Gold(III)-P-chirogenic complex induces mitochondrial dysfunction in triple-negative breast cancer

Chibuzor Olelewe; Jong Hyun Kim; Samuel Ofori; Randall T. Mertens; Sailajah Gukathasan; Samuel G. Awuah

doi:10.1016/j.isci.2022.104340

Gold(III)-P-chirogenic complex induces mitochondrial dysfunction in triple-negative breast cancer

Chibuzor Olelewe, Jong Hyun Kim, Samuel Ofori, Randall T. Mertens, Sailajah Gukathasan, Samuel G. Awuah

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

1 Scopus citations

Abstract

Chemical agents that specifically exploit metabolic vulnerabilities of cancer cells will be beneficial but are rare. The role of oxidative phosphorylation (OXPHOS) in promoting and maintaining triple-negative breast cancer (TNBC) growth provides new treatment opportunity. In this work, we describe AuPhos-19, a small-molecule gold(III)-based agent bearing a chiral phosphine ligand that selectively disrupts mitochondrial metabolism in murine and human TNBC cells but not normal epithelial cells. AuPhos-19 induces potent cytotoxic effect with half maximal inhibitory concentration (IC₅₀) in the nanomolar range (220–650 nM) across different TNBC cell lines. The lipophilic cationic character of AuPhos-19 facilitates interaction with mitochondrial OXPHOS. AuPhos-19 inhibits mitochondria respiration and induces significant AMPK activation. Depolarization of the mitochondria membrane, mitochondria ROS accumulation, and mitochondria DNA depletion provided further indication that AuPhos-19 perturbs mitochondria function. AuPhos-19 inhibits tumor growth in tumor-bearing mice. This study highlights the development of gold-based compounds targeting mitochondrial pathways for efficacious cancer treatment.

Original language	English
Article number	104340
Journal	iScience
Volume	25
Issue number	5
DOIs	https://doi.org/10.1016/j.isci.2022.104340
State	Published - May 20 2022

Bibliographical note

Funding Information:
We thank all the core facilities at the University of Kentucky who provided support in completion of the experiments detailed in this manuscript. Specifically, the UK NMR Center supported by NSF (CHE-997738) and the 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), and the microscopy facilities (UK Light Microscopy Core) for their assistance. We thank Dr. Kathleen O'Connor for generously providing us with some TNBC cell lines for this study. We thank Dr. Tomoko Sengoku PhD and Mr. Michael Alstott for their support with our redox metabolism experiments, supported by the shared resource(s) of the University of Kentucky Markey Cancer Center (P30CA177558). The University of Colorado, Boulder, supported by NIH S10RR026641 where the Waters Synapt G2 was used for high-resolution mass spectrometry. This work was funded by National Institutes of Health/NCI grant R01CA258421-01 (S.G.A.). S.G.A. conceptualized the project. C.N.O. led the project and performed most of the experiments. C.N.O. S.O. and S.G. worked on synthetic modification of parent compound used in this study. C.N.O. J.H.K. and S.O. carried out animal studies. C.N.O. and R.T.M performed flow cytometry and confocal microscopy experiments. C.N.O. wrote the manuscript with guidance from S.G.A. S.G.A. revised the manuscript before submission. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Samuel G. Awuah reports financial support was provided by University of Kentucky. Samuel G. Awuah reports a relationship with University of Kentucky that includes: funding grants. Samuel G. Awuah has patents pending to University of Kentucky Research Foundation.

Funding Information:
We thank all the core facilities at the University of Kentucky who provided support in completion of the experiments detailed in this manuscript. Specifically, the UK NMR Center supported by NSF ( CHE-997738 ) and the 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 ), and the microscopy facilities (UK Light Microscopy Core ) for their assistance. We thank Dr. Kathleen O'Connor for generously providing us with some TNBC cell lines for this study. We thank Dr. Tomoko Sengoku PhD and Mr. Michael Alstott for their support with our redox metabolism experiments, supported by the shared resource(s) of the University of Kentucky Markey Cancer Center ( P30CA177558 ). The University of Colorado, Boulder, supported by NIH S10RR026641 where the Waters Synapt G2 was used for high-resolution mass spectrometry. This work was funded by National Institutes of Health/NCI grant R01CA258421-01 (S.G.A.).

Funding Information:
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Samuel G. Awuah reports financial support was provided by University of Kentucky. Samuel G. Awuah reports a relationship with University of Kentucky that includes: funding grants. Samuel G. Awuah has patents pending to University of Kentucky Research Foundation.

Publisher Copyright:
© 2022

Keywords

Biochemistry
Biological sciences
Cancer
Small molecule

ASJC Scopus subject areas

General

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10.1016/j.isci.2022.104340

Cite this

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title = "Gold(III)-P-chirogenic complex induces mitochondrial dysfunction in triple-negative breast cancer",

abstract = "Chemical agents that specifically exploit metabolic vulnerabilities of cancer cells will be beneficial but are rare. The role of oxidative phosphorylation (OXPHOS) in promoting and maintaining triple-negative breast cancer (TNBC) growth provides new treatment opportunity. In this work, we describe AuPhos-19, a small-molecule gold(III)-based agent bearing a chiral phosphine ligand that selectively disrupts mitochondrial metabolism in murine and human TNBC cells but not normal epithelial cells. AuPhos-19 induces potent cytotoxic effect with half maximal inhibitory concentration (IC50) in the nanomolar range (220–650 nM) across different TNBC cell lines. The lipophilic cationic character of AuPhos-19 facilitates interaction with mitochondrial OXPHOS. AuPhos-19 inhibits mitochondria respiration and induces significant AMPK activation. Depolarization of the mitochondria membrane, mitochondria ROS accumulation, and mitochondria DNA depletion provided further indication that AuPhos-19 perturbs mitochondria function. AuPhos-19 inhibits tumor growth in tumor-bearing mice. This study highlights the development of gold-based compounds targeting mitochondrial pathways for efficacious cancer treatment.",

