Combined regimen of photodynamic therapy mediated by Gallium phthalocyanine chloride and Metformin enhances anti-melanoma efficacy

• Published in: PloS one 2017-03, Vol.12 (3), p.e0173241-e0173241
• Main Authors: Tudor, Diana, Nenu, Iuliana, Filip, Gabriela Adriana, Olteanu, Diana, Cenariu, Mihai, Tabaran, Flaviu, Ion, Rodica Mariana, Gligor, Lucian, Baldea, Ioana
• Format: Article
• Language: English
• Subjects: Angiogenesis; Antidiabetics; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Biology and Life Sciences; Cancer therapies; Care and treatment; Cell cycle; Cell death; Chlorides; Colorimetry; Complications and side effects; Confocal microscopy; Cytoskeleton; Damage assessment; Development and progression; Diabetes; Dosage and administration; Drug Combinations; Drug therapy; Effectiveness; Enzyme-linked immunosorbent assay; Gallium; Gene expression; Humans; Hypoglycemic Agents - pharmacology; Immune system; Indoles - pharmacology; Kinases; Light; Medicine and Health Sciences; Melanoma; Melanoma - drug therapy; Melanoma - metabolism; Melanoma - pathology; Metastases; Metformin; Metformin - pharmacology; Microscopy; Mortality; Organometallic Compounds - pharmacology; Pharmacology; Pharmacy; Photochemotherapy; Photodynamic therapy; Photosensitizing Agents - pharmacology; Physical Sciences; Physiology; R&D; Research & development; Research and Analysis Methods; Spectrophotometry; TRAIL protein; Transcription activation; Tumor Cells, Cultured; Tumor necrosis factor-α; Type 2 diabetes; Veterinary medicine; Western blotting
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0173241

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. 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. 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. Metformin addition to GaPc-PDT increased tumor cell killing through enhanced oxidative damage and induction of proapoptotic mechanisms, but altered PDT anti-angiogenic effects. Combination of Metformin and PDT might represent a solution to enhance the efficacy, leading to a potential adjuvant role of PDT in melanoma therapy.