Plitidepsin has a dual effect inhibiting cell cycle and inducing apoptosis via Rac1/JNK activation in human melanoma cells.
Munoz-Alonso MJ, Gonzalez-Santiago L, Zarich N, Martinez T, Alvarez E, Rojas JM, Munoz A
Instituto de Investigaciones Biomedicas "Alberto Sols" CSIC and Pharma Mar SA.
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 plitidepsin (Aplidin((R))) is an anti-tumoral 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 while at higher concentrations it induces apoptosis as assessed by PARP cleavage and the appearance of a hypodiploid peak in flow cytometry analyses. Plitidepsin activates Rac1 GTPase and c-Jun N-terminal kinase (JNK) and, in addition, it induces AKT and p38MAPK phosphorylation. By using inhibitors, we found that JNK and p38MAPK activation depends on Rac1 but not on PI3K, while AKT activation is independent of Rac1 but requires PI3K activity. Plitidepsin cytotoxicity diminishes by Rac1 inhibition or by the blockage of JNK and p38MAPK using SB203580, but not by PI3K inhibition using Wortmannin or LY294002. Remarkably, plitidepsin and dacarbazine, the alkylating agent most active for treating metastatic melanoma, show synergistic anti-proliferative 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.
LURBINECTEDIN EEUU : LAS VENTAS EN EL 1er SEMESTRE 25 HAN SIDO DE 137,5 MILL$ // SE HAN REDUCIDO UN 12% QUE SON 18,6 MILL$ MENOS Vs A LAS ALCANZADAS EN EL MISMO PERIODO DE 2024 QUE FUERON DE 156,1 MILL$ // VENTAS DE TARLATAMAB EN.EL 2o TRIM 25 HAN ALCANZADO LOS 134 MILL$ ... UN 65% MÁS ... VERSUS LOS 61 MILL$ QUE ALCANZÓ EN EL 1er TRIM25 // TARLA 1er SEMESTRE 25 = VENTAS DE 215 MILL$ ... QUE SON 77,8 MILL$ MÁS QUE LOS ALCANZADOS POR LURBI (137,5 MILL$) EN EL MISMO PERIODO