keywords = "Biochemistry, Biological sciences, Cancer, Small molecule",

author = "Chibuzor Olelewe and Kim, {Jong Hyun} and Samuel Ofori and Mertens, {Randall T.} and Sailajah Gukathasan and Awuah, {Samuel G.}",

note = "Funding Information: We thank all the core facilities at the University of Kentucky who provided support in completion of the experiments detailed in this manuscript. Specifically, the UK NMR Center supported by NSF (CHE-997738) and the 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), and the microscopy facilities (UK Light Microscopy Core) for their assistance. We thank Dr. Kathleen O'Connor for generously providing us with some TNBC cell lines for this study. We thank Dr. Tomoko Sengoku PhD and Mr. Michael Alstott for their support with our redox metabolism experiments, supported by the shared resource(s) of the University of Kentucky Markey Cancer Center (P30CA177558). The University of Colorado, Boulder, supported by NIH S10RR026641 where the Waters Synapt G2 was used for high-resolution mass spectrometry. This work was funded by National Institutes of Health/NCI grant R01CA258421-01 (S.G.A.). S.G.A. conceptualized the project. C.N.O. led the project and performed most of the experiments. C.N.O. S.O. and S.G. worked on synthetic modification of parent compound used in this study. C.N.O. J.H.K. and S.O. carried out animal studies. C.N.O. and R.T.M performed flow cytometry and confocal microscopy experiments. C.N.O. wrote the manuscript with guidance from S.G.A. S.G.A. revised the manuscript before submission. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Samuel G. Awuah reports financial support was provided by University of Kentucky. Samuel G. Awuah reports a relationship with University of Kentucky that includes: funding grants. Samuel G. Awuah has patents pending to University of Kentucky Research Foundation. Funding Information: We thank all the core facilities at the University of Kentucky who provided support in completion of the experiments detailed in this manuscript. Specifically, the UK NMR Center supported by NSF ( CHE-997738 ) and the 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 ), and the microscopy facilities (UK Light Microscopy Core ) for their assistance. We thank Dr. Kathleen O'Connor for generously providing us with some TNBC cell lines for this study. We thank Dr. Tomoko Sengoku PhD and Mr. Michael Alstott for their support with our redox metabolism experiments, supported by the shared resource(s) of the University of Kentucky Markey Cancer Center ( P30CA177558 ). The University of Colorado, Boulder, supported by NIH S10RR026641 where the Waters Synapt G2 was used for high-resolution mass spectrometry. This work was funded by National Institutes of Health/NCI grant R01CA258421-01 (S.G.A.). Funding Information: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Samuel G. Awuah reports financial support was provided by University of Kentucky. Samuel G. Awuah reports a relationship with University of Kentucky that includes: funding grants. Samuel G. Awuah has patents pending to University of Kentucky Research Foundation. Publisher Copyright: {\textcopyright} 2022",

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AU - Gukathasan, Sailajah

AU - Awuah, Samuel G.

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Y1 - 2022/5/20

N2 - Chemical agents that specifically exploit metabolic vulnerabilities of cancer cells will be beneficial but are rare. The role of oxidative phosphorylation (OXPHOS) in promoting and maintaining triple-negative breast cancer (TNBC) growth provides new treatment opportunity. In this work, we describe AuPhos-19, a small-molecule gold(III)-based agent bearing a chiral phosphine ligand that selectively disrupts mitochondrial metabolism in murine and human TNBC cells but not normal epithelial cells. AuPhos-19 induces potent cytotoxic effect with half maximal inhibitory concentration (IC50) in the nanomolar range (220–650 nM) across different TNBC cell lines. The lipophilic cationic character of AuPhos-19 facilitates interaction with mitochondrial OXPHOS. AuPhos-19 inhibits mitochondria respiration and induces significant AMPK activation. Depolarization of the mitochondria membrane, mitochondria ROS accumulation, and mitochondria DNA depletion provided further indication that AuPhos-19 perturbs mitochondria function. AuPhos-19 inhibits tumor growth in tumor-bearing mice. This study highlights the development of gold-based compounds targeting mitochondrial pathways for efficacious cancer treatment.

AB - Chemical agents that specifically exploit metabolic vulnerabilities of cancer cells will be beneficial but are rare. The role of oxidative phosphorylation (OXPHOS) in promoting and maintaining triple-negative breast cancer (TNBC) growth provides new treatment opportunity. In this work, we describe AuPhos-19, a small-molecule gold(III)-based agent bearing a chiral phosphine ligand that selectively disrupts mitochondrial metabolism in murine and human TNBC cells but not normal epithelial cells. AuPhos-19 induces potent cytotoxic effect with half maximal inhibitory concentration (IC50) in the nanomolar range (220–650 nM) across different TNBC cell lines. The lipophilic cationic character of AuPhos-19 facilitates interaction with mitochondrial OXPHOS. AuPhos-19 inhibits mitochondria respiration and induces significant AMPK activation. Depolarization of the mitochondria membrane, mitochondria ROS accumulation, and mitochondria DNA depletion provided further indication that AuPhos-19 perturbs mitochondria function. AuPhos-19 inhibits tumor growth in tumor-bearing mice. This study highlights the development of gold-based compounds targeting mitochondrial pathways for efficacious cancer treatment.

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Gold(III)-P-chirogenic complex induces mitochondrial dysfunction in triple-negative breast cancer

Abstract

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