RT Journal Article SR Electronic T1 Plitidepsin Has a Dual Effect Inhibiting Cell Cycle and Inducing Apoptosis via Rac1/c-Jun NH2-Terminal Kinase Activation in Human Melanoma Cells JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 1093 OP 1101 DO 10.1124/jpet.107.132662 VO 324 IS 3 A1 María J. Muñoz-Alonso A1 Laura González-Santiago A1 Natasha Zarich A1 Teresa Martínez A1 Enrique Alvarez A1 José María Rojas A1 Alberto Muñoz YR 2008 UL http://jpet.aspetjournals.org/content/324/3/1093.abstract AB Melanoma is the most aggressive skin cancer and a serious health problem worldwide because of its increasing incidence and the lack of satisfactory chemotherapy for late stages of the disease. The marine depsipeptide Aplidin (plitidepsin) is an antitumoral agent under phase II clinical development against several neoplasias, including melanoma. We report that plitidepsin has a dual effect on the human SK-MEL-28 and UACC-257 melanoma cell lines; at low concentrations (≤45 nM), it inhibits the cell cycle by inducing G1 and G2/M arrest, whereas at higher concentrations it induces apoptosis as assessed by poly-(ADP-ribose) polymerase cleavage and the appearance of a hypodiploid peak in flow cytometry analyses. Plitidepsin activates Rac1 GTPase and c-Jun NH2-terminal kinase (JNK). In addition, it induces AKT and p38 mitogen-activated protein kinase (MAPK) phosphorylation. By using inhibitors, we found that JNK and p38 MAPK activation depends on Rac1 but not on phosphatidylinositol 3-kinase (PI3K), whereas AKT activation is independent of Rac1 but requires PI3K activity. Plitidepsin cytotoxicity diminishes by Rac1 inhibition or by the blockage of JNK and p38 MAPK using 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580), but not by PI3K inhibition using wortmannin or 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). It is remarkable that plitidepsin and dacarbazine, the alkylating agent most active for treating metastatic melanoma, show a synergistic antiproliferative effect that was paralleled at the level of JNK activation. These results indicate that Rac1/JNK activation is critical for cell cycle arrest and apoptosis induction by plitidepsin in melanoma cells. They also support the combined use of plitidepsin and dacarbazine in in vivo studies. The American Society for Pharmacology and Experimental Therapeutics