Pharmacological characterization of a novel metal-based proteasome inhibitor Na-AuPT for cancer treatment

• Published in: Acta pharmacologica Sinica Vol. 43; no. 8; pp. 2128 - 2138
• Main Authors: Xu, Da-cai, Yang, Li, Zhang, Pei-quan, Yan, Ding, Xue, Qian, Huang, Qing-tian, Li, Xiao-fen, Hao, Ya-li, Tang, Dao-lin, Ping Dou, Q., Chen, Xin, Liu, Jin-bao
• Format: Journal Article
• Language: English
• Published: Singapore Springer Nature Singapore 01.08.2022; Nature Publishing Group
• Subjects: Acute myeloid leukemia; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antitumor activity; Apoptosis; Bax protein; Biomedical and Life Sciences; Biomedicine; Bortezomib; Cancer; Cancer therapies; Caspase-3; Cell death; Cell Line, Tumor; Homeostasis; Humans; Immunology; Internal Medicine; Leukocytes (mononuclear); Medical Microbiology; Mice; Mice, Nude; Neoplasms - drug therapy; Pharmacology/Toxicology; Proteasome Endopeptidase Complex - metabolism; Proteasome inhibitors; Proteasome Inhibitors - pharmacology; Proteasome Inhibitors - therapeutic use; Proteasomes; Proteolysis; Targeted cancer therapy; Toxicity; Tumor cell lines; Tumors; Ubiquitin; Ubiquitin - metabolism; Vaccine; Water; Xenografts; cancer therapy; proteasome; gold complex; Na-AuPT; apoptosis; bortezomib; deubiquitinase; ubiquitin
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/s41401-021-00816-z

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 2.5–20 μM) 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 IC 50 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.