Photodynamic therapy with zinc phthalocyanine enhances cisplatin sensitivity of human muscle-invasive bladder cancer cells by downregulation of PI3K/AKT/mTOR signaling pathway

Abstract

Cisplatin (CIS) is mainly used as a chemotherapeutic drug for bladder cancer (BLC). However, the total response of CIS-based chemotherapy in BLC remains unsatisfactory owing to the complex genomic differences, pathological subtypes, and drug resistance. In BLC cells, activation of the PI3K/AKT/mTOR signaling pathway escalates cell proliferation, invasion, and migration. Furthermore, due to the increase in BLC cell viability resulting from PI3K/AKT/mTOR upregulation, BLC cells may acquire resistance to anti-cancer treatments such as CIS-based chemotherapy. Also, the BLC response to CIS may be enhanced when combined with other therapeutic approaches. One such approach is photodynamic therapy (PDT), where a photosensitizer (PS) generates reactive oxygen species (ROS) after illumination of target cells. In this study, the combination of PDT and CIS was applied to treat EJ138 and 5637 cell lines. Cytotoxic effects were determined by MTT assay for assessment, and synergistic effects were estimated using the Combination Index (CI); synergistic effects were observed in all groups. Also, synergistic changes in cell viability, cell migration, and colony formation ability were observed after combination treatment. Moreover, PDT, CIS, and their combination down-regulated the expression of the MMP-9 gene, which impaired cell migration, especially in combination groups. Apoptosis induction was significantly increased compared to either treatment alone. Importantly, CIS, in combination with PDT, down-regulated the PI3K/AKT/mTOR that augmented the CIS sensitivity of BLC cells. In conclusion, it can be suggested that a combination treatment of CIS and PDT has high effects on sensitizing human muscle-invasive bladder cancer cells (EJ138 and 5637 cell lines) to CIS-based chemotherapy.