Abstract
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 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.
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Acknowledgements
The study was supported by the National Natural Science Foundation of China (81802405), the National Funds for Developing Local Colleges and Universities (B16056001), Natural Science Foundation Research Team of Guangdong Province (2018B030312001), the Science and Technology Program of Guangzhou (201604020001), Innovative Academic Team of Guangzhou Education System (1201610014), and the Research Team of Department of Education of Guangdong Province (2017KCXTD027).
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JBL and XC designed the study; DX, LY, and PQZ conducted the experiments and analyzed the data. DY, QX, QTH, XFL, and YLH participated in the experiments. DCX, LY, XC, and JL wrote the manuscript. DLT and QPD assisted in data interpretation and edited the manuscript.
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Xu, Dc., Yang, L., Zhang, Pq. et al. Pharmacological characterization of a novel metal-based proteasome inhibitor Na-AuPT for cancer treatment. Acta Pharmacol Sin 43, 2128–2138 (2022). https://doi.org/10.1038/s41401-021-00816-z
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DOI: https://doi.org/10.1038/s41401-021-00816-z
