Valproic acid induces apoptosis, p16INK4A upregulation and sensitization to chemotherapy in human melanoma cells.
It is known that melanoma develops as a consequence of multifactorial alterations. To date several studies indicate the effective implication of p16 as a tumor suppressor gene with a major role in either the development or progression of human melanoma. Deregulation of melanoma cell growth has been widely associated with mutations in the p16-cyclin D/cdk4-pRb pathway. Recently anticancer therapies are focused on restoration of p16 CDK inhibitory function and other proteins unregulated in melanoma cell cycle pathway (e.g., c-myc, p27). A combined strategy for restoration of normal homeostasis in the melanoma skin with targeted delivery of apoptosis-inducing agents does not seems to be far obtained. New class of antitumoral agents are emerging: histone deacetylase (HDAC) inhibitors have attracted much interest because of their ability to arrest cell growth, induce cell differentiation, and in some cases, induce apoptosis of cancer cells. Recently, attention has been focused on the ability of HDAC inhibitors to induce perturbation in cell cycle regulatory protein (e.g., p21(CIP1)) and down-regulation of survival signalling pathway. In the present study, we have examined the effect of valproic acid (VPA) on M14 human melanoma cell line. Here we observed that VPA induces cell cycle arrest and apoptosis sensitising melanoma cells to cis-platin and etoposide treatment. IC(50) dose (2.99 mM) of VPA was able to induce G(1) arrest (up to 75%) in association with upregulation of p16, p21 and cyclin-D1 related to Rb ipo-phosphorilation. In addition VPA activated apoptosis (50%) in M14 cells, when given alone or in combination with antitumoral agents. The ability of valproic acid to reestablished the G(1) pathway in melanoma cells suggests a potential application of VPA in melanoma therapeutic protocols.
Valentini
Alessandra
A
Department of Internal Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy. ales_valentini@yahoo.it
Gravina
Paolo
P
Federici
Giorgio
G
Bernardini
Sergio
S
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D019942:Genes, p16 / Q000187:drug effects*; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics; D015854:Up-Regulation; D014635:Valproic Acid / Q000494:pharmacology*
D000970:Antineoplastic Agents; D014635:Valproic Acid; D005047:Etoposide; D002945:Cisplatin