The inhibition of ferrochelatase enhances 5-aminolevulinic acid-based photodynamic action for prostate cancer

Hideo Fukuhara, Keiji Inoue, Atsushi Kurabayashi, Mutsuo Furihata, Hirofumi Fujita, Kozo Utsumi, Junzo Sasaki, Taro Shuin

Research output: Contribution to journalArticlepeer-review

27 Citations (Scopus)

Abstract

Background: The aim of this study was to clarify the mechanism of accumulation of 5-aminolevulinic acid (ALA)-dependent protoporphyrin IX (PpIX), ALA-photodynamic therapy (PDT)-induced cell death and enhanced efficiency by a ferrochelatase inhibitor in prostate cancer PC-3 cells. Methods: The accumulation of ALA-induced PpIX in PC-3 cells was observed by fluorescence microscopy and measured by flow cytometry analysis. The efficiency of ALA-PDT was analyzed by flow cytometry and assessed by cell death, caspase-3 activity and mitochondrial membrane potential. The ALA-PDT-promoting effects of ferrochelatase inhibitors, such as deferoxamine and NOC-18, were also analyzed. We confirmed the results obtained in vivo with an animal model using nude mice. Results: ALA-induced PpIX accumulation increased in time- and ALA concentration-dependent manners. ALA-PDT decreased the levels of mitochondrial membrane potential, and induced cell death occurred by both apoptosis and necrosis. Inhibition of ferrochelatase by deferoxamine and NOC-18 led to increase of PpIX accumulation and enhanced effect of ALA-PDT in PC-3 cells. In vivo, the degeneration of tumor tissue by ALA-PDT was observed within a broader range and led to apoptosis and necrosis. Conclusion: This study demonstrated ALA-PDT induced PC-3 cell death by the mechanisms of both necrosis and apoptosis through a caspase-independent mitochondrial pathway. Inhibition of ferrochelatase enhanced these effects, suggesting that ferrochelatase played an important role in ALA-PDT. ALA-PDT could be a new modality for focal therapy of prostate cancer.

Original languageEnglish
Pages (from-to)399-409
Number of pages11
JournalPhotodiagnosis and Photodynamic Therapy
Volume10
Issue number4
DOIs
Publication statusPublished - Dec 2013

Keywords

  • 5-Aminolevulinic acid
  • Ferrochelatase
  • Photodynamic therapy
  • Prostate cancer
  • Protoporphyrin IX

ASJC Scopus subject areas

  • Biophysics
  • Oncology
  • Dermatology
  • Pharmacology (medical)

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