Enhancing Therapeutic Efficacy of Cisplatin by Blocking DNA Damage Repair.

Abstract

Self-repair of nuclear DNA damage is the most known reason that leads to drug resistance of cancer tissue and limited therapeutic efficacy of anticancer drugs. Inhibition of protein phosphatase 2A (PP2A) would block DNA damage-induced defense of cancer cells to suppress DNA repair for enhanced cancer treatment. Here, we combined a PP2A inhibitor LB (4-(3-carboxy-7-oxa-bicyclo[2.2.1]heptane-2-carbonyl) piperazine-1-carboxylic acid tert-butyl ester) and the DNA damage chemotherapeutic drug cisplatin through a simple physical superposition. The two drugs administrated at a ratio of 1:1 exhibited an optional synergistic antitumor efficacy in vitro and in vivo. LB was demonstrated to specifically activate the protein kinase B (Akt) and mitogen-activated protein kinases (MAPK) signaling pathways by PP2A inhibition to overcome cell cycle arrest caused by cisplatin-induced DNA damage.