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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

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 AuIII 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 AuIII 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 languageEnglish (US)
Pages (from-to)13405-13413
Number of pages9
JournalAngewandte Chemie - International Edition
Volume60
Issue number24
DOIs
StatePublished - Jun 7 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-19-0024) and VEGA (grant 0504/20). 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‐19‐0024) and VEGA (grant 0504/20).

Keywords

  • antitumor agents
  • drug discovery
  • metabolism
  • metformin
  • prodrugs

ASJC Scopus subject areas

  • General Chemistry
  • Catalysis

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