TY - JOUR
T1 - A new gold(I) complex-Au(PPh3)PT is a deubiquitinase inhibitor and inhibits tumor growth
AU - Li, Xiaofen
AU - Huang, Qingtian
AU - Long, Huidan
AU - Zhang, Peiquan
AU - Su, Huabo
AU - Liu, Jinbao
N1 - Funding Information:
This work was supported by the National High Technology Research and Development Program of China (2006AA02Z4B5), NSFC (81272451/H1609, 81472762/H1609, 81602427/H1602), project of Guangdong Province Natural Science Foundation (2016A030310281), projects from Foundation for Higher Education of Guangdong (2015KQNCX126), project from Guangzhou Medical University for Doctor Scientists (2014C01), Medical Scientific Research Foundation of Guangdong Province (A2018421), and Guangzhou Key Medical Discipline Construction Project Fund.
Funding Information:
This work was supported by the National High Technology Research and Development Program of China ( 2006AA02Z4B5 ), NSFC ( 81272451/H1609 , 81472762/H1609 , 81602427/H1602 ), project of Guangdong Province Natural Science Foundation ( 2016A030310281 ), projects from Foundation for Higher Education of Guangdong ( 2015KQNCX126 ), project from Guangzhou Medical University for Doctor Scientists ( 2014C01 ), Medical Scientific Research Foundation of Guangdong Province ( A2018421 ), and Guangzhou Key Medical Discipline Construction Project Fund.
Publisher Copyright:
© 2018 The Authors
PY - 2019/1
Y1 - 2019/1
N2 - Background: Ubiquitin-proteasome system (UPS) is integral to cell survival by maintaining protein homeostasis, and its dysfunction has been linked to cancer and several other human diseases. Through counteracting ubiquitination, deubiquitinases (DUBs) can either positively or negatively regulate UPS function, thereby representing attractive targets of cancer therapies. Previous studies have shown that metal complexes can inhibit tumor growth through targeting the UPS; however, novel metal complexes with higher specificity for cancer therapy are still lacking. Methods: We synthesized a new gold(I) complex, Au(PPh3)PT. The inhibitory activity of Au(PPh3)PT on the UPS and the growth of multiple cancer cell types were tested in vitro, ex vivo, and in vivo. Furthermore, we compared the efficacy of Au(PPh3)PT with other metal compounds in inhibition of UPS function and tumor growth. Findings: Here we report that (i) a new gold(I) complex-pyrithione, i.e., Au(PPh3)PT, induced apoptosis in two lung cancer cell lines A549 and NCI-H1299; (ii) Au(PPh3)PT severely impaired UPS proteolytic function; (iii) Au(PPh3)PT selectively inhibited 19S proteasome-associated DUBs (UCHL5 and USP14) and other non-proteasomal DUBs with minimal effects on the function of 20S proteasome; (iv) Au(PPh3)PT induced apoptosis in cancer cells from acute myeloid leukemia patients; (v) Au(PPh3)PT effectively suppressed the growth of lung adenocarcinoma xenografts in nude mice; and (vi) Au (PPh3)PT elicited less cytotoxicity in normal cells than several other metal compounds. Interpretation: Together, this study discovers a new gold(I) complex to be an effective inhibitor of the DUBs and a potential anti-cancer drug. Fund: The National High Technology Research and Development Program of China, the project of Guangdong Province Natural Science Foundation, the projects from Foundation for Higher Education of Guangdong, the project from Guangzhou Medical University for Doctor Scientists, the Medical Scientific Research Foundation of Guangdong Province, and the Guangzhou Key Medical Discipline Construction Project Fund.
AB - Background: Ubiquitin-proteasome system (UPS) is integral to cell survival by maintaining protein homeostasis, and its dysfunction has been linked to cancer and several other human diseases. Through counteracting ubiquitination, deubiquitinases (DUBs) can either positively or negatively regulate UPS function, thereby representing attractive targets of cancer therapies. Previous studies have shown that metal complexes can inhibit tumor growth through targeting the UPS; however, novel metal complexes with higher specificity for cancer therapy are still lacking. Methods: We synthesized a new gold(I) complex, Au(PPh3)PT. The inhibitory activity of Au(PPh3)PT on the UPS and the growth of multiple cancer cell types were tested in vitro, ex vivo, and in vivo. Furthermore, we compared the efficacy of Au(PPh3)PT with other metal compounds in inhibition of UPS function and tumor growth. Findings: Here we report that (i) a new gold(I) complex-pyrithione, i.e., Au(PPh3)PT, induced apoptosis in two lung cancer cell lines A549 and NCI-H1299; (ii) Au(PPh3)PT severely impaired UPS proteolytic function; (iii) Au(PPh3)PT selectively inhibited 19S proteasome-associated DUBs (UCHL5 and USP14) and other non-proteasomal DUBs with minimal effects on the function of 20S proteasome; (iv) Au(PPh3)PT induced apoptosis in cancer cells from acute myeloid leukemia patients; (v) Au(PPh3)PT effectively suppressed the growth of lung adenocarcinoma xenografts in nude mice; and (vi) Au (PPh3)PT elicited less cytotoxicity in normal cells than several other metal compounds. Interpretation: Together, this study discovers a new gold(I) complex to be an effective inhibitor of the DUBs and a potential anti-cancer drug. Fund: The National High Technology Research and Development Program of China, the project of Guangdong Province Natural Science Foundation, the projects from Foundation for Higher Education of Guangdong, the project from Guangzhou Medical University for Doctor Scientists, the Medical Scientific Research Foundation of Guangdong Province, and the Guangzhou Key Medical Discipline Construction Project Fund.
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U2 - 10.1016/j.ebiom.2018.11.047
DO - 10.1016/j.ebiom.2018.11.047
M3 - Article
C2 - 30527624
AN - SCOPUS:85057805296
SN - 2352-3964
VL - 39
SP - 159
EP - 172
JO - EBioMedicine
JF - EBioMedicine
ER -
