The ubiquitin-proteasome system(UPS)is essential for maintaining cell homeostasis by orchestrating the protein degradation,but is impaired in various diseases,including cancers.Several proteasome inhibitors,such as bortezomib,are currently used in cancer treatment,but associated toxicity limits their widespread application.Recently metal complex-based drugs have attracted great attention in tumor therapy;however,their application is hindered by low water-solubility and poor absorbency.Herein,we synthesized a new type of gold(Ⅰ)complex named Na-AuPT,and further characterized its anticancer activity.Na-AuPT is highly water-soluble(6 mg/mL),and it was able to potently inhibit growth of a panel of 11 cancer cell lines(A549,SMMC7721,H460,HepG2,BEL7402,LNCap,PC3,MGC-803,SGC-7901,U266,and K562).In A549 and SMMC7721 cells,Na-AuPT(in a range of 2.5-20μM)inhibited the UPS function in a dose-dependent fashion by targeting and inhibiting both 20 S proteasomal proteolytic peptidases and 19 S proteasomal deubiquitinases.Furthermore,Na-AuPT induced caspase-dependent apoptosis in A549 and SMMC7721 cells,which was prevented by the metal chelator EDTA.Administration of Na-AuPT(40 mg·kg-1·d-1,ip)in nude mice bearing A549 or SMMC7721 xenografts significantly inhibited the tumor growth in vivo,accompanied by increased levels of total ubiquitinated proteins,cleaved caspase 3 and Bax protein in tumor tissue.Moreover,Na-AuPT induced cell death of primary mononuclear cells from 5 patients with acute myeloid leukemia ex vivo with an average IC50 value of 2.46 μM.We conclude that Na-AuPT is a novel metal-based proteasome inhibitor that may hold great potential for cancer therapy.

Da-cai Xu;Li Yang;Pei-quan Zhang;Ding Yan;Qian Xue;Qing-tian Huang;Xiao-fen Li;Ya-li Hao;Dao-lin Tang;Q.Ping Dou;Xin Chen;Jin-bao Liu

Affliated Cancer Hospital&Institute of Guangzhou Medical University,Guangzhou 510095,China;Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation,School of Basic Medical Sciences,Guangzhou Medical University,Guangzhou 511436,China;The Department of Physiology,School of Basic Medical Sciences,Guizhou Medical University,Guiyang 550003,China;Department of Surgery,UT Southwestern Medical Center,Dallas,TX 75390,USA;Barbara Ann Karmanos Cancer Institute and Departments of Oncology,Pharmacology&Pathology,School of Medicine,Wayne State University,Detroit,MI 48201,USA

中国药理学报（英文版）

[1]Da-cai Xu;Li Yang;Pei-quan Zhang;Ding Yan;Qian Xue;Qing-tian Huang;Xiao-fen Li;Ya-li Hao;Dao-lin Tang;Q.Ping Dou;Xin Chen;Jin-bao Liu-.Pharmacological characterization of a novel metal-based proteasome inhibitor Na-AuPT for cancer treatment)[J].中国药理学报（英文版）,2022(08):2128-2138

AuPT,absorbency,deubiquitinases

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