Int J Med Sci 2020; 17(18):2987-2997. doi:10.7150/ijms.48187 This issue

Research Paper

Gemcitabine and Selected mTOR Inhibitors in Uterine Sarcomas and Carcinosarcoma Cells- an Isobolographic Analysis

Marcin Bobiński1✉, Karolina Okła1, Jarogniew Łuszczki2, Wiesława Bednarek1, Anna Wawruszak3, Gema Moreno-Bueno4, Pablo Garcia-Sanz4, Magdalena Dmoszyńska-Graniczka3, Rafał Tarkowski1*, Jan Kotarski1*

1. Medical University of Lublin, I Chair and Department of Gynaecological Oncology and Gynaecology, Poland
2. Medical University of Lublin, Chair and Department of Pathophisiology, Poland
3. Medical University of Lublin, Chair and Department of Biochemistry and Molecular Biology, Poland
4. MD Anderson Cancer Centre Madrid, Laboratorio de Investigación Traslacional Madrid, Spain
*These authors contributed equally to the research

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Citation:
Bobiński M, Okła K, Łuszczki J, Bednarek W, Wawruszak A, Moreno-Bueno G, Garcia-Sanz P, Dmoszyńska-Graniczka M, Tarkowski R, Kotarski J. Gemcitabine and Selected mTOR Inhibitors in Uterine Sarcomas and Carcinosarcoma Cells- an Isobolographic Analysis. Int J Med Sci 2020; 17(18):2987-2997. doi:10.7150/ijms.48187. Available from https://www.medsci.org/v17p2987.htm

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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.

Keywords: uterine sarcomas, carcinosarcomas, mTOR, mTOR inhibitors, gemcitabine, isobolography, rapamycin