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Photodynamic Priming Overcomes Per- and Polyfluoroalkyl Substance (PFAS)-Induced Platinum Resistance in Ovarian Cancer

Brittany P Rickard, Xianming Tan, Suzanne E Fenton, Imran Rizvi

Publication

Publication

Photochemistry & Photobiology DOI: https://doi.org/10.1111/php.13728
DOI: https://doi.org/10.22427/NTP-DATA-021-00006-0002-0000-1
PMID: 36148678

Abstract

Per- and polyfluoroalkyl substances (PFAS) are widespread environmental contaminants linked to adverse outcomes, including for female reproductive biology and related cancers. We recently reported, for the first time, that PFAS induce platinum resistance in ovarian cancer, potentially through altered mitochondrial function. Platinum resistance is a major barrier in the management of ovarian cancer, necessitating complementary therapeutic approaches. Photodynamic therapy (PDT) is a light-based treatment modality that reverses platinum resistance and synergizes with platinum-based chemotherapy. The present study is the first to demonstrate the ability of photodynamic priming (PDP), a low-dose, sub-cytotoxic variant of PDT, to overcome PFAS-induced platinum resistance. Comparative studies of PDP efficacy using either benzoporphyrin derivative (BPD) or 5-aminolevulinic acid-induced protoporphyrin IX (PpIX) were conducted in two human ovarian cancer cell lines (NIH:OVCAR-3 and Caov-3). BPD and PpIX are clinically approved photosensitizers that preferentially localize to, or are partly synthesized in, mitochondria. PDP overcomes carboplatin resistance in PFAS-exposed ovarian cancer cells, demonstrating the feasibility of this approach to target the deleterious effects of environmental contaminants. Decreased survival fraction in PDP + carboplatin treated cells was accompanied by decreased mitochondrial membrane potential, suggesting that PDP modulates the mitochondrial membrane, reducing membrane potential and re-sensitizing ovarian cancer cells to carboplatin.

Graphical Abstract

Tables

Table 1. Summary of Results

Figures

All Figures were made from this data file:

Figure 1. Effect of PFHpA and PFPA on light-dose-dependent responses to BPD-PDT (green box) or ALA-PpIX-PDT (black box) in OVCAR-3 and Caov-3 cells.

Figure 2. Effect of PFAS mixtures on light-dose-dependent responses to BPD-PDT (green box) or ALA-PpIX-PDT (black box) in OVCAR-3 and Caov-3 cells

Figure 3. Survival fraction decreased in PFAS-exposed OVCAR-3 and Caov-3 cells post-BPD-PDP or ALA-PpIX-PDP + carboplatin

Figure 4. In OVCAR-3 and Caov-3 cells exposed to PFAS mixtures, BPD-PDP was more effective than ALA-PpIX-PDP at reducing survival fraction in combination with carboplatin

Figure 5. In OVCAR-3 and Caov-3 cell exposure groups where platinum resistance was not observed, photosensitizer efficacy for PDP differed between BPD and ALA-PpIX

Figure 6. BPD-PDP and ALA-PpIX-PDP overcame resistance to carboplatin induced by PFAS and PFAS mixtures in OVCAR-3 (blue) and Caov-3 (red) cells

Figure 7. DΨm decreased in PFAS-exposed OVCAR-3 and Caov-3 cells after BPD-PDP (green box) or ALA-PpIX-PDP (black box) in combination with carboplatin

Figure 8. DΨm decreased after BPD-PDP (green box) or ALA-PpIX-PDP (black box) in combination with carboplatin in OVCAR-3 and Caov-3 cells exposed to PFAS mixtures

Supplemental Tables

Table S1. Summary of results.

Supplemental Figures

Figure S1. Absorbance spectra for the PFAS agents evaluated in the present study.

Figure S2. Effect of 1% methanol on survival fraction post-BPD-PDT (green box) or ALA-PpIX-PDT (black box) in OVCAR-3 and Caov-3 cells.

Figure S3. Effect of PFOA on BPD-PDT (green box) and ALA-PpIX-PDT (black box) dose-response curves in OVCAR-3 and Caov-3 cells.

Figure S4. Effect of PFAS mixtures on BPD-PDT (green box) and ALA-PpIX-PDT (black box) dose-response curves in OVCAR-3 and Caov-3 cells.

Figure S5. Survival fraction decreased in PFAS-exposed OVCAR-3 and Caov-3 cells post-BPD-PDP and ALA-PpIX-PDP + carboplatin.

Figure S6. Survival fraction remained largely unchanged in PFAS mixture-exposed OVCAR-3 and Caov-3 cells post-BPD-PDP or ALA-PpIX-PDP.

Figure S7. In OVCAR-3 cell exposure groups where platinum resistance was observed, photosensitizer efficacy for PDP in combination with 100 μm carboplatin did not differ between BPD and ALA-PpIX

Figure S8. In Caov-3 cell exposure groups where platinum resistance was observed, photosensitizer efficacy for PDP in combination with 100 μm carboplatin did not differ between BPD and ALA-PpIX.

Figure S9. Survival fraction in OVCAR-3 cells was largely unaffected by 630 nm or 690 nm light after PFAS exposure.

Figure S10. Survival fraction in Caov-3 cells was not affected by 630 nm or 690 nm light after PFAS exposure.

Figure S11. Survival fraction in OVCAR-3 cells was not affected by 630 nm or 690 nm light after exposure to PFAS mixtures.

Figure S12. Survival fraction in Caov-3 cells was not affected by 630 nm or 690 nm light after exposure to PFAS mixtures.

Figure S13. ΔΨm decreased in PFOA-exposed OVCAR-3 and Caov-3 cells after BPD-PDP (green box) or ALA-PpIX-PDP (black box) and carboplatin treatment.

Figure S14. ΔΨm decreased in PFAS mixture-exposed OVCAR-3 and Caov-3 cells after BPD-PDP (green box) or ALA-PpIX-PDP (black box) and carboplatin treatment.

Figure S15. ΔΨm was unchanged in OVCAR-3 (blue) and Caov-3 (red) cells pre- and post-BPD-PDP or ALA-PpIX-PDP, photosensitizer incubation, and irradiation.