Roscovitine inhibits differentiation and invasion in a three-dimensional skin reconstruction model of metastatic melanoma.
The aim of this study was to investigate the therapeutic potential of a cyclin-dependent kinase inhibitor, roscovitine, in cultured melanoma cells and a three-dimensional skin reconstruction model of metastatic melanoma. The modulatory effects of roscovitine on the growth and survival of normal melanocytes and cultured melanoma cell lines were tested. Additionally, we investigated the potential of roscovitine to regulate the growth and differentiation of a metastatic melanoma cell line (A375) in a three-dimensional skin reconstruction culture consisting of A375 cells admixed with normal human keratinocytes embedded within a collagen-constricted fibroblast matrix. We show that roscovitine is able to induce apoptosis in the melanoma cell lines A375, 888, and 624 but not in normal human cultured epithelial melanocytes. The degree of apoptosis within these cell lines correlated with the accumulation of p53 protein and concomitant reduction of X-linked inhibitor of apoptosis protein, with no change in the proteins Bcl-2 and survivin. We also found that roscovitine inhibited the growth and differentiation of A375 melanoma cells within the dermal layer of the skin. The results of this study show that roscovitine has the potential to inhibit the differentiation and invasion of metastatic melanoma and may be useful as a therapy for the treatment of patients with metastatic melanoma.
Mohapatra
Subhra
S
Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute and the University of South Florida Medical Center, 12902 Magnolia Drive, Tampa, FL 33612, USA. Subhra.Mohapatra@moffitt.org
Coppola
Domenico
D
Riker
Adam I
AI
Pledger
W Jack
WJ
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology* / Q000556:secondary; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology*; D000077546:Roscovitine; D012878:Skin Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D046509:Tissue Culture Techniques / Q000379:methods*
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011687:Purines; D000077546:Roscovitine