The MEK1 inhibitor PD98059 sensitizes C8161 melanoma cells to cisplatin-induced apoptosis

The regulation of apoptosis is believed to be dependent on the balance of t he activities of different intracellular signalling systems. Activation of the SAPK/JNK pathway is implied in pro-apoptotic signalling, while activati on of the MEK1/ERK pathway may have a viability-promoting effect. We show h ere that treatment with the MEK1 inhibitor PD98059 sensitizes the human mel anoma cell line C8161 to cisplatin-induced apoptosis. In these cells, cispl atin at 40 muM did not elicit significant cell death, whereas massive cell death was seen when cells were pretreated for 20 h with 40 muM PD98059 befo re the addition of cisplatin. Concomitant addition of PD98059 and cisplatin did not have any sensitizing effect, and PD98059 on its own did not induce apoptosis. However, in three other human melanoma cell lines PD98059 did n ot potentiate cisplatin-induced apoptosis. Instead, in one of these cell li nes (AA), PD98059 protected against cisplatin-induced cytotoxicity. We conc lude that blocking of the MEK1/ERK pathway may, in some instances, potentia te the cytotoxic effect of cisplatin on human melanoma cell lines, whereas in other instances it may have a protective effect. Thus it cannot be regar ded as a general approach to sensitizing melanoma cells to drug-induced apo ptosis. (C) 2001 Lippincott Williams & Wilkins.