C-Phycocyanin-Cisplatin Combination Targeting Redox Balance for Enhanced Efficacy Against Glioblastoma Cells

Cisplatin (CDDP) therapy for glioblastoma (GBM) is linked with several limitations, which include poor penetration of the blood-brain barrier (BBB), systemic toxicity, and the development of drug resistance mechanisms implicating oxidative stress dysregulation and compromised apoptotic pathways. This study evaluates C-Phycocyanin (C-PC) as a potential adjuvant to enhance CDDP efficacy by modulating redox balance and apoptosis.

GBM cells (U87 and U87-EGFRvIII) were treated with CDDP, C-PC, or their combination. Cell viability was assessed by MTT assay; apoptosis was evaluated by DAPI staining and Western blot analysis of cleaved Caspase-3 and poly (ADP-ribose) polymerase (PARP). Both intracellular and extracellular reactive oxygen species (ROS) were measured using 2^',7^'-dichlorodihydrofluorescein diacetate (DCF-DA) fluorescence and lucigenin chemiluminescence, respectively. Catalase activity was quantified via hydrogen peroxide (H₂O₂) decomposition assay, and manganese superoxide dismutase (MnSOD) expression by Western blot.

C-PC selectively decreased U87 GBM cell viability while sparing normal cells. C-PC enhanced CDDP cytotoxicity, reducing viability to 26.5% vs. 53.2% for CDDP alone. This effect correlated with increased apoptosis, evidenced by DNA fragmentation and higher cleaved caspase-3 and PARP levels. Combined treatment lowered ROS below survival thresholds while upregulating MnSOD and catalase activity. In U87-EGFRvIII cells, CDDP reduced viability modestly (85.2%), C-PC alone decreased viability significantly (51.5%) and induced cell death, but the combination did not further increase apoptosis. Here, C-PC's pro-apoptotic effects, alone or with CDDP, were also associated with reduced oxidative stress in cells.

We demonstrate that C-PC enhances CDDP cytotoxicity in sensitive U87 cells by promoting apoptosis and modulating ROS, suggesting potential for improved therapeutic efficacy with reduced systemic toxicity. Compared to the combination, C-PC monotherapy achieves superior cytotoxicity in CDDP-resistant U87-EGFRvIII cells, underscoring its potential as a standalone therapeutic approach for chemotherapy-resistant glioblastoma subtypes.