Effect of mTOR inhibitors in nude mice with endometrial carcinoma and variable PTEN expression status
1School of Health Sciences, Macao Polytechnic Institute, Macao, China (mainland).
Background:
The aim of this study was to investigate the sensitivity to rapamycin of endometrial cancer cells with different phosphatase and tensin homologue (PTEN) expression to understand the mechanism of resistance to mammalian target of rapamycin (mTOR) inhibitors in the treatment of endometrial cancer.
Material And Methods:
Twenty specific pathogen-free female BALB/c mice received transplants of either HEC-1A (PTEN-positive) or Ishikawa (PTEN-negative) cells. Mice in the treatment group were injected intraperitoneally once a week for 4 consecutive weeks. The control group was injected weekly with phosphate buffer saline (PBS) for 4 consecutive weeks. Tumor volume, tumor mass, growth curves, and inhibition rate were measured, after which the mice were killed.
Results:
Both tumor growth rate and size were slower in the treatment group than in the control group for all mice that received transplants of either HEC-1A or Ishikawa cells. The tumor inhibition rates in the treatment group were 48.1% and 67.1% in mice transplanted with HEC-1A and Ishikawa cells, respectively.
Conclusions:
The inhibitory effects of rapamycin were enhanced in PTEN-negative Ishikawa tumor cells compared with PTEN-positive HEC-1A cells, which could explain the reduced effect of rapalogues in some endometrial cancer patients and help to understand the mechanism of resistance to this drug.
Insights
Rapamycin showed enhanced inhibitory effects on PTEN-negative endometrial cancer cells compared to PTEN-positive cells. This finding helps explain resistance to mammalian target of rapamycin (mTOR) inhibitors in endometrial cancer treatment.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Endometrial cancer treatment resistance to mammalian target of rapamycin (mTOR) inhibitors is a clinical challenge.
- Phosphatase and tensin homologue (PTEN) expression levels vary in endometrial cancer cells.
- Understanding PTEN's role in drug resistance is crucial for effective therapy.
Purpose of the Study:
- To investigate the sensitivity of endometrial cancer cells with differing PTEN expression to rapamycin.
- To elucidate the mechanism of resistance to mTOR inhibitors in endometrial cancer.
Main Methods:
- In vivo study using BALB/c mice xenograft models with PTEN-positive (HEC-1A) and PTEN-negative (Ishikawa) endometrial cancer cells.
- Mice received weekly intraperitoneal injections of rapamycin or phosphate-buffered saline (PBS) for four weeks.
- Tumor volume, mass, growth rates, and inhibition rates were measured.
Main Results:
- Rapamycin treatment significantly slowed tumor growth rate and reduced tumor size in both HEC-1A and Ishikawa cell xenografts compared to controls.
- Tumor inhibition rates were higher in the PTEN-negative Ishikawa cell group (67.1%) than in the PTEN-positive HEC-1A cell group (48.1%).
Conclusions:
- Rapamycin's inhibitory effects are enhanced in PTEN-negative endometrial cancer cells.
- This differential sensitivity may explain the reduced efficacy of rapalogues in some endometrial cancer patients.
- The findings provide insights into the mechanisms of resistance to mTOR inhibitors in endometrial cancer.
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