Serum-Stable Gold(III) Bisphosphine Complex Induces Mild Mitochondrial Uncoupling and In Vivo Antitumor Potency in Triple Negative Breast Cancer

Adedamola S. Arojojoye; Chibuzor Olelewe; Sailajah Gukathasan; Jong H. Kim; Hemendra Vekaria; Sean Parkin; Patrick G. Sullivan; Samuel G. Awuah

doi:10.1021/acs.jmedchem.3c00238

Serum-Stable Gold(III) Bisphosphine Complex Induces Mild Mitochondrial Uncoupling and In Vivo Antitumor Potency in Triple Negative Breast Cancer

Adedamola S. Arojojoye, Chibuzor Olelewe, Sailajah Gukathasan, Jong H. Kim, Hemendra Vekaria, Sean Parkin, Patrick G. Sullivan, Samuel G. Awuah

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

The preparation of cyclometalated complexes offers a path to stable materials, catalysts, and therapeutic agents. Here, we explore the anticancer potential of novel biphenyl organogold(III) cationic complexes supported by diverse bisphosphine ligands, Au-1-Au-5, toward aggressive glioblastoma and triple negative breast cancer cells (TNBCs). The [C^C] gold(III) complex, Au-3, exhibits significant tumor growth inhibition in a metastatic TNBC mouse model. Remarkably, Au-3 displays promising blood serum stability over a relevant therapeutic window of 24 h and alteration in the presence of excess L-GSH. The mechanism-of-action studies show that Au-3 induces mitochondrial uncoupling, membrane depolarization, and G1 cell cycle arrest and prompts apoptosis. To the best of our knowledge, Au-3 is the first biphenyl gold-phosphine complex to uncouple mitochondria and inhibit TNBC growth in vivo.

Original language	English
Pages (from-to)	7868-7879
Number of pages	12
Journal	Journal of Medicinal Chemistry
Volume	66
Issue number	12
DOIs	https://doi.org/10.1021/acs.jmedchem.3c00238
State	Published - Jun 22 2023

Bibliographical note

Funding Information:
We are grateful for financial support from the National Cancer Institute (NCI) R01CA258421-01 (S.G.A.). We would like to thank the following 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 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). We thank Dr. Chris Richard’s lab for access and assistance with fluorescence microscopy. We would also like to thank Dr. Steven Van Lanen’s laboratory for access to their APCI-MS.

Publisher Copyright:
© 2023 American Chemical Society.

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/acs.jmedchem.3c00238

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title = "Serum-Stable Gold(III) Bisphosphine Complex Induces Mild Mitochondrial Uncoupling and In Vivo Antitumor Potency in Triple Negative Breast Cancer",

abstract = "The preparation of cyclometalated complexes offers a path to stable materials, catalysts, and therapeutic agents. Here, we explore the anticancer potential of novel biphenyl organogold(III) cationic complexes supported by diverse bisphosphine ligands, Au-1-Au-5, toward aggressive glioblastoma and triple negative breast cancer cells (TNBCs). The [C^C] gold(III) complex, Au-3, exhibits significant tumor growth inhibition in a metastatic TNBC mouse model. Remarkably, Au-3 displays promising blood serum stability over a relevant therapeutic window of 24 h and alteration in the presence of excess L-GSH. The mechanism-of-action studies show that Au-3 induces mitochondrial uncoupling, membrane depolarization, and G1 cell cycle arrest and prompts apoptosis. To the best of our knowledge, Au-3 is the first biphenyl gold-phosphine complex to uncouple mitochondria and inhibit TNBC growth in vivo.",

author = "Arojojoye, {Adedamola S.} and Chibuzor Olelewe and Sailajah Gukathasan and Kim, {Jong H.} and Hemendra Vekaria and Sean Parkin and Sullivan, {Patrick G.} and Awuah, {Samuel G.}",

note = "Funding Information: We are grateful for financial support from the National Cancer Institute (NCI) R01CA258421-01 (S.G.A.). We would like to thank the following 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 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). We thank Dr. Chris Richard{\textquoteright}s lab for access and assistance with fluorescence microscopy. We would also like to thank Dr. Steven Van Lanen{\textquoteright}s laboratory for access to their APCI-MS. Publisher Copyright: {\textcopyright} 2023 American Chemical Society.",

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AU - Parkin, Sean

AU - Sullivan, Patrick G.

AU - Awuah, Samuel G.

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N2 - The preparation of cyclometalated complexes offers a path to stable materials, catalysts, and therapeutic agents. Here, we explore the anticancer potential of novel biphenyl organogold(III) cationic complexes supported by diverse bisphosphine ligands, Au-1-Au-5, toward aggressive glioblastoma and triple negative breast cancer cells (TNBCs). The [C^C] gold(III) complex, Au-3, exhibits significant tumor growth inhibition in a metastatic TNBC mouse model. Remarkably, Au-3 displays promising blood serum stability over a relevant therapeutic window of 24 h and alteration in the presence of excess L-GSH. The mechanism-of-action studies show that Au-3 induces mitochondrial uncoupling, membrane depolarization, and G1 cell cycle arrest and prompts apoptosis. To the best of our knowledge, Au-3 is the first biphenyl gold-phosphine complex to uncouple mitochondria and inhibit TNBC growth in vivo.

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Serum-Stable Gold(III) Bisphosphine Complex Induces Mild Mitochondrial Uncoupling and In Vivo Antitumor Potency in Triple Negative Breast Cancer

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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