title: Combined effects of melatonin and all-trans retinoic acid and somatostatin on breast cancer cell proliferation and death: molecular basis for the anticancer effect of these molecules.
abstract: Melatonin has been shown to inhibit breast cancer cell growth in numerous studies. However, our understanding of the therapeutic effects of this hormone is still marginal and there is little information concerning its combination with other antitumor agents to achieve additional potential benefits. All-trans retinoic acids or somatostatin have been used in combination with melatonin in several pre-clinical and clinical trials, but they have never been combined altogether as an anti-breast cancer treatment. In the present study, we investigated whether the association of melatonin, all-trans retinoic acid and somatostatin leads to an enhanced anticancer activity in MCF-7 breast cancer cells. In such conditions, MCF-7 cells were investigated for cell growth/viability and proliferation, as well as for the expression of cyclin A, and components of the Notch and EGFR pathways, by Western blotting and confocal immunofluorescence. Electrophysiological, morphological, and biochemical analysis were also performed to reveal signs of cell damage and death. We found that melatonin in combination with all-trans retinoic acid and somatostatin potentiated the effects of melatonin alone on MCF-7 cell viability and growth inhibition; this phenomenon was associated with altered conductance through Ca²⁺ and voltage-activated K⁺ (BK) channels, and with substantial impairments of Notch-1 and epidermal growth factor (EGF)-mediated signaling. The combined treatment also caused a marked reduction in mitochondrial membrane potential and intracellular ATP production as well as induction of necrotic cell death. Taken together our results indicate that co-administration of melatonin with all-trans retinoic acid and somatostatin may be of significant therapeutic benefit in breast cancer.
authors.affiliation: Department of Anatomy, Histology, Forensic Medicine, University of Florence, 50134 Florence, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Margheri
authors.forename: Nicola
authors.initials: N
authors.lastname: Pacini
authors.forename: Alessia
authors.initials: A
authors.lastname: Tani
authors.forename: Daniele
authors.initials: D
authors.lastname: Nosi
authors.forename: Roberta
authors.initials: R
authors.lastname: Squecco
authors.forename: Aida
authors.initials: A
authors.lastname: Dama
authors.forename: Erico
authors.initials: E
authors.lastname: Masala
authors.forename: Fabio
authors.initials: F
authors.lastname: Francini
authors.forename: Sandra
authors.initials: S
authors.lastname: Zecchi-Orlandini
authors.forename: Lucia
authors.initials: L
authors.lastname: Formigli
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism; D008550:Melatonin / Q000008:administration & dosage; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D013004:Somatostatin / Q000008:administration & dosage; D014212:Tretinoin / Q000008:administration & dosage
chemical_list: D051036:Large-Conductance Calcium-Activated Potassium Channels; D013004:Somatostatin; D014212:Tretinoin; D000255:Adenosine Triphosphate; D008550:Melatonin