Chemo-sensitivity of ovarian cancer cells enhanced by nanotechnology-based cisplatin intracellular delivery

Platinum resistance is a major challenge in the management of ovarian cancer. Epithelial-Mesenchymal Transition (EMT) and cancer stem cells (CSC) have been associated with platinum resistance. Nanoparticle-mediated cisplatin delivery may serve as an intracellular depot increasing cisplatin efficiency, hence improving the therapeutic efficacy of free cisplatin. Herein, the putative role of intracellular cisplatin concentration in regulating EMT, CSC-like changes and chemo-sensitivity of ovarian cancer SKOV3 cells was investigated. Cell cytotoxicity was assessed after exposure of the cell culture to cisplatin or nanoparticle-cisplatin, analyzing cell viability and apoptosis. The effect of treatments on EMT and CSC-like phenotype was studied by analyzing a panel of markers by flow cytometry. Intracellular platinum concentration was determined by ICS-MS. Gene expression was evaluated by RNAseq analysis. We demonstrate that platinum concentration functions as a key factor to drive features of EMT. The highest intracellular platinum concentration obtained with nanoparticle-cisplatin treatment significantly enhanced apoptosis and prevented EMT phenotype in ovarian tumor cells. Several pathways were associated with chemo-sensitivity, and we identified genes consistently up-regulated or down-regulated shared by the nanoparticle-treated samples compared to the free drug.