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Gemcitabine and Selected mTOR Inhibitors in Uterine Sarcomas and Carcinosarcoma Cells- an Isobolographic Analysis
Marcin Bobiński1, Karolina Okła1, Jarogniew Łuszczki2
1Medical University of Lublin, I Chair and Department of Gynaecological Oncology and Gynaecology, Poland.
Abstract:
Introduction: mTOR inhibitors are anticancer agents affecting mTOR/AKT/PI3K pathway that is one of the most important in human cancer cells. Hyperactivation of mTOR/AKT/PI3K and overexpression of this pathway members are frequently reported in uterine sarcoma and carcinosarcoma. Present study is aimed to assess the activity of the two mTOR inhibitors (rapamycin - RAP and sapanisertib - MLN) as a single agent and combined with gemcitabine (GEM, one of substances commonly used in systemic anticancer treatment) in uterine sarcoma and carcinosarcoma in vitro models. Material and methods: SK-UT-1 and SK-UT1-B (uterine carcinosarcoma), MES-SA (leiomyosarcoma) and ESS-1 (endometrial stromal sarcoma) cell lines were used. An MTT assay was performed to examine the cytotoxicity of RAP, MLN and mixtures: RAP+MLN, RAP+GEM, MLN+GEM against these cells. The interactions between tested compounds were assessed in isobolographic analysis. Results and conclusions: Carcinosarcoma cell lines (both SK-UT-1 and SK-UT-1B) do not respond to RAP and respond relatively weakly to MLN treatment. Additive and supraadditive effects were noted for combined treatment with GEM and MLN. Endometrial stromal sarcoma cell line (ESS-1) occured to be sensitive to both RAP and MLN, but the response was stronger for MLN. Additive effect of all tested drug combinations was observed for ESS-1. Leiomyosarcoma cell line (MES-SA) was found sensitive to both mTOR inhibitors. Additive effects in combinations of GEM, RAP and MLN were observed, what makes them promising for future preclinical and clinical trials. Additivity with slight tendency towards antagonism between GEM and MLN observed in MES-SA cell line is unexpected finding and might prompt the mechanistic research aimed to explain this phenomenon.
Insights
Two mTOR inhibitors (rapamycin and sapanisertib) combined with gemcitabine show promise for treating uterine cancers. Combinations demonstrated additive or supraadditive effects in preclinical models, suggesting potential for clinical trials.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- The mTOR/AKT/PI3K pathway is crucial in human cancer cells, with frequent hyperactivation in uterine sarcoma and carcinosarcoma.
- mTOR inhibitors offer a targeted approach to anticancer therapy by modulating this key pathway.
Purpose of the Study:
- To evaluate the efficacy of rapamycin (RAP) and sapanisertib (MLN), both mTOR inhibitors, as single agents and in combination with gemcitabine (GEM).
- To assess these combinations in in vitro models of uterine sarcoma and carcinosarcoma.
Main Methods:
- Utilized uterine carcinosarcoma (SK-UT-1, SK-UT1-B), leiomyosarcoma (MES-SA), and endometrial stromal sarcoma (ESS-1) cell lines.
- Performed MTT assays to determine cytotoxicity of individual drugs and combinations (RAP+MLN, RAP+GEM, MLN+GEM).
- Employed isobolographic analysis to assess drug interactions.
Main Results:
- Carcinosarcoma cell lines showed limited response to RAP and weak response to MLN; however, MLN combined with GEM exhibited additive and supraadditive effects.
- ESS-1 cells were sensitive to both RAP and MLN (stronger response to MLN), with additive effects observed for all drug combinations.
- MES-SA cells responded to both mTOR inhibitors, with additive effects for GEM, RAP, and MLN combinations, though a slight antagonism was noted between GEM and MLN.
Conclusions:
- Combined treatment with mTOR inhibitors and gemcitabine shows potential for uterine sarcoma and carcinosarcoma therapy.
- The observed additive effects in most cell lines support further preclinical and clinical investigation.
- The unexpected antagonism between gemcitabine and sapanisertib in leiomyosarcoma warrants mechanistic investigation.
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