Comparison between endothelial and tumor cells in the response to verteporfin-photodynamic therapy and a PI3K pathway inhibitor

Photodiagnosis Photodyn Ther. 2015 Mar;12(1):19-26. doi: 10.1016/j.pdpdt.2015.01.004. Epub 2015 Jan 28.

Abstract

Background: Photodynamic therapy (PDT) is an established cancer treatment. Molecular-targeted agents targeting phosphatidylinositol 3-kinase (PI3K) pathway is showing great promise as anticancer drugs. This study compared SVEC mouse endothelial and PC-3 human prostate tumor cells in the response to verteporfin-mediated photodynamic therapy (PDT) and a pan-PI3K pathway inhibitor LY294002.

Methods: Verteporfin cellular uptake and intracellular localization was determined by spectrofluorometry and confocal fluorescence microscopy, respectively, in the SVEC and PC-3 cells. Cytotoxicity induced by LY294002 and verteporfin-PDT was assessed by the MTS assay. Effects of treatments on cell survival and death signaling were examined by Western blot analysis.

Results: PC-3 cells had a higher cellular uptake of verteporfin than SVEC cells at 15min after incubation with verteporfin. Verteporfin was mainly localized in mitochondria in both SVEC and PC-3 cells. Verteporfin-PDT alone as well as PDT in combination with LY294002 induced more apoptosis and caused more reduction in cell viability in SVEC cells than in PC-3 cells. PC-3 cells exhibited a higher level of anti-apoptotic Bcl-2 family proteins than SVEC cells.

Conclusions: SVEC cells were more responsive to verteporfin-PDT and PI3K pathway inhibitor LY294002 than PC-3 cells. Such differences in response were likely due to differences in Bcl-2 family protein level. These results support tumor vascular targeting by verteporfin-PDT and its therapeutic enhancement by PI3K pathway inhibition.

Keywords: Apoptosis; LY294002; Phosphatidylinositol 3-kinase (PI3K) inhibitor; Photodynamic therapy (PDT); Verteporfin.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects
  • Cell Line
  • Cell Survival / drug effects
  • Cell Survival / radiation effects
  • Chromones / therapeutic use
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects*
  • Endothelial Cells / metabolism
  • Humans
  • Male
  • Mice
  • Morpholines / therapeutic use
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Photochemotherapy / methods*
  • Photosensitizing Agents / therapeutic use
  • Porphyrins / therapeutic use*
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / metabolism*
  • Signal Transduction / drug effects
  • Treatment Outcome
  • Verteporfin

Substances

  • Antineoplastic Agents
  • Chromones
  • Morpholines
  • Photosensitizing Agents
  • Porphyrins
  • Verteporfin
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Phosphatidylinositol 3-Kinases