title: Combined regimen of photodynamic therapy mediated by Gallium phthalocyanine chloride and Metformin enhances anti-melanoma efficacy.
abstract: BACKGROUND
  Melanoma therapy is challenging, especially in advanced cases, due to multiple developed tumor defense mechanisms. Photodynamic therapy (PDT) might represent an adjuvant treatment, because of its bimodal action: tumor destruction and immune system awakening. In this study, a combination of PDT mediated by a metal substituted phthalocyanine-Gallium phthalocyanine chloride (GaPc) and Metformin was used against melanoma. The study aimed to: (1) find the anti-melanoma efficacy of GaPc-PDT, (2) assess possible beneficial effects of Metformin addition to PDT, (3) uncover some of the mechanisms underlining cell killing and anti-angiogenic effects.
  
  
  METHODS
  Two human lightly pigmented melanoma cell lines: WM35 and M1/15 subjected to previous Metformin exposure were treated by GaPc-PDT. Cell viability, death mechanism, cytoskeleton alterations, oxidative damage, were assessed by means of colorimetry, flowcytometry, confocal microscopy, spectrophotometry, ELISA, Western Blotting.
  
  
  RESULTS
  GaPc proved an efficient photosensitizer. Metformin addition enhanced cell killing by mechanisms dependent on the cell line, namely apoptosis in the metastatic M1/15 and necrosis in the radial growth phase, WM35. Cell death mechanism relied on the inhibition of nuclear transcription factor (NF)-κB activation and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) sensitization, leading to TRAIL and TNF-α induced apoptosis. Metformin diminished the anti-angiogenic effect of PDT.
  
  
  CONCLUSIONS
  Metformin addition to GaPc-PDT increased tumor cell killing through enhanced oxidative damage and induction of proapoptotic mechanisms, but altered PDT anti-angiogenic effects.
  
  
  CONCLUSIONS
  Combination of Metformin and PDT might represent a solution to enhance the efficacy, leading to a potential adjuvant role of PDT in melanoma therapy.
authors.affiliation: Department of Physiology, University of Medicine and Pharmacy, Cluj-Napoca, Romania.
authors.forename: Diana
authors.initials: D
authors.lastname: Tudor
authors.affiliation: Department of Physiology, University of Medicine and Pharmacy, Cluj-Napoca, Romania.
authors.forename: Iuliana
authors.initials: I
authors.lastname: Nenu
authors.affiliation: Department of Physiology, University of Medicine and Pharmacy, Cluj-Napoca, Romania.
authors.forename: Gabriela Adriana
authors.initials: GA
authors.lastname: Filip
authors.affiliation: Department of Physiology, University of Medicine and Pharmacy, Cluj-Napoca, Romania.
authors.forename: Diana
authors.initials: D
authors.lastname: Olteanu
authors.affiliation: Department of Biochemistry, University of Agricultural Sciences and Veterinary Medicine, Cluj-Napoca, Romania.
authors.forename: Mihai
authors.initials: M
authors.lastname: Cenariu
authors.affiliation: Department of Pathology University of Agricultural Sciences and Veterinary Medicine, Cluj-Napoca, Romania.
authors.forename: Flaviu
authors.initials: F
authors.lastname: Tabaran
authors.affiliation: Nanomedicine Research Group, National Institute for Research & Development in Chemistry and Petrochemistry - ICECHIM, Bucharest, Romania.
authors.forename: Rodica Mariana
authors.initials: RM
authors.lastname: Ion
authors.affiliation: OSRAM Opto Semiconductors, OSRAM Romania, Global City Business Park, Voluntari, Ilfov, Romania.
authors.forename: Lucian
authors.initials: L
authors.lastname: Gligor
authors.affiliation: Department of Physiology, University of Medicine and Pharmacy, Cluj-Napoca, Romania.
authors.forename: Ioana
authors.initials: I
authors.lastname: Baldea
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D004338:Drug Combinations; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008687:Metformin / Q000494:pharmacology*; D009942:Organometallic Compounds / Q000494:pharmacology*; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004338:Drug Combinations; D007004:Hypoglycemic Agents; D007211:Indoles; D009942:Organometallic Compounds; D017319:Photosensitizing Agents; C515959:phthalocyanine gallium chloride; D008687:Metformin