Optimize the combination regimen of Trastuzumab and Nab-paclitaxel in HER2-positive tumors via modulating Caveolin-1 expression by lovastatin  

作　　者：Canyu Yang Shumin Fan Xing Wang Wei Liu Long Yang Bing He Wenbing Dai Hua Zhang Xueqing Wang Qiang Zhang 

机构地区：[1]Department of Pharmacy Administration and Clinical Pharmacy,School of Pharmaceutical Science,Peking University,Beijing 100191,China [2]Beijing Key Laboratory of Molecular Pharmaceutics,New Drug Delivery Systems,School of Pharmaceutical Sciences,Peking University,Beijing 100191,China [3]State Key Laboratory of Natural and Biomimetic Drugs,Peking University,Beijing 100191,China [4]Department of Pharmacy,Peking University Third Hospital,Beijing,100083,China

出　　处：《Asian Journal of Pharmaceutical Sciences》2022年第5期697-712,共16页亚洲药物制剂科学（英文）

基　　金：by the National Natural Science Foundation of China(Nos.81872809,82073786);the Beijing Natural Science Foundation(L212013).

摘　　要：The combination regimen of trastuzumab(Tras)plus Nab-paclitaxel(Nab)is recommended to treat HER2-positive(HER2+)cancers.However,they exert effects in different mechanisms:Tras need to stay on cell membranes,while Nab need to be endocytosed,therefore the concurrent combination regimen may not be the best one in HER2+tumors treatment.Caveolin-1(Cav-1)is a key player in mediating their endocytosis and is associated with their efficacy,but few researches noticed the opposite effect of Cav-1 expression on the combination efficacy.Herein,we systematically studied the Cav-1 expression level on the combination efficacy and proposed an optimized and clinically feasible combination regimen for HER2+Cav-1 High tumor treatment.In the regimen,lovastatin(Lova)was introduced to modulate the Cav-1 expression and the results indicated that Lova could downregulate Cav-1 expression,increase Tras retention on cell membrane and enhance the in vitro cytotoxicity of Tras in HER2+Cav-1 High cells but not in HER2+Cav-1 Low cells.Therefore,by exchanging the dosing sequence of Nab and Tras,and by adding Lova at appropriate time points,the precise three-drug-sequential regimen(PTDS,Nab(D1)-Lova(D2)-Lova&Tras(D2+12 h))was established.Compared with the concurrent regimen,the PTDS regimen exhibited a higher in vitro cytotoxicity and a stronger tumor growth inhibition in HER2+Cav-1 High tumors,which might be a promising combination regimen for these patients in clinics.

关 键 词：CAVEOLIN-1 NAB-PACLITAXEL TRASTUZUMAB Combination regimen optimization 

分 类 号：R730.5[医药卫生—肿瘤]