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Published on: August 27, 2019
YM155 reverses rapamycin resistance in renal cancer by decreasing survivin
Hidekazu Koike1, Takashi Nitta, Yoshitaka Sekine
1Department of Urology, Gunma University Graduate School of Medicine, 3-39-22 Showa-Machi, Maebashi, 371-8511, Japan, hkoike@gunma-u.ac.jp.
Purpose:
Mammalian target of rapamycin inhibitor has exhibited promising anticancer activity for the treatment of renal cell carcinoma (RCC). However, many patients acquire resistance to therapeutic agents leading to treatment failure. The objective of this study was to determine whether treatment with YM155, a novel small molecule inhibitor of survivin, could reverse rapamycin resistance in a rapamycin-resistant RCC.
Methods:
We induced a rapamycin-resistant clear cell carcinoma cell line (Caki-1-RapR). We showed that survivin gene expression was significantly up-regulated in Caki-1-RapR compared with that in its parent cells (Caki-1). Therefore, we hypothesized that targeting of survivin in Caki-1-RapR could reverse the resistant phenotype in tumor cells, thereby enhancing the therapeutic efficacy of rapamycin. We used both in vitro and in vivo models to test the efficacy of YM155 either as a single agent or in combination with rapamycin.
Results:
In Caki-1-RapR cells, YM155 significantly decreased survivin gene and protein expression levels and cell proliferation in a dose-dependent manner in vitro. In addition, YM155 treatment significantly reversed rapamycin resistance in cancer cells. In a nude mouse tumor xenograft model, YM155 significantly inhibited the growth of Caki-1-RapR tumor. In addition, YM155 significantly enhanced the antitumor effects of rapamycin in Caki-1-RapR tumor.
Conclusions:
Our results suggest a potentially novel strategy to use YM155 to overcome the resistance in tumor cells, thereby enhancing the effectiveness of molecular target therapy in RCC.
Insights
YM155, a survivin inhibitor, reversed rapamycin resistance in renal cell carcinoma (RCC) cells. This novel approach enhances the effectiveness of targeted cancer therapy by overcoming drug resistance.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Mammalian target of rapamycin (mTOR) inhibitors show promise for renal cell carcinoma (RCC) treatment.
- Acquired resistance to mTOR inhibitors is a significant cause of treatment failure in RCC patients.
Purpose of the Study:
- To investigate if YM155, a survivin inhibitor, can overcome rapamycin resistance in RCC.
- To evaluate the efficacy of YM155 alone and in combination with rapamycin in preclinical models.
Main Methods:
- Developed a rapamycin-resistant RCC cell line (Caki-1-RapR) with elevated survivin expression.
- Assessed YM155's effect on survivin expression, cell proliferation, and rapamycin sensitivity in vitro.
- Tested YM155 and rapamycin combination therapy in a Caki-1-RapR tumor xenograft model in vivo.
Main Results:
- YM155 dose-dependently reduced survivin expression and proliferation in Caki-1-RapR cells.
- YM155 treatment effectively reversed rapamycin resistance in vitro.
- In vivo, YM155 inhibited tumor growth and synergistically enhanced rapamycin's antitumor effects.
Conclusions:
- YM155 demonstrates potential as a strategy to overcome therapeutic resistance in RCC.
- Targeting survivin with YM155 may enhance the efficacy of molecular targeted therapies for RCC.
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