Metformin sensitises hepatocarcinoma cells to methotrexate by targeting dihydrofolate reductase

Area of Science:

• Biochemistry
• Oncology
• Pharmacology

Background:

• Metformin, a type II diabetes drug, is explored for anticancer properties.
• The precise mechanisms behind metformin's anti-cancer effects are not fully understood.

Purpose of the Study:

• To investigate metformin's molecular targets and mechanisms in hepatocarcinoma.
• To determine if metformin can enhance the efficacy of chemotherapy drugs like methotrexate (MTX).

Main Methods:

• Investigated metformin's effect on DHFR expression and protein levels in hepatocarcinoma cells.
• Assessed the impact of metformin and MTX combination on nucleotide metabolism and cell cycle progression.
• Utilized patient-derived hepatocarcinoma and normal liver organoids to evaluate therapeutic response and toxicity.

Main Results:

• Metformin suppresses dihydrofolate reductase (DHFR) expression and promotes its degradation, increasing sensitivity to methotrexate (MTX).
• The combination of metformin and MTX effectively inhibits hepatocarcinoma cell cycle progression and tumorigenesis by blocking nucleotide metabolism.
• Metformin significantly improved MTX response in patient-derived hepatocarcinoma organoids with minimal toxicity to normal liver organoids.

Conclusions:

• Dihydrofolate reductase (DHFR) plays a key role in metformin's ability to overcome therapeutic resistance in hepatocarcinoma.
• Targeting DHFR presents a potential therapeutic strategy for enhancing hepatocarcinoma treatment outcomes.