title: Gap junction enhances phototoxicity of photodynamic therapy agent 2-[1-hexyloxyethyl]-2-devinylpyropheophorbide-a (HPPH).
abstract: OBJECTIVE
  It has been reported that 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH)-mediated photodynamic therapy (PDT) effects on antitumor. However, it remains unclear whether gap junction (GJ) acts on phototoxicity of HPPH and which pathways are involved in the process.
  
  
  METHODS
  We determine the effect of HPPH on cancer cell viability and the apoptosis-associated signaling by cell viability assay, reactive oxygen species (ROS) measurement, and caspase-3 activity assay.
  
  
  RESULTS
  Our study uniquely showed that there is a strong correlation between GJ and HPPH-PDT cytotoxicity, that inhibition of GJ function in U87 cells by tetradecanoylphorbol-13-aaetate or carbenoxolone reduces HPPH-PDT cytotoxicity, that and the enhancement of GJ function by retinoid acid in U87 cells increases HPPH-PDT cytotoxicity. We also observed that GJ intercellular communication composed of connexin 32 (Cx32) induced by doxycycline in Hela cells enhances HPPH-PDT phototoxicity. In addition, we indicated that GJ prompts the HPPH-induced apoptosis likely due to the "bystander effect" of passing apoptotic signals between cells, which results in improving the accumulation of ROS, which also amplifies mitochondria depolarization and the activation of caspase-3.
  
  
  CONCLUSIONS
  GJ enhances the efficacy of HPPH-PDT in U87 and Hela; GJ augments ROS production, which enhances the loss of mitochondrial membrane potential and the activation of caspase-3, and increases apoptosis in the tumor cells induced by HPPH-PDT. Our findings provide a basis for further development of GJ as a potential prediction of the efficacy of photodynamic therapy.
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, 74 Zhongshan 2nd Road, Guangzhou, 510080, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Liu
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.forename: Lixia
authors.initials: L
authors.lastname: Fan
authors.forename: Deng Pan
authors.initials: DP
authors.lastname: Wu
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Lucy
authors.initials: L
authors.lastname: Liu
authors.forename: Liang
authors.initials: L
authors.lastname: Tao
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D015415:Biomarkers / Q000378:metabolism; D024201:Bystander Effect; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002734:Chlorophyll / Q000031:analogs & derivatives* / Q000494:pharmacology; D017629:Gap Junctions / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D017319:Photosensitizing Agents / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D015415:Biomarkers; D017319:Photosensitizing Agents; D017382:Reactive Oxygen Species; D002734:Chlorophyll; C083998:2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a; D053148:Caspase 3
keywords: HPPH; Hela; U87; bystander effect; photodynamic therapy