Abstract
Background
One of the main problems in the treatment of ovarian cancer is resistance to the main drug (cisplatin). Thiostrepton (TST), a thiazole antibiotic, helps weaken cancer cells and enhance the efficacy of platinum-based therapy. This study examines the combination of TST and cisplatin in the SKOV3/CDDP model of resistance, focusing on associated changes in oxidative stress, mitochondrial function, genotoxicity, apoptosis, inflammatory mediators, and Wnt/β-catenin output.Methods
SKOV3/CDDP cells were treated with cisplatin at an IC50 concentration, TST at concentrations (1, 2.5, 5 µM), and the combination of these two substances for 24 h. Cell viability, intracellular energy, and membrane damage were measured by MTT and ATP assays and LDH release, respectively. Apoptosis was assessed using caspase-3/7 and TUNEL activity.DNA damage was analyzed using the Comet and CBMN assays. Oxidative stress and antioxidant defense were assessed by measuring ROS, MDA, GSH/GSSG ratio, and SOD, catalase, and GPx activities. Mitochondrial dysfunction (ΔΨm, NAD+/NADH), cytokines (IL-6, IL-8, TNF-α, IL-1β), and Wnt/β-catenin target genes (c-MYC, AXIN2) were evaluated.Results
The combination of cisplatin and TST was much more potent than when either was used alone. This combination increased oxidative stress processes, increased DNA damage, and decreased antioxidant capacity in cancer cells. Inflammatory cytokine levels were also increased, and c-MYC and AXIN2 expression were reduced, which was accompanied by the attenuation of β-catenin-dependent transcription.Conclusion
Overall, TST increased the sensitivity of resistant ovarian cancer cells to cisplatin. Its anticancer effect was enhanced by oxidative-mitochondrial stress and DNA damage pathways, along with reduced Wnt/β-catenin transcription.