Cong Yuwei, Wang Liangyan, Wang Zigui, He Shasha, Zhou Dongfang, Jing Xiabin, Huang Yubin
State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China; University of Chinese Academy of Sciences, Beijing 100049, P. R. China.
Nanjing Orientleader Technology Co., Ltd. , Nanjing 210028, P. R. China.
ACS Med Chem Lett. 2016 Aug 24;7(10):924-928. doi: 10.1021/acsmedchemlett.6b00236. eCollection 2016 Oct 13.
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 -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 and . 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.
核DNA损伤的自我修复是导致癌组织耐药和抗癌药物治疗效果有限的最广为人知的原因。抑制蛋白磷酸酶2A（PP2A）可阻断DNA损伤诱导的癌细胞防御，从而抑制DNA修复以增强癌症治疗效果。在此，我们通过简单的物理叠加将PP2A抑制剂LB（4-(3-羧基-7-氧杂-双环[2.2.1]庚烷-2-羰基)哌嗪-1-羧酸丁酯）与DNA损伤化疗药物顺铂相结合。两种药物以1:1的比例给药时表现出最佳的协同抗肿瘤疗效。已证明LB通过抑制PP2A特异性激活蛋白激酶B（Akt）和丝裂原活化蛋白激酶（MAPK）信号通路，以克服顺铂诱导的DNA损伤所导致的细胞周期停滞。
