Therapeutic potential of the metabolic modulator phenformin in targeting the stem cell compartment in melanoma
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Tiziana Petrachi1,*, Alessandra Romagnani1,*, Adriana Albini2, Caterina Longo3, Giuseppe Argenziano3,4, Giulia Grisendi5, Massimo Dominici5, Alessia Ciarrocchi1, Katiuscia Dallaglio1
1Laboratory of Translational Research, Department of Scientific Direction, Arcispedale S. Maria Nuova-IRCCS, Reggio Emilia, Italy
2Scientific and Technologic Park, IRCCS MultiMedica, Milan, Italy
3Skin Cancer Unit, IRCCS-Arcispedale Santa Maria Nuova, Reggio Emilia, Italy
4Dermatology Unit, Second University of Naples, Naples, Italy
5Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena and Reggio Emilia, Modena, Italy
*These authors have contributed equally to the work
Katiuscia Dallaglio, email: Katiuscia.Dallaglio@asmn.re.it
Keywords: melanoma, cancer stem cells, phenformin, therapy, ALDH
Received: July 16, 2016 Accepted: December 12, 2016 Published: December 28, 2016
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.
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