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

Abstract

Metformin increased cellular ROS levels in AsPC-1 pancreatic cancer cells, with minimal effect in HDF, human primary dermal fibroblasts. Metformin reduced cellular ATP levels in HDF, but not in AsPC-1 cells. Metformin increased AMPK, p-AMPK (Thr172), FOXO3a, p-FOXO3a (Ser413), and MnSOD levels in HDF, but not in AsPC-1 cells. p-AMPK and p-FOXO3a also translocated from the cytosol to the nucleus by metformin in HDF, but not in AsPC-1 cells. Transfection of si-FOXO3a in HDF increased ROS levels, while wt-FOXO3a-transfected AsPC-1 cells decreased ROS levels. Metformin combined with apigenin increased ROS levels dramatically and decreased cell viability in various cancer cells including AsPC-1 cells, with each drug used singly having a minimal effect. Metformin/apigenin combination synergistically decreased mitochondrial membrane potential in AsPC-1 cells but to a lesser extent in HDF cells. Metformin/apigenin combination in AsPC-1 cells increased DNA damage-, apoptosis-, autophagy- and necroptosis-related factors, but not in HDF cells. Oral administration with metformin/apigenin caused dramatic blocks tumor size in AsPC-1-xenografted nude mice. Our results suggest that metformin in cancer cells differentially regulates cellular ROS levels via AMPK-FOXO3a-MnSOD pathway and combination of metformin/apigenin exerts anticancer activity through DNA damage-induced apoptosis, autophagy and necroptosis by cancer cell-specific ROS amplification.

• Authors: Madhuri Shende Warkad, Chea-Ha Kim, Beom-Goo Kang, Soo-Hyun Park, Jun-Sub Jung, Jing-Hui Feng, Gozde Inci, Sung-Chan Kim, Hong-Won Suh, Soon Sung Lim, Jae-Yong Lee
• Journal: Scientific reports (Sci Rep) Vol. 11 Issue 1 Pg. 14002 (07 07 2021) ISSN: 2045-2322 [Electronic] England
• PMID: 34234193 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• FOXO3 protein, human
• Forkhead Box Protein O3
• Reactive Oxygen Species
• Apigenin
• Adenosine Triphosphate
• Metformin
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (metabolism)
• Adenosine Triphosphate (metabolism)
• Antineoplastic Agents (pharmacology)
• Apigenin (pharmacology)
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Drug Synergism
• Fibroblasts
• Forkhead Box Protein O3 (metabolism)
• Humans
• Metformin (pharmacology)
• Models, Biological
• Reactive Oxygen Species (metabolism)
• Signal Transduction