Metformin-induced ROS upregulation as amplified by apigenin causes profound anticancer activity while sparing normal cells
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.
Medienart: |
E-Artikel |
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Erscheinungsjahr: |
2021 |
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Erschienen: |
2021 |
Enthalten in: |
Zur Gesamtaufnahme - volume:11 |
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Enthalten in: |
Scientific reports - 11(2021), 1 vom: 07. Juli, Seite 14002 |
Sprache: |
Englisch |
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Beteiligte Personen: |
Warkad, Madhuri Shende [VerfasserIn] |
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Links: |
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Anmerkungen: |
Date Completed 23.11.2021 Date Revised 23.11.2021 published: Electronic Citation Status MEDLINE |
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doi: |
10.1038/s41598-021-93270-0 |
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funding: |
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Förderinstitution / Projekttitel: |
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PPN (Katalog-ID): |
NLM327801778 |
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520 | |a 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 | ||
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