Abstract
Metal-based drugs, such as cisplatin and auranofin, are used for the treatment of cancer and rheumatoid arthritis, respectively. Auranofin and other gold-derived compounds have been shown to possess anticancer, anti-inflammatory, antimicrobial, and antiparasitic activity in preclinical and clinical trials. Unlike platinum agents which are known to target DNA, the target of gold is not well elucidated. To better understand the targets and effects of gold agents in mammalian cells, we used a targeted CRISPR (ToxCRISPR) screen in K562 cancer cells to identify genes that modulate cellular sensitivity to gold. We synthesized a novel chiral gold(I) compound, JHK-21, with potent anticancer activity. Among the most sensitizing hits were proteins involved in mitochondrial carriers, mitochondrial metabolism, and oxidative phosphorylation. Further analysis revealed that JHK-21 induced inner mitochondria membrane dysfunction and modulated ATP-binding cassette subfamily member C (ABCC1) function in a manner distinct from auranofin. Characterizing the therapeutic effects and toxicities of metallodrugs in mammalian cells is of growing interest to guide future drug discovery, and cellular and preclinical/clinical studies.
| Original language | English |
|---|---|
| Pages (from-to) | 39197-39205 |
| Number of pages | 9 |
| Journal | ACS Omega |
| Volume | 7 |
| Issue number | 43 |
| DOIs | |
| State | Published - Nov 1 2022 |
Bibliographical note
Publisher Copyright:© 2022 The Authors. Published by American Chemical Society
Funding
We are grateful to the University of Kentucky for funding. This work was funded by National Institutes of Health/NCI grant R01CA258421-01 (S.G.A.). We would like to acknowledge all of those who helped contribute to the project. We would like to thank all of the facilities at the University of Kentucky, who provided support in completion of the experiments detailed in this manuscript. The UK NMR Center is supported by the NSF (CHE-997738), and the UK X-ray facility is supported by the MRI program from NSF (CHE-1625732). For the flow cytometry experiments we would like to thank Greg Bauman Ph.D. UK Flow Cytometry and Immune Function Core is supported by the Office of the Vice President of Research, the Markey Cancer Center, and NCI Center Core Support Grant (P30 CA177558). For microscopy, we would like to thank Thomas Wilkop Ph.D. We would also like to thank Tomoko Sengoku Ph.D. and Mr. Michael Alstott for the support with our redox metabolism experiments, supported by the shared resource(s) of the University of Kentucky Markey Cancer Center (P30CA177558).
| Funders | Funder number |
|---|---|
| Office of the Vice President for Research | |
| National Science Foundation Arctic Social Science Program | CHE-997738, CHE-1625732 |
| National Science Foundation Arctic Social Science Program | |
| National Institutes of Health (NIH) | |
| National Childhood Cancer Registry – National Cancer Institute | P30 CA177558, R01CA258421-01 |
| National Childhood Cancer Registry – National Cancer Institute | |
| University of Kentucky | |
| University of Kentucky Markey Cancer Center | P30CA177558 |
| University of Kentucky Markey Cancer Center |
ASJC Scopus subject areas
- General Chemistry
- General Chemical Engineering
