A gold-based inhibitor of oxidative phosphorylation is effective against triple negative breast cancer

R. Tyler Mertens; Jong Hyun Kim; Samuel Ofori; Chibuzor Olelewe; Paul J. Kamitsuka; Gunnar F. Kwakye; Samuel G. Awuah

doi:10.1016/j.biopha.2023.116010

A gold-based inhibitor of oxidative phosphorylation is effective against triple negative breast cancer

R. Tyler Mertens
, Jong Hyun Kim
, Samuel Ofori
, Chibuzor Olelewe
, Paul J. Kamitsuka
, Gunnar F. Kwakye
, Samuel G. Awuah

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

10 Scopus citations

Abstract

Triple-negative breast cancer (TNBC) is associated with metabolic heterogeneity and poor prognosis with limited treatment options. New treatment paradigms for TNBC remains an unmet need. Thus, therapeutics that target metabolism are particularly attractive approaches. We previously designed organometallic Au(III) compounds capable of modulating mitochondrial respiration by ligand tuning with high anticancer potency in vitro and in vivo. Here, we show that an efficacious Au(III) dithiocarbamate (AuDTC) compound induce mitochondrial dysfunction and oxidative damage in cancer cells. Efficacy of AuDTC in TNBC mouse models harboring mitochondrial oxidative phosphorylation (OXPHOS) dependence and metabolic heterogeneity establishes its therapeutic potential following systemic delivery. This provides evidence that AuDTC is an effective modulator of mitochondrial respiration worthy of clinical development in the context of TNBC. One sentence summary: Metabolic-targeting of triple-negative breast cancer by gold anticancer agent may provide efficacious therapy.

Original language	English
Article number	116010
Journal	Biomedicine and Pharmacotherapy
Volume	170
DOIs	https://doi.org/10.1016/j.biopha.2023.116010
State	Published - Jan 2024

Bibliographical note

Publisher Copyright:
© 2023 The Authors

Funding

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 UK X-ray facility supported by the MRI program from NSF (CHE-1625732), 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. Tomoko Sengoku 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). We are grateful for the use of Dr Steven Van Lanen's laboratory (UK College of Pharmacy) LC-MS. National Institutes of Health-NCI grant R01CA258421-01 (S.G.A.), and Oberlin College (G.F.K.). The authors also acknowledge support of the Center for Pharmaceutical Research and Innovation ( CPRI , NIH P20 GM130456 ). National Institutes of Health-NCI grant R01CA258421-01 (S.G.A.), and Oberlin College (G.F.K.). The authors also acknowledge support of the Center for Pharmaceutical Research and Innovation (CPRI, NIH P20 GM130456).

Funders	Funder number
National Science Foundation Arctic Social Science Program	CHE-997738, CHE-1625732
National Institutes of Health (NIH)	R01CA258421-01, P20 GM130456
National Childhood Cancer Registry – National Cancer Institute	P30 CA177558
University of Kentucky Markey Comprehensive Cancer Center
Center for Pharmaceutical Research and Innovation, University of Kentucky
Oberlin College and Conservatory
Office of the Executive Vice President for Research and Partnerships, Purdue University

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Gold
Mitochondria
OXPHOS
Triple negative breast cancer

ASJC Scopus subject areas

Pharmacology

Access to Document

10.1016/j.biopha.2023.116010

Cite this

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title = "A gold-based inhibitor of oxidative phosphorylation is effective against triple negative breast cancer",

abstract = "Triple-negative breast cancer (TNBC) is associated with metabolic heterogeneity and poor prognosis with limited treatment options. New treatment paradigms for TNBC remains an unmet need. Thus, therapeutics that target metabolism are particularly attractive approaches. We previously designed organometallic Au(III) compounds capable of modulating mitochondrial respiration by ligand tuning with high anticancer potency in vitro and in vivo. Here, we show that an efficacious Au(III) dithiocarbamate (AuDTC) compound induce mitochondrial dysfunction and oxidative damage in cancer cells. Efficacy of AuDTC in TNBC mouse models harboring mitochondrial oxidative phosphorylation (OXPHOS) dependence and metabolic heterogeneity establishes its therapeutic potential following systemic delivery. This provides evidence that AuDTC is an effective modulator of mitochondrial respiration worthy of clinical development in the context of TNBC. One sentence summary: Metabolic-targeting of triple-negative breast cancer by gold anticancer agent may provide efficacious therapy.",

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doi = "10.1016/j.biopha.2023.116010",

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AU - Mertens, R. Tyler

AU - Kim, Jong Hyun

AU - Ofori, Samuel

AU - Olelewe, Chibuzor

AU - Kamitsuka, Paul J.

AU - Kwakye, Gunnar F.

AU - Awuah, Samuel G.

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N2 - Triple-negative breast cancer (TNBC) is associated with metabolic heterogeneity and poor prognosis with limited treatment options. New treatment paradigms for TNBC remains an unmet need. Thus, therapeutics that target metabolism are particularly attractive approaches. We previously designed organometallic Au(III) compounds capable of modulating mitochondrial respiration by ligand tuning with high anticancer potency in vitro and in vivo. Here, we show that an efficacious Au(III) dithiocarbamate (AuDTC) compound induce mitochondrial dysfunction and oxidative damage in cancer cells. Efficacy of AuDTC in TNBC mouse models harboring mitochondrial oxidative phosphorylation (OXPHOS) dependence and metabolic heterogeneity establishes its therapeutic potential following systemic delivery. This provides evidence that AuDTC is an effective modulator of mitochondrial respiration worthy of clinical development in the context of TNBC. One sentence summary: Metabolic-targeting of triple-negative breast cancer by gold anticancer agent may provide efficacious therapy.

AB - Triple-negative breast cancer (TNBC) is associated with metabolic heterogeneity and poor prognosis with limited treatment options. New treatment paradigms for TNBC remains an unmet need. Thus, therapeutics that target metabolism are particularly attractive approaches. We previously designed organometallic Au(III) compounds capable of modulating mitochondrial respiration by ligand tuning with high anticancer potency in vitro and in vivo. Here, we show that an efficacious Au(III) dithiocarbamate (AuDTC) compound induce mitochondrial dysfunction and oxidative damage in cancer cells. Efficacy of AuDTC in TNBC mouse models harboring mitochondrial oxidative phosphorylation (OXPHOS) dependence and metabolic heterogeneity establishes its therapeutic potential following systemic delivery. This provides evidence that AuDTC is an effective modulator of mitochondrial respiration worthy of clinical development in the context of TNBC. One sentence summary: Metabolic-targeting of triple-negative breast cancer by gold anticancer agent may provide efficacious therapy.

KW - Gold

KW - Mitochondria

KW - OXPHOS

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ER -

A gold-based inhibitor of oxidative phosphorylation is effective against triple negative breast cancer

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

ASJC Scopus subject areas

Access to Document

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