title: Fisetin, a dietary flavonoid, augments the anti-invasive and anti-metastatic potential of sorafenib in melanoma.
abstract: Melanoma is the most aggressive and deadly form of cutaneous neoplasm due to its propensity to metastasize. Oncogenic BRAF drives sustained activation of the BRAF/MEK/ERK (MAPK) pathway and cooperates with PI3K/AKT/mTOR (PI3K) signaling to induce epithelial to mesenchymal transition (EMT), leading to cell invasion and metastasis. Therefore, targeting these pathways is a promising preventive/therapeutic strategy. We have shown that fisetin, a flavonoid, reduces human melanoma cell invasion by inhibiting EMT. In addition, fisetin inhibited melanoma cell proliferation and tumor growth by downregulating the PI3K pathway. In this investigation, we aimed to determine whether fisetin can potentiate the anti-invasive and anti-metastatic effects of sorafenib in BRAF-mutated melanoma. We found that combination treatment (fisetin + sorafenib) more effectively reduced the migration and invasion of BRAF-mutated melanoma cells both in vitro and in raft cultures compared to individual agents. Combination treatment also effectively inhibited EMT as observed by a decrease in N-cadherin, vimentin and fibronectin and an increase in E-cadherin both in vitro and in xenograft tumors. Furthermore, combination therapy effectively inhibited Snail1, Twist1, Slug and ZEB1 protein expression compared to monotherapy. The expression of MMP-2 and MMP-9 in xenograft tumors was further reduced in combination treatment compared to individual agents. Bioluminescent imaging of athymic mice, intravenously injected with stably transfected CMV-luciferase-ires-puromycin.T2A.EGFP-tagged A375 melanoma cells, demonstrated fewer lung metastases following combination treatment versus monotherapy. Our findings demonstrate that fisetin potentiates the anti-invasive and anti-metastatic effects of sorafenib. Our data suggest that fisetin may be a worthy adjuvant chemotherapy for the management of melanoma.
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Harish C
authors.initials: HC
authors.lastname: Pal
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Ariana C
authors.initials: AC
authors.lastname: Diamond
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Leah R
authors.initials: LR
authors.lastname: Strickland
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Kappes
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama, USA.|Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Santosh K
authors.initials: SK
authors.lastname: Katiyar
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama, USA.|Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Elmets
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama, USA.|Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Athar
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama, USA.|Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Farrukh
authors.initials: F
authors.lastname: Afaq
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004357:Drug Synergism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage / Q000494:pharmacology; D044948:Flavonols; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008819:Mice, Nude; D009154:Mutation; D009361:Neoplasm Invasiveness; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D000077157:Sorafenib; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D015820:Cadherins; D005419:Flavonoids; D044948:Flavonols; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C017875:fisetin
keywords: EMT; fisetin; invasion; melanoma; sorafenib