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Metformin-induced ROS upregulation as amplified by apigenin causes profound anticancer activity while sparing normal

Madhuri Shende Warkad1, Chea-Ha Kim1, Beom-Goo Kang1

  • 1Department of Biochemistry, Institute of Cell Differentiation and Aging, College of Medicine, Hallym University, 1 Hallymdeahak-gil, Chuncheon, 24252, Republic of Korea (South Korea).

Scientific Reports
|July 8, 2021
PubMed

Insights

Metformin differentially affects cancer cells and normal cells by altering reactive oxygen species (ROS) and ATP levels. Combining metformin with apigenin shows potent anticancer effects by inducing cell death pathways and reducing tumor growth.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Oncology

Background:

  • Metformin is a widely used drug for type 2 diabetes.
  • Its potential anticancer effects are under investigation.
  • Understanding its mechanism in cancer cells versus normal cells is crucial.

Purpose of the Study:

  • To investigate the differential effects of metformin on pancreatic cancer cells (AsPC-1) and human dermal fibroblasts (HDF).
  • To explore the role of the AMPK-FOXO3a-MnSOD pathway in metformin's action.
  • To evaluate the synergistic anticancer effects of combining metformin with apigenin.

Main Methods:

  • Cellular assays measuring reactive oxygen species (ROS), ATP levels, and mitochondrial membrane potential.
  • Western blotting to assess protein levels (AMPK, p-AMPK, FOXO3a, p-FOXO3a, MnSOD).
  • In vivo studies using AsPC-1 xenografted nude mice.

Main Results:

  • Metformin increased ROS in AsPC-1 cells but not HDF; it decreased ATP in HDF but not AsPC-1 cells.
  • Metformin modulated the AMPK-FOXO3a-MnSOD pathway in HDF, with nuclear translocation of p-AMPK and p-FOXO3a.
  • The combination of metformin and apigenin significantly reduced cancer cell viability, induced DNA damage, apoptosis, autophagy, and necroptosis, and inhibited tumor growth in vivo.

Conclusions:

  • Metformin's effects on ROS and ATP are cell-specific, involving the AMPK-FOXO3a-MnSOD pathway.
  • Metformin combined with apigenin exhibits synergistic anticancer activity through ROS amplification and induction of multiple cell death pathways.
  • This combination demonstrates significant therapeutic potential against pancreatic cancer.

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