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Porphyrin photosensitization of multi-drug resistant cell types
1Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201.
Abstract:
The P388 murine leukemia and P388/ADR, a subline expressing the multi-drug resistance (MDR) phenotype, were examined with regard to the role of MDR as a determinant of responsiveness to photodynamic therapy in vitro. Mesoporphyrin was used as a model substrate. We found no differences in porphyrin accumulation nor transport alterations associated with exposure of P388/ADR cells to the verapamil analog DMDP. There was a significant correlation between photodamage to mitochondria vs loss of cell viability in both cell lines, and LD50 sensitizer levels were not significantly different in P388 vs P388/ADR. P388/ADR cells were partly resistant to porphyrin-catalyzed photodamage to amino acid transport, but this result was not associated with differences in sensitizer localization, as indicated by fluorescence studies. Moreover, photodamage to membrane transport was not associated with loss of viability. These studies suggest that cells which express the MDR phenotype are unlikely to be cross-resistant to photodynamic therapy.
Insights
Multi-drug resistance (MDR) does not confer cross-resistance to photodynamic therapy (PDT). Porphyrin accumulation and cell death mechanisms in MDR cells were similar to non-MDR cells, suggesting PDT efficacy against resistant cancers.
Area of Science:
- Photodynamic therapy
- Cancer research
- Cell biology
Background:
- Multi-drug resistance (MDR) is a major challenge in cancer chemotherapy, limiting treatment efficacy.
- Photodynamic therapy (PDT) is an alternative cancer treatment modality using photosensitizers and light.
- The potential for cross-resistance between MDR and PDT is not well understood.
Purpose of the Study:
- To investigate the role of MDR in determining cellular responsiveness to photodynamic therapy (PDT) in vitro.
- To compare porphyrin accumulation, photodamage, and cell viability in P388 leukemia cells and their MDR subline (P388/ADR).
Main Methods:
- Utilized P388 murine leukemia cells and a P388/ADR MDR subline.
- Employed mesoporphyrin as a model photosensitizer for PDT.
- Assessed porphyrin accumulation, mitochondrial photodamage, amino acid transport, and cell viability.
Main Results:
- No significant differences in porphyrin accumulation or transport alterations were observed in P388/ADR cells.
- A strong correlation existed between mitochondrial photodamage and cell viability loss in both cell lines.
- P388/ADR cells showed partial resistance to photodamage of amino acid transport, but this did not impact overall cell viability or sensitizer localization.
Conclusions:
- The MDR phenotype does not appear to confer significant cross-resistance to photodynamic therapy.
- PDT remains a viable therapeutic option for cancers exhibiting multi-drug resistance.
- Mitochondrial photodamage is a key determinant of cell death in PDT, irrespective of MDR status.