title: Therapeutic potential of the metabolic modulator phenformin in targeting the stem cell compartment in melanoma.
abstract: Melanoma is the most dangerous and treatment-resistant skin cancer. Tumor resistance and recurrence are due to the persistence in the patient of aggressive cells with stem cell features, the cancer stem cells (CSC). Recent evidences have shown that CSC display a distinct metabolic profile as compared to tumor bulk population: a promising anti-tumor strategy is therefore to target specific metabolic pathways driving CSC behavior. Biguanides (metformin and phenformin) are anti-diabetic drugs able to perturb cellular metabolism and displaying anti-cancer activity. However, their ability to target the CSC compartment in melanoma is not known. Here we show that phenformin, but not metformin, strongly reduces melanoma cell viability, growth and invasion in both 2D and 3D (spheroids) models. While phenformin decreases melanoma CSC markers expression and the levels of the pro-survival factor MITF, MITF overexpression fails to prevent phenformin effects. Phenformin significantly reduces cell viability in melanoma by targeting both CSC (ALDHhigh) and non-CSC cells and by significantly reducing the number of viable cells in ALDHhigh and ALDHlow-derived spheroids. Consistently, phenformin reduces melanoma cell viability and growth independently from SOX2 levels. Our results show that phenformin is able to affect both CSC and non-CSC melanoma cell viability and growth and suggests its potential use as anti-cancer therapy in melanoma.
authors.affiliation: Laboratory of Translational Research, Department of Scientific Direction, Arcispedale S. Maria Nuova-IRCCS, Reggio Emilia, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Petrachi
authors.affiliation: Laboratory of Translational Research, Department of Scientific Direction, Arcispedale S. Maria Nuova-IRCCS, Reggio Emilia, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Romagnani
authors.affiliation: Scientific and Technologic Park, IRCCS MultiMedica, Milan, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Albini
authors.affiliation: Skin Cancer Unit, IRCCS-Arcispedale Santa Maria Nuova, Reggio Emilia, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Longo
authors.affiliation: Skin Cancer Unit, IRCCS-Arcispedale Santa Maria Nuova, Reggio Emilia, Italy.|Dermatology Unit, Second University of Naples, Naples, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Argenziano
authors.affiliation: Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Grisendi
authors.affiliation: Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Dominici
authors.affiliation: Laboratory of Translational Research, Department of Scientific Direction, Arcispedale S. Maria Nuova-IRCCS, Reggio Emilia, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Ciarrocchi
authors.affiliation: Laboratory of Translational Research, Department of Scientific Direction, Arcispedale S. Maria Nuova-IRCCS, Reggio Emilia, Italy.
authors.forename: Katiuscia
authors.initials: K
authors.lastname: Dallaglio
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008687:Metformin / Q000494:pharmacology; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010629:Phenformin / Q000494:pharmacology*; D010641:Phenotype; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018874:Spheroids, Cellular; D013997:Time Factors; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D008687:Metformin; D010629:Phenformin; D000444:Aldehyde Dehydrogenase
keywords: ALDH; cancer stem cells; melanoma; phenformin; therapy