Article first published online: 29 MAY 2009
Copyright © 2009 American Cancer Society
Volume 115, Issue 17, pages 3887–3896, 1 September 2009
How to Cite
Bae-Jump, V. L., Zhou, C., Boggess, J. F. and Gehrig, P. A. (2009), Synergistic effect of rapamycin and cisplatin in endometrial cancer cells. Cancer, 115: 3887–3896. doi: 10.1002/cncr.24431
- Issue published online: 20 AUG 2009
- Article first published online: 29 MAY 2009
- Manuscript Accepted: 20 JAN 2009
- Manuscript Revised: 17 DEC 2008
- Manuscript Received: 9 SEP 2008
- University of North Carolina Clinical Translational Science Award-K12 Scholars Program. Grant Number: KL2 RR025746
- V Foundation
- Steelman Fund
- endometrial cancer;
- mammalian target of rapamycin inhibitors;
- DNA mismatch repair
Mammalian target of rapamycin (mTOR) inhibitors modulate signaling pathways involved in cell cycle progression, and phase 2 trials for endometrial cancer are currently being conducted. Because rapamycin is known to enhance the cytotoxicity of chemotherapeutic drugs, the authors' goal was to examine the effects of rapamycin and cisplatin in endometrial cancer cell lines.
By using Ishikawa and ECC-1 cells, cell proliferation was assessed after exposure to rapamycin, cisplatin, or both in combination. The combination index (CI) was calculated using the method of Chou and Talalay. Apoptosis was evaluated by flow cytometry. Immunoblot analysis was performed to assess expression of S6 kinase 1 and the DNA mismatch repair proteins, MSH2 and MSH6. mTOR small interfering (siRNA) was transfected into the cell lines, and proliferation and apoptosis were assessed after exposure to cisplatin.
Cisplatin inhibited growth in a dose-dependent manner in both cell lines (median inhibition concentration of 8-13 μM). Simultaneous exposure of cisplatin in combination with rapamycin resulted in a significant synergistic antiproliferative effect (CI < 1). Rapamycin increased cisplatin-induced apoptosis and stimulated expression of MSH2 and MSH6 in the cisplatin-treated cell lines. Cell growth was significantly decreased in cells transfected with mTOR siRNA and treated with cisplatin compared with either alone (CI < 1). Transfection of mTOR siRNA did not induce apoptosis, but combined treatment with cisplatin increased apoptosis over that of cisplatin alone.
The results of the current study provide evidence of a synergistic relation between rapamycin and cisplatin in both inhibition of cell growth and induction of apoptosis. This suggests that rapamycin and cisplatin may be a rational combination of a targeted therapy for endometrial cancer. Cancer 2009. © 2009 American Cancer Society.