Ras inhibitor farnesylthiosalicylic acid conjugated with IR783 dye exhibits improved tumor-targeting and altered anti-breast cancer mechanisms in mice  

作　　者：Qiu-ju Huang Guo-chao Liao Xue-rong Zhuang Meng-lan Yang Jing-jing Yao Jian-hua Deng Yan-min Zhang Ying Wang Xiao-xiao Qi Dong-feng Pan Yang Guan Zhi-ying Huang Feng-xue Zhang Zhong-qiu Liu Lin-lin Lu 

机构地区：[1]Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People’s Republic of China,International Institute for Translational Chinese Medicine,Guangzhou University of Chinese Medicine,Guangzhou 510006,China [2]School of Basic Medical Sciences,Guangzhou University of Chinese Medicine,Guangzhou 510006,China [3]Department of Radiology and Medical Imaging,University of Virginia,Charlottesville,VA 22903,USA [4]State Key Laboratory of Quality Research in Chinese Medicine/Macao Institute for Applied Research in Medicine and Health,Macao University of Science and Technology,Macao,SAR,China

出　　处：《Acta Pharmacologica Sinica》2022年第7期1843-1856,共14页中国药理学报（英文版）

基　　金：This work was supported by the projets of National Natural Science Foundation of China[81720108033,81930114,and 81874367];Natural Science Foundation_of Guangdong Province[2018B030322011];Natural Science_Foundation for Distinguished Young Scholars of Guangdong Province[2017A030306033].

摘　　要：Ras has long been viewed as a promising target for cancer therapy.Farnesylthiosalicylic acid(FTS),as the only Ras inhibitor has ever entered phase II clinical trials,has yielded disappointing results due to its strong hydrophobicity,poor tumor-targeting capacity,and low therapeutic efficiency.Thus,enhancing hydrophilicity and tumor-targeting capacity of FTS for improving its therapeutic efficacy is of great significance.In this study we conjugated FTS with a cancer-targeting small molecule dye IR783 and characterized the anticancer properties of the conjugate FTS-IR783.We showed that IR783 conjugation greatly improved the hydrophilicity,tumor-targeting and therapeutic potential of FTS.After a single oral administration in Balb/c mice,the relative bioavailability of FTS-IR783 was increased by 90.7%compared with FTS.We demonstrated that organic anion transporting polypeptide(OATP)and endocytosis synergistically drove the uptake of the FTS-IR783 conjugate in breast cancer MDA-MB-231 cells,resulting in superior tumor-targeting ability of the conjugate both in vitro and in vivo.We further revealed that FTS-IR783 conjugate could bind with and directly activate AMPK rather than affecting Ras,and subsequently regulate the TSC2/mTOR signaling pathway,thus achieving 2–10-fold increased anti-cancer therapeutic efficacy against 6 human breast cancer cell lines compared to FTS both in vivo and in vitro.Overall,our data highlights a promising approach for the modification of the anti-tumor drug FTS using IR783 and makes it possible to return FTS back to the clinic with a better efficacy.

关 键 词：Ras inhibitor Farnesylthiosalicylic acid IR783 TUMOR-TARGETING breast neoplasm AMPK mTOR 

分 类 号：R737.9[医药卫生—肿瘤]