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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.

SUBMITTER: Warkad MS

PROVIDER: S-EPMC8263563 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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

Warkad Madhuri Shende MS Kim Chea-Ha CH Kang Beom-Goo BG Park Soo-Hyun SH Jung Jun-Sub JS Feng Jing-Hui JH Inci Gozde G Kim Sung-Chan SC Suh Hong-Won HW Lim Soon Sung SS Lee Jae-Yong JY

Scientific reports 20210707 1

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, w ...[more]

PMID: 34234193

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Project description:PurposeTreatment for bilateral breast cancer with radiation therapy is technically challenging. We evaluated the clinical and dosimetric outcomes of a small series of patients with synchronous bilateral breast cancer, including a photon dosimetric comparison, to identify optimal treatment planning approaches.Materials and methodsWe reviewed a registry of patients (simultaneously) diagnosed with synchronous bilateral breast cancers who underwent postoperative definitive adjuvant proton therapy at our institution between 2012 and 2021. All patients were treated with double-scattered proton or pencil-beam scanning therapies. For comparison, intensity-modulated radiation therapy photon plans optimized for organ sparing and coverage were generated after treatment.ResultsSix patients were included. The median patient age was 66 years; all were female with no history of breast cancer or radiation therapy. Two (33%) patients received breast/chest wall-only treatments, 1 (17%) required breast plus level I axillary treatment to one side and breast plus regional nodal irradiation (RNI) to the other, and 3 (50%) received bilateral breast/chest plus RNI; dosimetric results are reported for each group's median. Analysis showed clinical target coverage was comparable between proton and photon techniques (V95% of 96.4% with proton, 97.8% with photon). However, protons could deliver superior organ sparing at clinically relevant dose metrics for virtually all structures: a 6.7 Gy absolute reduction in the mean heart dose (7.5 Gy with photons to 0.7 Gy with protons), a 47% to 57% relative reduction in D0.1cm3 to coronary arteries, a 54% relative reduction in lung V20 Gy, and an absolute 7.6 Gy reduction to the brachial plexus. There was also greater esophagus and spinal cord sparing. The overall survival rate was 100% at 1.5 years of median follow-up (0.5-4.9), and all patients were free of disease. For toxicity, all patients had some form of acute side effects: 66% experienced grade 2 breast/chest pain or soreness; 100% had grade 2 radiation dermatitis or skin induration; 33% had grade 2 fatigue; and 17% had grade 2 esophagitis (per the Common Terminology Criteria for Adverse Events [CTCAE] version 5.0; US National Cancer Institute, Bethesda, Maryland). Subacute toxicity (within 6 months) was observed for 17% of patients with delayed onset of grade 3 dermatitis in the setting of preexisting lupus, 17% with a delayed surgical wound complication, and 17% with grade 2 soft tissue fibrosis. No grade 4 or 5 events were observed.ConclusionsSubstantial dose reductions to multiple organs at risk while maintaining target coverage make proton the preferred modality for bilateral breast cancer treatment when available.

Dataset Information

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

Publications

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

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