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

Area of Science:

• Medicinal Chemistry
• Cancer Biology
• Nanomedicine

Background:

• Triple-negative breast cancer (TNBC) is an aggressive subtype with poor patient prognosis due to its metastatic potential and aberrant metabolism.
• Current treatments for TNBC have limitations, necessitating the development of novel therapeutic strategies.
• Targeting cancer cell metabolism presents a promising avenue for TNBC treatment.

Purpose of the Study:

• To design and synthesize novel gold(III) cyclometalated prodrugs of antidiabetic drugs (metformin and phenformin).
• To evaluate the in vitro cytotoxicity and in vivo efficacy of these prodrugs against triple-negative breast cancer.
• To investigate the mechanism of action, focusing on energy metabolism disruption in TNBC cells.

Main Methods:

• Synthesis and characterization of novel gold(III) cyclometalated complexes.
• In vitro cytotoxicity assays using TNBC cell lines.
• In vivo studies in mouse models of aggressive breast cancer to assess tumor burden reduction.
• Mechanistic studies to evaluate the impact on cellular energy production and pro-survival pathways.

Main Results:

• The lead gold(III) complex, 3met, demonstrated 6000-fold higher cytotoxicity than metformin alone.
• 3met significantly reduced tumor burden in mice bearing aggressive breast cancers.
• The observed efficacy is attributed to 3met's ability to disrupt energy production in TNBC cells, inhibiting pro-survival responses and inducing metabolic catastrophe.

Conclusions:

• Novel gold(III) cyclometalated prodrugs show potent anti-cancer activity against triple-negative breast cancer.
• These compounds effectively target TNBC's metabolic vulnerabilities, offering a promising new therapeutic approach.
• The lead compound, 3met, warrants further investigation as a potential treatment for aggressive breast cancers.