Hypoxia, but Not Normoxia, Reduces Effects of Resveratrol on Cisplatin Treatment in A2780 Ovarian Cancer Cells: A Challenge for Resveratrol Use in Anticancer Adjuvant Cisplatin Therapy

• Published in: International journal of molecular sciences 2023-03, Vol.24 (6), p.5715
• Main Authors: Synowiec, Agnieszka, Brodaczewska, Klaudia, Wcisło, Gabriel, Majewska, Aleksandra, Borkowska, Agata, Filipiak-Duliban, Aleksandra, Gawrylak, Aleksandra, Wilkus, Kinga, Piwocka, Katarzyna, Kominek, Agata, Waś, Halina, Lewicki, Sławomir, Siewiera, Jacek, Szczylik, Cezary, Szenajch, Jolanta, Kubiak, Jacek Z, Kieda, Claudine
• Format: Article
• Language: English
• Subjects: Adjuvant treatment; Adjuvants; Angiogenesis; Apoptosis; BAX protein; Cancer; Cancer therapies; Caspase-3; Cell cycle; Cell division; Cell growth; Cell Hypoxia; Cell Line, Tumor; Chemotherapy; Cisplatin; Cisplatin - pharmacology; Cisplatin - therapeutic use; Cytotoxicity; Development and progression; Drug resistance; Drug therapy; epithelial–mesenchymal transition markers; Female; Growth factors; Gynecology and obstetrics; Human health and pathology; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factor 1a; Life Sciences; Medical equipment and supplies industry; Medical test kit industry; Metastasis; Mortality; Necrosis; normoxia; Ovarian cancer; Ovarian Neoplasms - metabolism; Patients; Pharmaceutical sciences; Pharmacology; Reactive oxygen species; Resveratrol; Resveratrol - pharmacology; Scientific equipment and supplies industry; Signal transduction; Snail protein; Solid tumors; Tumor Microenvironment; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factors - metabolism; Vimentin; Zonula occludens-1 protein
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24065715

Natural compounds, such as resveratrol (Res), are currently used as adjuvants for anticancer therapies. To evaluate the effectiveness of Res for the treatment of ovarian cancer (OC), we screened the response of various OC cell lines to the combined treatment with cisplatin (CisPt) and Res. We identified A2780 cells as the most synergistically responding, thus optimal for further analysis. Because hypoxia is the hallmark of the solid tumor microenvironment, we compared the effects of Res alone and in combination with CisPt in hypoxia (pO = 1%) vs. normoxia (pO = 19%). Hypoxia caused an increase (43.2 vs. 5.0%) in apoptosis and necrosis (14.2 vs. 2.5%), reactive oxygen species production, pro-angiogenic HIF-1α (hypoxia-inducible factor-1α) and VEGF (vascular endothelial growth factor), cell migration, and downregulated the expression of ZO1 (zonula occludens-1) protein in comparison to normoxia. Res was not cytotoxic under hypoxia in contrast to normoxia. In normoxia, Res alone or CisPt+Res caused apoptosis via caspase-3 cleavage and BAX, while in hypoxia, it reduced the accumulation of A2780 cells in the G2/M phase. CisPt+Res increased levels of vimentin under normoxia and upregulated SNAI1 expression under hypoxia. Thus, various effects of Res or CisPt+Res on A2780 cells observed in normoxia are eliminated or diminished in hypoxia. These findings indicate the limitations in using Res as an adjuvant with CisPt therapy in OC.