Interfering with Metabolic Profile of Triple-Negative Breast Cancers Using Rationally Designed Metformin Prodrugs

Maria V. Babak; Kai Ren Chong; Peter Rapta; Markella Zannikou; Hui Min Tang; Lisa Reichert; Meng Rui Chang; Vladimir Kushnarev; Petra Heffeter; Samuel M. Meier-Menches; Zhi Chiaw Lim; Jian Yu Yap; Angela Casini; Irina V. Balyasnikova; Wee Han Ang

doi:10.1002/anie.202102266

Interfering with Metabolic Profile of Triple-Negative Breast Cancers Using Rationally Designed Metformin Prodrugs

Maria V. Babak (Corresponding author)
, Kai Ren Chong
, Peter Rapta
, Markella Zannikou
, Hui Min Tang
, Lisa Reichert
, Meng Rui Chang
, Vladimir Kushnarev
, Petra Heffeter
, Samuel M. Meier-Menches
, Zhi Chiaw Lim
, Jian Yu Yap
, Angela Casini
, Irina V. Balyasnikova
, Wee Han Ang (Corresponding author)

Department of Analytical Chemistry

Publications: Contribution to journal › Article › Peer Reviewed

Abstract

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterized by an aberrant metabolic phenotype with high metastatic capacity, resulting in poor patient prognoses and low survival rates. We designed a series of novel Au-III cyclometalated prodrugs of energy-disrupting Type II antidiabetic drugs namely, metformin and phenformin. Prodrug activation and release of the metformin ligand was achieved by tuning the cyclometalated Au-III fragment. The lead complex 3met was 6000-fold more cytotoxic compared to uncoordinated metformin and significantly reduced tumor burden in mice with aggressive breast cancers with lymphocytic infiltration into tumor tissues. These effects was ascribed to 3met interfering with energy production in TNBCs and inhibiting associated pro-survival responses to induce deadly metabolic catastrophe.

Original language	English
Pages (from-to)	13405-13413
Number of pages	9
Journal	Angewandte Chemie (International Edition)
Volume	60
Issue number	24
DOIs	https://doi.org/10.1002/anie.202102266
Publication status	Published - 7 Jun 2021

Funding

The work described in this paper was funded by Ministry of Education Singapore (MOE2018-T2-1-139 to W.H.A.). M.V.B. acknowledges financial support from City University of Hong Kong (Project No. 7200682 and 9610518). I.V.B. acknowledges support from the Lynn Sage Cancer Research Foundation. M.V.B. acknowledges Tibor Hajsz for generating the artworks and Siti Nuraisyah Bte Nordin for help with Seahorse experiments. A.C. acknowledges Cardiff University for funding. This work was also supported by the Northwestern University the Center for Advanced Microscopy and the Mouse Histology and Phenotyping Laboratory supported by NCI P30-CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. P.R. acknowledges financial support from Slovak Grant Agencies APVV (grant APVV-190024) and VEGA (grant 0504/20).

UN SDGs

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

SDG 3 Good Health and Well-being

Austrian Fields of Science 2012

301904 Cancer research
301207 Pharmaceutical chemistry

Keywords

antitumor agents
drug discovery
metabolism
metformin
prodrugs

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10.1002/anie.202102266

Cite this

Babak, M. V., Chong, K. R., Rapta, P., Zannikou, M., Tang, H. M., Reichert, L., Chang, M. R., Kushnarev, V., Heffeter, P., Meier-Menches, S. M., Lim, Z. C., Yap, J. Y., Casini, A., Balyasnikova, I. V., & Ang, W. H. (2021). Interfering with Metabolic Profile of Triple-Negative Breast Cancers Using Rationally Designed Metformin Prodrugs. Angewandte Chemie (International Edition), 60(24), 13405-13413. https://doi.org/10.1002/anie.202102266

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title = "Interfering with Metabolic Profile of Triple-Negative Breast Cancers Using Rationally Designed Metformin Prodrugs",

abstract = "Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterized by an aberrant metabolic phenotype with high metastatic capacity, resulting in poor patient prognoses and low survival rates. We designed a series of novel Au-III cyclometalated prodrugs of energy-disrupting Type II antidiabetic drugs namely, metformin and phenformin. Prodrug activation and release of the metformin ligand was achieved by tuning the cyclometalated Au-III fragment. The lead complex 3met was 6000-fold more cytotoxic compared to uncoordinated metformin and significantly reduced tumor burden in mice with aggressive breast cancers with lymphocytic infiltration into tumor tissues. These effects was ascribed to 3met interfering with energy production in TNBCs and inhibiting associated pro-survival responses to induce deadly metabolic catastrophe.",

keywords = "antitumor agents, drug discovery, metabolism, metformin, prodrugs",

author = "Babak, \{Maria V.\} and Chong, \{Kai Ren\} and Peter Rapta and Markella Zannikou and Tang, \{Hui Min\} and Lisa Reichert and Chang, \{Meng Rui\} and Vladimir Kushnarev and Petra Heffeter and Meier-Menches, \{Samuel M.\} and Lim, \{Zhi Chiaw\} and Yap, \{Jian Yu\} and Angela Casini and Balyasnikova, \{Irina V.\} and Ang, \{Wee Han\}",

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year = "2021",

month = jun,

day = "7",

doi = "10.1002/anie.202102266",

language = "English",

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Babak, MV, Chong, KR, Rapta, P, Zannikou, M, Tang, HM, Reichert, L, Chang, MR, Kushnarev, V, Heffeter, P, Meier-Menches, SM, Lim, ZC, Yap, JY, Casini, A, Balyasnikova, IV & Ang, WH 2021, 'Interfering with Metabolic Profile of Triple-Negative Breast Cancers Using Rationally Designed Metformin Prodrugs', Angewandte Chemie (International Edition), vol. 60, no. 24, pp. 13405-13413. https://doi.org/10.1002/anie.202102266

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T1 - Interfering with Metabolic Profile of Triple-Negative Breast Cancers Using Rationally Designed Metformin Prodrugs

AU - Babak, Maria V.

AU - Chong, Kai Ren

AU - Rapta, Peter

AU - Zannikou, Markella

AU - Tang, Hui Min

AU - Reichert, Lisa

AU - Chang, Meng Rui

AU - Kushnarev, Vladimir

AU - Heffeter, Petra

AU - Meier-Menches, Samuel M.

AU - Lim, Zhi Chiaw

AU - Yap, Jian Yu

AU - Casini, Angela

AU - Balyasnikova, Irina V.

AU - Ang, Wee Han

PY - 2021/6/7

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AB - Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterized by an aberrant metabolic phenotype with high metastatic capacity, resulting in poor patient prognoses and low survival rates. We designed a series of novel Au-III cyclometalated prodrugs of energy-disrupting Type II antidiabetic drugs namely, metformin and phenformin. Prodrug activation and release of the metformin ligand was achieved by tuning the cyclometalated Au-III fragment. The lead complex 3met was 6000-fold more cytotoxic compared to uncoordinated metformin and significantly reduced tumor burden in mice with aggressive breast cancers with lymphocytic infiltration into tumor tissues. These effects was ascribed to 3met interfering with energy production in TNBCs and inhibiting associated pro-survival responses to induce deadly metabolic catastrophe.

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KW - drug discovery

KW - metabolism

KW - metformin

KW - prodrugs

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ER -

Interfering with Metabolic Profile of Triple-Negative Breast Cancers Using Rationally Designed Metformin Prodrugs

Abstract

Funding

UN SDGs

Austrian Fields of Science 2012

Keywords

Access to Document

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