Metformin as an Adjuvant to Photodynamic Therapy in Resistant Basal Cell Carcinoma Cells

Mascaraque, Marta; Delgado-Wicke, Pablo; Nuevo‐Tapioles, Cristina; Gracia‐Cazaña, Tamara; Abarca-Lachen, Edgar; González, Salvador; Cuezva, José M.; Gilaberte, Yolanda; Juarranz, Ángeles

doi:10.3390/cancers12030668

Cited by 15 publications

(21 citation statements)

References 48 publications

(70 reference statements)

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“…The reprogramming of mitochondrial metabolism is a common hallmark of cancer 10 . Cancer cells often switch metabolism from OXPHOS to aerobic glycolysis in order to produce energy, which can allow them to better adapt to the hypoxic tumor microenvironment and aid rapid proliferation 29 , 30 . The Warburg effect is associated with increased levels of glucose uptake and high rates of glycolysis, combined with the production of lactic acid, even in the presence of oxygen 11 .…”

Section: Role Of Mitochondrial Dysfunction In Cancer Developmentmentioning

confidence: 99%

The crosstalk between HIFs and mitochondrial dysfunctions in cancer development

et al. 2021

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Mitochondria are essential cellular organelles that are involved in regulating cellular energy, metabolism, survival, and proliferation. To some extent, cancer is a genetic and metabolic disease that is closely associated with mitochondrial dysfunction. Hypoxia-inducible factors (HIFs), which are major molecules that respond to hypoxia, play important roles in cancer development by participating in multiple processes, such as metabolism, proliferation, and angiogenesis. The Warburg phenomenon reflects a pseudo-hypoxic state that activates HIF-1α. In addition, a product of the Warburg effect, lactate, also induces HIF-1α. However, Warburg proposed that aerobic glycolysis occurs due to a defect in mitochondria. Moreover, both HIFs and mitochondrial dysfunction can lead to complex reprogramming of energy metabolism, including reduced mitochondrial oxidative metabolism, increased glucose uptake, and enhanced anaerobic glycolysis. Thus, there may be a connection between HIFs and mitochondrial dysfunction. In this review, we systematically discuss the crosstalk between HIFs and mitochondrial dysfunctions in cancer development. Above all, the stability and activity of HIFs are closely influenced by mitochondrial dysfunction related to tricarboxylic acid cycle, electron transport chain components, mitochondrial respiration, and mitochondrial-related proteins. Furthermore, activation of HIFs can lead to mitochondrial dysfunction by affecting multiple mitochondrial functions, including mitochondrial oxidative capacity, biogenesis, apoptosis, fission, and autophagy. In general, the regulation of tumorigenesis and development by HIFs and mitochondrial dysfunction are part of an extensive and cooperative network.

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Section: Role Of Mitochondrial Dysfunction In Cancer Developmentmentioning

confidence: 99%

The crosstalk between HIFs and mitochondrial dysfunctions in cancer development

et al. 2021

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“…After irradiation, cells were incubated for 24 h in normal conditions before evaluation. This treatment conditions were selected according to previous works performed in our research group as capable to induce cell death in SCC13 and in A431 [ 10 , 40 ].…”

Section: Methodsmentioning

confidence: 99%

“…PDT is a non-invasive and localized therapy that exerts minimal or no damage and improved healing capacity in the surrounding healthy tissues [ 10 , 11 ]. It consists of a two-step procedure by which the local or systemic administration of a photosensitizer (PS) or its precursor is followed by the irradiation of the lesion with light of a specific wavelength.…”

Section: Introductionmentioning

confidence: 99%

TGFβ1 Secreted by Cancer-Associated Fibroblasts as an Inductor of Resistance to Photodynamic Therapy in Squamous Cell Carcinoma Cells

Gallego-Rentero

Gutiérrez-Pérez

Fernández‐Guarino

et al. 2021

Cancers

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As an important component of tumor microenvironment, cancer-associated fibroblasts (CAFs) have lately gained prominence owing to their crucial role in the resistance to therapies. Photodynamic therapy (PDT) stands out as a successful therapeutic strategy to treat cutaneous squamous cell carcinoma. In this study, we demonstrate that the transforming growth factor β1 (TGFβ1) cytokine secreted by CAFs isolated from patients with SCC can drive resistance to PDT in epithelial SCC cells. To this end, CAFs obtained from patients with in situ cSCC were firstly characterized based on the expression levels of paramount markers as well as the levels of TGFβ1 secreted to the extracellular environment. On a step forward, two established human cSCC cell lines (A431 and SCC13) were pre-treated with conditioned medium obtained from the selected CAF cultures. The CAF-derived conditioned medium effectively induced resistance to PDT in A431 cells through a reduction in the cell proliferation rate. This resistance effect was recapitulated by treating with recombinant TGFβ1 and abolished by using the SB525334 TGFβ1 receptor inhibitor, providing robust evidence of the role of TGFβ1 secreted by CAFs in the development of resistance to PDT in this cell line. Conversely, higher levels of recombinant TGFβ1 were needed to reduce cell proliferation in SCC13 cells, and no induction of resistance to PDT was observed in this cell line in response to CAF-derived conditioned medium. Interestingly, we probed that the comparatively higher intrinsic resistance to PDT of SCC13 cells was mediated by the elevated levels of TGFβ1 secreted by this cell line. Our results point at this feature as a promising biomarker to predict both the suitability of PDT and the chances to optimize the treatment by targeting CAF-derived TGFβ1 in the road to a more personalized treatment of particular cSCC tumors.

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“…Metformin as an Adjuvant to Photodynamic Therapy in Resistant Basal Cell Carcinoma Cells: Mascaraque et al showed evidence, in vitro and in vivo in mice, that metformin improves the cytotoxic effect of MAL-PDT either in PDT sensitive or resistant cells [ 12 ]. This effect was not related with an increase in PpIX accumulation but related to the activation of pAMPK and the suppression of the mTOR pathway.…”

Section: Research Snippetsmentioning

confidence: 99%