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

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 lev...

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Autores principales: 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
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Lenguaje:EN
Publicado: Nature Portfolio 2021
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Science
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Acceso en línea:https://doaj.org/article/3dbbd54394c347a68799a0da2672a100
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spelling oai:doaj.org-article:3dbbd54394c347a68799a0da2672a1002021-12-02T18:33:57ZMetformin-induced ROS upregulation as amplified by apigenin causes profound anticancer activity while sparing normal cells10.1038/s41598-021-93270-02045-2322https://doaj.org/article/3dbbd54394c347a68799a0da2672a1002021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-93270-0https://doaj.org/toc/2045-2322Abstract 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.Madhuri Shende WarkadChea-Ha KimBeom-Goo KangSoo-Hyun ParkJun-Sub JungJing-Hui FengGozde InciSung-Chan KimHong-Won SuhSoon Sung LimJae-Yong LeeNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
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
Metformin-induced ROS upregulation as amplified by apigenin causes profound anticancer activity while sparing normal cells
description 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.
format article
author 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
author_facet 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
author_sort Madhuri Shende Warkad
title Metformin-induced ROS upregulation as amplified by apigenin causes profound anticancer activity while sparing normal cells
title_short Metformin-induced ROS upregulation as amplified by apigenin causes profound anticancer activity while sparing normal cells
title_full Metformin-induced ROS upregulation as amplified by apigenin causes profound anticancer activity while sparing normal cells
title_fullStr Metformin-induced ROS upregulation as amplified by apigenin causes profound anticancer activity while sparing normal cells
title_full_unstemmed Metformin-induced ROS upregulation as amplified by apigenin causes profound anticancer activity while sparing normal cells
title_sort metformin-induced ros upregulation as amplified by apigenin causes profound anticancer activity while sparing normal cells
publisher Nature Portfolio
publishDate 2021
url https://doaj.org/article/3dbbd54394c347a68799a0da2672a100
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