Abstract
Metabolic reprogramming is a key cancer hallmark that has led to the therapeutic targeting of glycolysis. However, agents that target dysfunctional mitochondrial respiration for targeted therapy remains underexplored. We report the synthesis and characterization of ten (10) novel, highly potent organometallic gold(iii) complexes supported by dithiocarbamate ligands as selective inhibitors of mitochondrial respiration. The structure of dithiocarbamates employed dictates the biological stability and cellular cytotoxicity. Most of the compounds exhibit 50% inhibitory concentration (IC50) in the low-micromolar (0.50-2.9 μM) range when tested in a panel of aggressive cancer types with significant selectivity for cancer cells over normal cells. Consequently, there is great interest in the mechanism of action of gold chemotherapeutics, particularly, considering that DNA is not the major target of most gold complexes. We investigate the mechanism of action of representative complexes,1aand2ain the recalcitrant triple negative breast cancer (TNBC) cell line, MDA-MB-231. Whole-cell transcriptomics sequencing revealed genes related to three major pathways, namely: cell cycle, organelle fission, and oxidative phosphorylation.2airreversibly and rapidly inhibits maximal respiration in TNBC with no effect on normal epithelial cells, implicating mitochondrial OXPHOS as a potential target. Furthermore, the modulation of cyclin dependent kinases and G1 cell cycle arrest induced by these compounds is promising for the treatment of cancer. This work contributes to the need for mitochondrial respiration modulators in biomedical research and outlines a systematic approach to study the mechanism of action of metal-based agents.
| Original language | English |
|---|---|
| Pages (from-to) | 10465-10482 |
| Number of pages | 18 |
| Journal | Chemical Science |
| Volume | 11 |
| Issue number | 38 |
| DOIs | |
| State | Published - Oct 14 2020 |
Bibliographical note
Funding Information:We would like to acknowledge all of those who helped contribute to the project: Samuel Ofori who gratefully cultured the MRC5 cell line used in this manuscript. 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 supported by NSF (CHE-997738) and the UK X-ray facility supported by the MRI program from NSF (CHE-1625732). For the flow cytometry experiments we would like to thank Greg Bauman PhD (UK Flow Cytometry and Immune Function core 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 PhD and Mr James Schwartz (UK Light Microscopy Core) for their assistance. We would also like to thank Tomoko Sengoku PhD 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). We are grateful for the use of Dr Steven Van Lanen's laboratory (UK College of Pharmacy) for the use of their LC-MS.
Funding Information:
We would like to acknowledge all of those who helped contribute to the project: Samuel Ofori who gratefully cultured the MRC5 cell line used in this manuscript. 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 supported by NSF (CHE-997738) and the UK X-ray facility supported by the MRI program from NSF (CHE-1625732). For the ow cytometry experiments we would like to thank Greg Bauman PhD (UK Flow Cytometry and Immune Function core 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 PhD and Mr James Schwartz (UK Light Microscopy Core) for their assistance. We would also like to thank Tomoko Sengoku PhD 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). We are grateful for the use of Dr Steven Van Lanen's laboratory (UK College of Pharmacy) for the use of their LC-MS.
Funding Information:
We are grateful to the University of Kentucky for funding. The authors acknowledge support of the Center for Pharmaceutical Research and Innovation (NIH P20 GM130456).
Publisher Copyright:
© The Royal Society of Chemistry 2020.
ASJC Scopus subject areas
- Chemistry (all)
