Photodynamic priming ( <scp>PDP</scp> ) targets platinum resistance from chronic perfluoroalkyl substances ( <scp>PFAS</scp> ) exposure in ovarian cancer cells

Photodynamic therapy (PDT) is a photochemistry-based treatment modality that synergizes with traditional agents and can overcome chemoresistance. Eighty percent of ovarian cancer patients develop chemoresistant disease, highlighting the need to identify sources of treatment failure and develop rational combinations. Studies have shown that perfluoroalkyl substances (PFAS) induce chemoresistance in a duration-dependent manner in OVCAR-3 cells. PFAS are widespread drinking water contaminants present in the blood of nearly all Americans. The present study evaluated the ability of photodynamic priming (PDP), a sub-cytotoxic variant of PDT, in combination with chemotherapy to overcome chemoresistance in two OVCAR-3 cell cohorts: PFAS chronically-exposed and outgrown (allowed to "recover" from chronic PFAS exposure). Effectiveness of benzoporphyrin derivative- (BPD-) or aminolevulinic acid-induced protoporphyrin IX-PDP (ALA-PpIX-PDP) was assessed in combination with carboplatin and doxorubicin. In PFAS chronically-exposed cells, BPD-PDP + carboplatin reduced survival fraction compared to carboplatin alone. Mitochondrial membrane potential also decreased significantly in both cohorts following ALA-PpIX-PDP-based combinations. PDP + doxorubicin also successfully overcame chemoresistance arising from chronic PFAS exposure but was less effective than PDP + carboplatin. Together, these findings demonstrate the efficacy of PDP-based combinations in overcoming chronic PFAS exposure-induced chemoresistance and should be explored in pre-clinical models of ovarian cancer.