Synergistic effects of hypericin-mediated photodynamic therapy and low-dose cisplatin on cervical cancer cells

Cisplatin-based chemotherapy has played an important role in increasing patient survival and improving outcomes in cervical cancer. However, the limitations of this therapy on selectivity, invasiveness, drug resistance, and side effects highlight the need to explore innovative approaches. Photodynamic therapy (PDT) has gained attention due to its possible synergistic interactions with conventional treatments and can be easily applied to the cervix. In this study, we evaluated the sequential combination of hypericin-mediated PDT with cisplatin-based chemotherapy against cervical cancer cells and non-tumor control cells. HeLa, SiHa, and HaCaT cells were exposed to cisplatin, hypericin loaded in Pluronic® P123 micelles (Hyp/P123) followed by light irradiation (400-800 nm, 4.1 mW cm^-2, 7.4 J cm^-2), and the combination of both in different administration sequence. The cell viability, morphological changes, proliferation, cell death pathways, and migration capability were assessed. The combined treatment significantly reduced cell viability and was influenced by the sequence in which the treatment was applied. The effects were more pronounced in cervical cancer cells than in non-tumor cells. The optimal combination was Hyp/P123 PDT before cisplatin, which resulted in a 22-fold decrease in the cisplatin IC₅₀ and synergistically inhibited cell viability (Combination Index <1). Moreover, the combined treatment completely inhibited cell proliferation and migration, while increasing late apoptotic-necrotic populations and autophagy-associated activity. These findings suggest that combining Hyp/P123 PDT to increase cisplatin sensitivity is a promising strategy for improving efficacy and reducing dose related toxicity in the treatment of cervical cancer.