title: Silymarin inhibits melanoma cell growth both in vitro and in vivo by targeting cell cycle regulators, angiogenic biomarkers and induction of apoptosis.
abstract: Cutaneous malignant melanoma is the leading cause of death from skin diseases and is often associated with activating mutations of the proto-oncogene BRAF. To develop more effective strategies for the prevention or treatment of melanoma, we have examined the inhibitory effects of silymarin, a flavanoid from Silybum marianum, on melanoma cells. Using A375 (BRAF-mutated) and Hs294t (non BRAF-mutated but highly metastatic) human melanoma cell lines, we found that in vitro treatment with silymarin resulted in a dose-dependent: (i) reduction in cell viability; (ii) enhancement of either Go/G1 (A375) or G2-M (Hs294t) phase cell cycle arrest with corresponding alterations in cyclins and cyclin-dependent kinases; and (iii) induction of apoptosis. The silymarin-induced apoptosis of human melanoma cells was associated with a reduction in the levels of anti-apoptotic proteins (Bcl-2 and Bcl-xl), an increase in the levels of pro-apoptotic protein (Bax), and activation of caspases. Further, oral administration of silymarin (500 mg/kg body weight/2× a week) significantly inhibited (60%, P < 0.01) the growth of BRAF-mutated A375 melanoma tumor xenografts, and this was associated with: (i) inhibition of cell proliferation; (ii) induction of apoptosis of tumor cells; (iii) alterations in cell cycle regulatory proteins; and (iv) reduced expression of tumor angiogenic biomarkers in tumor xenograft tissues. These results indicate that silymarin may have a chemotherapeutic effect on human melanoma cell growth and warrant its further evaluation.
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Mudit
authors.initials: M
authors.lastname: Vaid
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Tripti
authors.initials: T
authors.lastname: Singh
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Ram
authors.initials: R
authors.lastname: Prasad
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama.|Birmingham Veterans Affairs Medical Center, Birmingham, Alabama.
authors.forename: Santosh K
authors.initials: SK
authors.lastname: Katiyar
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000235:genetics*; D020169:Caspases / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000235:genetics*; D000090063:Proto-Oncogene Mas; D012838:Silymarin / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000235:genetics; D051020:bcl-X Protein / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D012838:Silymarin; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D020169:Caspases
keywords: angiogenesis; apoptosis; cell proliferation; melanoma; silymarin; tumor xenograft