Metformin associated with photodynamic therapy – A novel oncological direction

Nenu, Iuliana; Popescu, Tiberiu; Aldea, Mihaela; Craciun, Lucian; Olteanu, Diana; Tatomir, Corina; Bolfă, Pompei; Ion, Rodica‐Mariana; Muresan, Adriana; Filip, Gabriela Adriana

doi:10.1016/j.jphotobiol.2014.04.027

Cited by 21 publications

(14 citation statements)

References 38 publications

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“…Addition of Metformin to the GaPc-PDT treatment increased the therapy efficiency in both cell lines, similarly to our previous report for Walker carcinosarcoma PDT [7]. In the M1-15 metastatic melanoma, Metformin significantly increased PDT cell killing and induced apoptosis of the melanoma cells.…”

Section: Discussionsupporting

confidence: 88%

“…There is a strong, GaPc-PDT induced inhibition of VEGF and HIF-1α, consistent for both cell lines, while combined regimen decreased this effect. Previously, we have reported that the combination of Metformin and PDT reduced angiogenesis in vivo , on Walker carcinosarcoma [7]. There are reports showing a beneficial role of Metformin in the inhibition of neoangiogenesis [81, 82, 83].…”

Section: Discussionmentioning

confidence: 99%

“…In anti-melanoma therapy there are three ongoing clinical trials that are recruiting patients and are using Metformin in combination with BRAF inhibitors (ClinicalTrials.gov, Identifier: NCT01638676 and NCT02143050) and also in association with Dacarbazine (ClinicalTrials.gov, Identifier: NCT02190838). In a previous study conducted by our group, association of Metformin to PDT in Walker-256 carcinosarcoma experimental model improved the overall anti-tumor effects [7]. Based on these findings, the current research aims to study the possible anti-tumor role of Metformin as an adjuvant in photodynamic therapy against melanoma.…”

Section: Introductionmentioning

confidence: 94%

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

et al. 2017

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

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

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

et al. 2017

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“…PDT is an ideal theoretical approach because it induces direct tumor cell photodamage, targets tumor vasculature, and activates the immune response. Due to a limited experience of PDT in melanoma, extensive clinical studies need to be conducted, using selected photosensitizers and standard irradiation protocols and also several combination regimens with chemotherapy or immunotherapy, in order to obtain an established antitumoral effect [107,112].…”

Section: Photodynamic Therapymentioning

confidence: 99%

Current position of TNF-α in melanomagenesis

et al. 2015

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Melanoma is one of the most heterogeneous and immunogenic forms of cancer. Both tumor and stroma cells synthesize many cytokines involved in rapid development and metastasis. One of these cytokines from the tumor milieu is tumor necrosis factor-alpha (TNF-α), which seems to have an intricate role in melanomagenesis. Initially, it was found that TNF-α can induce apoptosis of tumor cells through both extrinsic and intrinsic pathways, in contrast with later studies that revealed its protumoral activity. TNF-α is involved in inflammation, inducing the secretion of survival molecules like antiapoptotic proteins, proangiogenetic factors and metastasis markers. Although there are many therapeutic strategies against melanoma, the prognosis of advanced stages remains poor, due to several tumor resistance mechanisms. TNF seems to be a negative prognostic factor in melanoma surgery and correlates with chemotherapy resistance. However, high intratumoral levels of TNF-α might be beneficial for immunotherapy. Researchers may redirect their studies in the future by double activating of the proinflammatory molecule TNF-α and the immune cells in order to obtain an antitumoral response in metastatic melanoma.

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“…Cellular morphology visible by electron microscopy necessary for identifying the apoptotic cells. After PDT treatment, cells are developing morphological features characteristic of apoptosis: chromatin compaction into uniform electron-dense masses with nuclear margination, nuclear fragmentation, cellular shrinkage, cell membrane vacuolization and blebbing, and the increase in electron-density of the cytosol [63][64][65].…”

mentioning

confidence: 99%

Oxidative Stress-Based Photodynamic Therapy with Synthetic Sensitizers and/or Natural Antioxidants

Ion¹,

Şuică-Bunghez²

2015

Basic Principles and Clinical Significance of Oxidative Stress

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Photodynamic therapy (also called PDT, photoirradiation therapy, phototherapy, or photochemotherapy) as a new modality for cancer treatment involves the combination of light with a photosensitizing drug in an oxygen-rich environment. PDT consists in the systemic administration of a photosensitizer (PS), which is selectively retained by tumor cells and the subsequent irradiation with visible light of the affected area.

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Metformin associated with photodynamic therapy – A novel oncological direction

Cited by 21 publications

References 38 publications

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

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

Current position of TNF-α in melanomagenesis

Oxidative Stress-Based Photodynamic Therapy with Synthetic Sensitizers and/or Natural Antioxidants

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