Photodynamic priming overcomes platinum resistance from short‐term exposure to select perfluoroalkyl substances in endometrial cancer cell lines

Abstract First‐line treatment for advanced‐stage or recurrent endometrial cancer consists of platinum‐ and taxane‐based chemotherapy, to which many patients will develop resistance. Determining the factors that contribute to platinum resistance and developing alternate treatment options for patients with advanced‐stage gynecologic malignancies is critical to improving survival outcomes. Recently, we published the first study evaluating the contribution of perfluoroalkyl substances (PFAS) exposure to platinum resistance in endometrial cancer cell lines and found that select PFAS induce carboplatin resistance, potentially by dysregulating mitochondrial function. The present study expands upon those findings by examining the efficacy of photodynamic priming (PDP) in combination with carboplatin to overcome PFAS‐induced platinum resistance. Due to the suspected role of mitochondrial dysfunction in platinum resistance, two clinically approved photosensitizers that, in part, localize to mitochondrial membranes or are synthesized in mitochondria were evaluated: benzoporphyrin derivative (BPD) and aminolevulinic acid‐induced protoporphyrin IX (ALA‐PpIX), respectively. Combination of ALA‐PpIX‐mediated PDP + carboplatin resulted in a greater reduction in survival fraction than the same combination with BPD. While PDP with both photosensitizers reduced mitochondrial membrane potential, the reduction was greater with BPD‐PDP than ALA‐PpIX‐PDP. These findings demonstrate that BPD‐PDP and ALA‐PpIX‐PDP in combination with carboplatin can be used to overcome PFAS‐induced platinum resistance in endometrial cancer cells.