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Hosted by the SOT Risk Assessment Specialty Section
Photodynamic priming (PDP), which generates reactive molecular species following light-based activation of an intracellular photosensitizer, can synergize with traditional chemotherapies to overcome chemoresistance. Such contemporary treatment combinations are needed in ovarian cancer (OC), where ~80% of patients develop platinum (Pt)-resistant disease characterized by functional mitochondrial enhancements. While factors underlying the development of Pt resistance are not fully understood, our group recently reported that chronic exposure to per- and poly-fluoroalkyl substances (PFAS) induced Pt resistance in a duration-dependent manner in OC, potentially via inciting mitochondrial biogenesis. Importantly, several photosensitizers used for PDP localize to mitochondria and enable preferential photodamage to this organelle. As a result, PDP may be valuable for targeting mitochondrial effects underlying Pt resistance. The present study evaluated the ability of PDP ± low-dose chemotherapy to overcome Pt resistance in two OVCAR-3 cell cohorts: PFAS chronically-exposed (~35 days of 0.5 µM perfluoroheptanoic acid exposure) and outgrown (allowed to “recover” for ~35 days following chronic PFAS exposure). Two mitochondria-localized photosensitizers, benzoporphyrin derivative (BPD) and aminolevulinic acid-induced protoporphyrin IX (ALA-PpIX), were employed for PDP. Efficacy of PDP + carboplatin (1st line Pt) or doxorubicin (2nd line) and impacts on mitochondrial membrane potential (MMP) and content were compared. In PFAS chronically-exposed cells, which displayed significant resistance to carboplatin and doxorubicin, heightened sensitivity to BPD-PDP + carboplatin or doxorubicin was observed compared to outgrown cells, which had renewed sensitivity to most chemotherapy only treatments. Conversely, while ALA-PpIX-PDP + carboplatin displayed similar efficacies in both cell cohorts, ALA-PpIX-PDP + doxorubicin was much more potent in PFAS chronically-exposed cells. In both cell cohorts, regardless of photosensitizer used, PDP + doxorubicin was not as effective at reducing cell survival as PDP + carboplatin. When evaluating mitochondrial parameters, significant decreases in MMP, which can be suggestive of cell death, occurred in both cell cohorts treated with ALA-PpIX-PDP-based combinations, but not following BPD-PDP-based combinations. Mitochondrial content, however, decreased across all combination therapy groups, indicative of mitochondrial photodamage. Together, these findings demonstrate the efficacy of PDP-based combinations for overcoming PFAS-induced chemoresistance and associated mitochondrial enhancements. Future studies will evaluate PDP-based combinations in spheroid models of OC, which have increased physiological relevance compared to monolayer cultures, as well as the use of BPD-photoimmunoconjugates (PICs), which enable increased tumor-specific uptake compared to free photosensitizers.
Speaker
Brittany Rickard, PhD, North Carolina State University
Winner of the 2026 RASS John Doull Risk Assessment Award