Interfering with Metabolic Profile of Triple-Negative Breast Cancers Using Rationally Designed Metformin Prodrugs
- Author(s)
- 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
- 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.
- Organisation(s)
- Department of Analytical Chemistry
- External organisation(s)
- National University of Singapore (NUS), Slovak University of Technology in Bratislava, Medizinische Universität Wien, Technische Universität München, City University of Hong Kong (CityU), Northwestern University, Moscow Healthcare Department
- Journal
- Angewandte Chemie (International Edition)
- Volume
- 60
- Pages
- 13405-13413
- No. of pages
- 9
- ISSN
- 1433-7851
- DOI
- https://doi.org/10.1002/anie.202102266
- Publication date
- 06-2021
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 301904 Cancer research, 301207 Pharmaceutical chemistry
- Keywords
- ASJC Scopus subject areas
- General Chemistry, Catalysis
- Sustainable Development Goals
- SDG 3 - Good Health and Well-being
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/59b8038d-a366-4da0-b10b-cb4df4415ec9