Circumvention of resistance to photodynamic therapy in doxorubicin-resistant sarcoma by photochemical internalization of gelonin

Free Radic Biol Med. 2013 Dec;65:1300-1309. doi: 10.1016/j.freeradbiomed.2013.09.010. Epub 2013 Sep 26.


A wide range of anti-cancer therapies have been shown to induce resistance upon repetitive treatment and such adapted resistance may also cause cross-resistance to other treatment modalities. We here show that MES-SA/Dx5 cells with adapted resistance to doxorubicin (DOX) are cross-resistant to photodynamic therapy (PDT). A DOX-induced increased expression of the reactive oxygen species (ROS)-scavenging proteins glutathione peroxidase (GPx) 1 and GPx4 in MES-SA/Dx5 cells was indicated as the mechanism of resistance to PDT in line with the reduction in PDT-generated ROS observed in this cell line. ROS-induced p38 activation was, in addition, shown to be reduced to one-third of the signal of the parental MES-SA cells 2h after PDT, and addition of the p38 inhibitor SB203580 confirmed p38 activation as a death signal after PDT in the MES-SA cells. The MES-SA/Dx5 cells were also cross-resistant to ionizing radiation in agreement with the increased GPx1 and GPx4 expression. Surprisingly, PDT-induced endo/lysosomal release of the ribosome-inactivating protein gelonin (photochemical internalization (PCI)) was more effective in the PDT-resistant MES-SA/Dx5 cells, as measured by synergy calculations in both cell lines. Analysis of death-inducing signaling indicated a low activation of caspase-3 and a strong PARP I cleavage after PDT and PCI in both cell lines. The PARP I activation was, however, stronger after PCI than after PDT in the MES-SA cells, but not in the MES-SA/Dx5 cells, and therefore cannot explain the strong PCI effect in the MES-SA/Dx5 cells. In conclusion PCI of recombinant gelonin circumvents ROS resistance in an apoptosis-independent manner.

Keywords: Doxorubicin, ROS; Free radicals; Glutathione peroxidase; Ionizing radiation; Photochemical internalization; Photodynamic therapy; Resistance; Toxin; p38.

MeSH terms

  • Apoptosis / drug effects
  • Caspase 3 / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Doxorubicin / pharmacology*
  • Drug Resistance, Neoplasm*
  • Enzyme Inhibitors / pharmacology
  • Glutathione Peroxidase / biosynthesis
  • Glutathione Peroxidase GPX1
  • Humans
  • Imidazoles / pharmacology
  • Phospholipid Hydroperoxide Glutathione Peroxidase
  • Phosphorylation
  • Photochemotherapy*
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases / metabolism
  • Pyridines / pharmacology
  • Reactive Oxygen Species
  • Ribosome Inactivating Proteins, Type 1 / pharmacology*
  • Sarcoma* / drug therapy
  • Sarcoma* / radiotherapy
  • Sarcoma* / therapy
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Enzyme Inhibitors
  • Imidazoles
  • Pyridines
  • Reactive Oxygen Species
  • Ribosome Inactivating Proteins, Type 1
  • GEL protein, Gelonium multiflorum
  • Doxorubicin
  • Phospholipid Hydroperoxide Glutathione Peroxidase
  • Glutathione Peroxidase
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases
  • p38 Mitogen-Activated Protein Kinases
  • Caspase 3
  • SB 203580
  • Glutathione Peroxidase GPX1
  • GPX1 protein, human