Author/Authors :
Cossa، نويسنده , , Giacomo and Lanzi، نويسنده , , Cinzia and Cassinelli، نويسنده , , Giuliana and Carenini، نويسنده , , Nives and Arrighetti، نويسنده , , Noemi and Gatti، نويسنده , , Laura and Corna، نويسنده , , Elisabetta and Zunino، نويسنده , , Franco and Zaffaroni، نويسنده , , Nadia and Perego، نويسنده , , Paola، نويسنده ,
Abstract :
Deregulated pro-survival signalling plays a role in ovarian carcinoma drug resistance. Here, we show that cisplatin or oxaliplatin in combination with the MEK1/2 inhibitor CI-1040 resulted in a synergistic effect associated with enhanced apoptotic response in platinum-sensitive cells. The drug combinations were additive in platinum-resistant cells exhibiting increased phospho-ERK1/2, down-regulation of apoptosis-related factors (BAX, PUMA, FOXO1) and of phosphatases inhibiting ERK1/2 (DUSP5, DUSP6). Consistently, FOXO1 knockdown in sensitive cells reduced the efficacy of the combination treatment. Pharmacological targeting of ERK1/2 pathway increases cell sensitivity to platinum compounds by interfering with multiple events, ultimately favouring apoptosis induction in selected molecular backgrounds.
Keywords :
MEK inhibitors , Foxo1 , Platinum compounds , Ovarian Carcinoma , Drug resistance
