title: Fisetin, a phytochemical, potentiates sorafenib-induced apoptosis and abrogates tumor growth in athymic nude mice implanted with BRAF-mutated melanoma cells.
abstract: Melanoma is the most deadly form of cutaneous malignancy, and its incidence rates are rising worldwide. In melanoma, constitutive activation of the BRAF/MEK/ERK (MAPK) and PI3K/AKT/mTOR (PI3K) signaling pathways plays a pivotal role in cell proliferation, survival and tumorigenesis. A combination of compounds that lead to an optimal blockade of these critical signaling pathways may provide an effective strategy for prevention and treatment of melanoma. The phytochemical fisetin is known to possess anti-proliferative and pro-apoptotic activities. We found that fisetin treatment inhibited PI3K signaling pathway in melanoma cells. Therefore, we investigated the effect of fisetin and sorafenib (an RAF inhibitor) alone and in combination on cell proliferation, apoptosis and tumor growth. Combination treatment (fisetin + sorafenib) more effectively reduced the growth of BRAF-mutated human melanoma cells at lower doses when compared to individual agents. In addition, combination treatment resulted in enhanced (i) apoptosis, (ii) cleavage of caspase-3 and PARP, (iii) expression of Bax and Bak, (iv) inhibition of Bcl2 and Mcl-1, and (v) inhibition of expression of PI3K, phosphorylation of MEK1/2, ERK1/2, AKT and mTOR. In athymic nude mice subcutaneously implanted with melanoma cells (A375 and SK-MEL-28), we found that combination therapy resulted in greater reduction of tumor growth when compared to individual agents. Furthermore, combination therapy was more effective than monotherapy in: (i) inhibition of proliferation and angiogenesis, (ii) induction of apoptosis, and (iii) inhibition of the MAPK and PI3K pathways in xenograft tumors. These data suggest that simultaneous inhibition of both these signaling pathways using combination of fisetin and sorafenib may serve as a therapeutic option for the management of melanoma.
authors: Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors: Harish Chandra
authors: HC
authors: Pal
authors: Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors: Ronald D
authors: RD
authors: Baxter
authors: Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors: Katherine M
authors: KM
authors: Hunt
authors: Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors: Jyoti
authors: J
authors: Agarwal
authors: Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA.|Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors: Craig A
authors: CA
authors: Elmets
authors: Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA.|Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors: Mohammad
authors: M
authors: Athar
authors: Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA.|Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors: Farrukh
authors: F
authors: Afaq
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage / Q000494:pharmacology*; D044948:Flavonols; D006801:Humans; D007150:Immunohistochemistry; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D053148:Caspase 3; D005419:Flavonoids; D044948:Flavonols; D020928:Mitogen-Activated Protein Kinases; D009536:Niacinamide; D010671:Phenylurea Compounds; D019869:Phosphatidylinositol 3-Kinases; D011065:Poly(ADP-ribose) Polymerases; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D019253:Proto-Oncogene Proteins c-bcl-2; D000077157:Sorafenib; C017875:fisetin
keywords: apoptosis; cell proliferation; fisetin; melanoma; sorafenib