Enhanced production of reactive oxygen species in HeLa cells under concurrent low-dose carboplatin and Photofrin((R)) photodynamic therapy

摘要

Concurrent low-dose carboplatin/Photofrin((R)) photodynamic therapy (ccPDT) has been shown to promote relapse-free complete tumor regression in cervical or endometrial cancer patients as a fertility-preservation therapy. This study aimed to investigate the molecular mechanism of the enhanced therapeutic efficacy of ccPDT by determining intracellular reactive oxygen species (ROS) and necrotic or apoptotic cell damage in HeLa cells loaded with fluorescent oxidant agents and Photofrin or/and carboplatin under light irradiation. The cytotoxic effects of ccPDT were compared when monitored with a light dose under carboplatin or Photofrin alone. Photofrin-PDT alone did not enhance either hydroxyl radicals (OH center dot) or superoxide anions (O-2(center dot-)), but a slight enhancement of hydrogen peroxide (H2O2) production was observed. A larger enhancement of ROS production was obtained in a dose-dependent manner following ccPDT, especially OH center dot and H2O2, in conjunction with both necrotic and apoptotic cell death, compared with necrotic-prone PDT alone. The carboplatin-mediated Fenton reaction: 2[Pt-II](2) + H2O2 [Pt-2.25](4) + OH+ OH center dot was proposed to explain the dose-dependent enhancement of OH center dot. In conclusion, the therapeutic enhancement of ccPDT in vitro was attributable to the carboplatin-mediated synergetic production of OH and apoptotic cellular damage, compared with Photofrin-PDT alone.