title: Aloe-emodin exerts a potent anticancer and immunomodulatory activity on BRAF-mutated human melanoma cells.
abstract: Aim of this study was to extend the knowledge on the antineoplastic effect of aloe-emodin (AE), a natural hydroxyanthraquinone compound, both in metastatic human melanoma cell lines and in primary stem-like cells (melanospheres). Treatment with AE caused reduction of cell proliferation and induction of SK-MEL-28 and A375 cells differentiation, characterized by a marked increase of transamidating activity of transglutaminase whose expression remained unmodified. In vitro antimetastatic property of AE was evaluated by adhesion and Boyden chamber invasion assays. The effect of AE on melanoma cytokines/chemokines production was determined by a multiplex assay: interestingly AE showed an immunomodulatory activity through GM-CSF and IFN-γ production. We report also that AE significantly reduced the proliferation, stemness and invasive potential of melanospheres. Moreover, AE treatment significantly enhanced dabrafenib (a BRAF inhibitor) antiproliferative activity in BRAF mutant cell lines. Our results confirm that AE possesses remarkable antineoplastic properties against melanoma cells, indicating this anthraquinone as a promising agent for differentiation therapy of cancer, or as adjuvant in chemotherapy and targeted therapy. Further, its mechanisms of action support a potential efficacy of AE treatment to counteract resistance of BRAF-mutated melanoma cells to target therapy.
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy; Department of Biology, University "Tor Vergata", Rome, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Tabolacci
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Cordella
authors.affiliation: Department of Biology, University "Tor Vergata", Rome, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Turcano
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Rossi
authors.affiliation: Department of Biology, University "Tor Vergata", Rome, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Lentini
authors.affiliation: Department of Infectious, Parasitic, and Immunomediated Diseases, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Mariotti
authors.affiliation: Department of Infectious, Parasitic, and Immunomediated Diseases, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Nisini
authors.affiliation: Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Sette
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Eramo
authors.affiliation: Department of Biology, University "Tor Vergata", Rome, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Piredda
authors.affiliation: Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Ruggero
authors.initials: R
authors.lastname: De Maria
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy. Electronic address: francesco.facchiano@iss.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Facchiano
authors.affiliation: Department of Biology, University "Tor Vergata", Rome, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Beninati
mesh_terms: D000880:Anthraquinones / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007155:Immunologic Factors / Q000494:pharmacology*; D008545:Melanoma / Q000235:genetics / Q000473:pathology*; D009154:Mutation; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010091:Oximes / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*
chemical_list: D000880:Anthraquinones; D000970:Antineoplastic Agents; D007093:Imidazoles; D007155:Immunologic Factors; D010091:Oximes; C518327:aloe emodin; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib
keywords: Aloe-emodin; BRAF-mutation; Cytokines; Melanoma cell differentiation; Melanoma-initiating cells