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

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

doi:10.3390/cancers12030668

Abstract

Photodynamic Therapy (PDT) with methyl-aminolevulinate (MAL-PDT) is being used for the treatment of Basal Cell Carcinoma (BCC), although resistant cells may appear. Normal differentiated cells depend primarily on mitochondrial oxidative phosphorylation (OXPHOS) to generate energy, but cancer cells switch this metabolism to aerobic glycolysis (Warburg effect), influencing the response to therapies. We have analyzed the expression of metabolic markers (β-F1-ATPase/GAPDH (glyceraldehyde-3-phosphate dehydrogenase) ratio, pyruvate kinase M2 (PKM2), oxygen consume ratio, and lactate extracellular production) in the resistance to PDT of mouse BCC cell lines (named ASZ and CSZ, heterozygous for ptch1). We have also evaluated the ability of metformin (Metf), an antidiabetic type II compound that acts through inhibition of the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway to sensitize resistant cells to PDT. The results obtained indicated that resistant cells showed an aerobic glycolysis metabolism. The treatment with Metf induced arrest in the G0/G1 phase and a reduction in the lactate extracellular production in all cell lines. The addition of Metf to MAL-PDT improved the cytotoxic effect on parental and resistant cells, which was not dependent on the PS protoporphyrin IX (PpIX) production. After Metf + MAL-PDT treatment, activation of pAMPK was detected, suppressing the mTOR pathway in most of the cells. Enhanced PDT-response with Metf was also observed in ASZ tumors. In conclusion, Metf increased the response to MAL-PDT in murine BCC cells resistant to PDT with aerobic glycolysis.

Highlights

Basal cell carcinoma (BCC) is the most common skin cancer worldwide, and its incidence rate has increased in recent decades [1]
Since the combination of treatments improved the response to Photodynamic Therapy (PDT), we evaluated if Metf increased the intracellular protoporphyrin IX (PpIX) production, since the amount of this heme metabolite is the basis treatment increased the intracellular PpIX production, since the amount of this heme metabolite is of PDT action
Resistant cells were inoculated in immunosuppressed mice, and the induced tumors were subcultured by explants to obtain a cell population called 10 GT [2]; this process was carried under the basis that the in vivo microenvironment promotes the selection of cells with higher tumorigenic properties

Summary

Introduction

Basal cell carcinoma (BCC) is the most common skin cancer worldwide, and its incidence rate has increased in recent decades [1]. Since BCC usually appears in photo-exposed areas, such as face or extremities, noninvasive therapies such as Photodynamic Therapy (PDT) have been developed for its treatment [3]. PDT is approved in the clinic for the treatment of several forms of non-melanoma skin cancer [4], and there are several clinical trials for gastrointestinal and prostate carcinomas, among other type of cancers [5,6]. MAL is approved for the treatment of actinic keratosis (AKs) in the U.S and the E.U. and for superficial and nodular BCC and Bowen’s disease in the E.U. MAL is approved for the treatment of actinic keratosis (AKs) in the U.S and the E.U. and for superficial and nodular BCC and Bowen’s disease in the E.U. [8,10]

Methods

Results

Conclusion