A new gold(I) complex-Au(PPh3)PT is a deubiquitinase inhibitor and inhibits tumor growth

Xiaofen Li, Qingtian Huang, Huidan Long, Peiquan Zhang, Huabo Su, Jinbao Liu

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)159-172
Number of pages14
JournalEBioMedicine
Volume39
DOIs
StatePublished - Jan 1 2019

Fingerprint

Proteasome Endopeptidase Complex
Gold
Tumors
Ubiquitin
Growth
Neoplasms
Cells
Coordination Complexes
Metals
Apoptosis
Natural Science Disciplines
Natural sciences
Deubiquitinating Enzymes
Ubiquitination
Cytotoxicity
Heterografts
Acute Myeloid Leukemia
Nude Mice
Biomedical Research
China

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

A new gold(I) complex-Au(PPh3)PT is a deubiquitinase inhibitor and inhibits tumor growth. / Li, Xiaofen; Huang, Qingtian; Long, Huidan; Zhang, Peiquan; Su, Huabo; Liu, Jinbao.

In: EBioMedicine, Vol. 39, 01.01.2019, p. 159-172.

Research output: Contribution to journalArticle

Li, Xiaofen ; Huang, Qingtian ; Long, Huidan ; Zhang, Peiquan ; Su, Huabo ; Liu, Jinbao. / A new gold(I) complex-Au(PPh3)PT is a deubiquitinase inhibitor and inhibits tumor growth. In: EBioMedicine. 2019 ; Vol. 39. pp. 159-172.
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AU - Su, Huabo

AU - Liu, Jinbao

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