Quercetin induces mitochondrial-derived apoptosis via reactive oxygen species-mediated ERK activation in HL-60 leukemia cells and xenograft

Lee, Wei-Jiunn; Hsiao, Michael; Chang, Junn Liang; Yang, Shun Fa; Tseng, Tsui Hwa; Cheng, Chao‐Wen; Chow, Julie Chi; Lin, Ke; Lin, Yung Wei; Liu, Chung Chi; Lee, Liang‐Ming; Chien, Ming‐Hsien

doi:10.1007/s00204-014-1300-0

Cited by 86 publications

(77 citation statements)

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“…In various types of cancer cells, Q inhibits cell growth and induces apoptosis; however, it also induces the expression of antioxidant proteins involved in the elimination of ROS, thus protecting cells against oxidative damage (32,33). Flavonoids, including VC and Q, have emerged as an effective adjuvant in cancer therapy, due to acting as free radical scavengers and immune system modulators, in addition to .05 compared with the control group and vehicle.…”

Section: Discussionmentioning

confidence: 99%

The role of quercetin and vitamin C in Nrf2-dependent oxidative stress production in breast cancer cells

et al. 2017

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Abstract.The balance between the production and elimination of reactive oxygen species (ROS) is essential in determining whether cells survive or undergo apoptosis. Nuclear factor erythroid 2-related factor 2 (Nrf2) may act as a sensor for electrophilic stress, thus regulating the intracellular antioxidant response. The present study investigated the role of vitamin C (VC) and quercetin (Q) in the induction of Nrf2-mediated oxidative stress in cancer cells. An MTT assay was conducted to examine the anti-proliferative effects of VC and Q. Reverse transcription-quantitative polymerase chain reaction and western blot analysis were performed to determine the messenger RNA (mRNA) and protein expression of Nrf2, respectively. The activity of nicotinamide adenine dinucleotide phosphate dehydrogenase quinone 1, heme oxygenase 1, glutathione peroxidase, glutathione reductase and reduced glutathione were measured by spectrophotometric analysis. Intracellular generation of ROS was determined using 2'-7'-dichlorodihydrofluorescein diacetate fluorescent probes. The results demonstrated that the cytotoxicity (50% inhibitory concentration) of VC and Q were 271.6-480.1 and 155.1-232.9 µM, respectively. Additionally, there was a significant decrease in the expression of Nrf2 mRNA and protein levels following the treatment of breast cancer cells with VC and Q (P=0.024). Following treatment with VC and Q, the nuclear/cytosolic Nrf2 ratio was reduced by 1.7-fold in MDA-MB 231 cells, 2-fold in MDA-MB 468 cells, 1.4-fold in MCF-7 cells and 1.2 fold in A549 cells. Sequential treatment with VC and Q decreased endogenous production of ROS in a dose-dependent manner (P=0.027). The results of the current study suggest that VC and Q treatment may be developed as an adjuvant for patients with cancer and overexpression of Nrf2.

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Section: Discussionmentioning

confidence: 99%

The role of quercetin and vitamin C in Nrf2-dependent oxidative stress production in breast cancer cells

et al. 2017

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“…St-Hil., a plant used in folk medicine induced OS in D. melanogaster followed consumption (Pinho et al 2014). It has been demonstrated that some compounds of plants as flavonoids, may present beneficial as well as pro-oxidative effects, depending on the concentration and frequency of exposure (Lee et al 2015).…”

Section: Introductionmentioning

confidence: 99%

“…In D. melanogaster, the MAPK pathway is known to be involved in numerous processes during normal development and in the regulation of immune response (Stronach & Perrimon 1999). Botanical extracts and isolated phytochemicals are able to modulate the phosphorylation of these kinases showing that a broad range of cellular functions may be affected by plant derived compounds (Pinho et al 2014;Lee et al 2015).…”

Section: Introductionmentioning

confidence: 99%

Oxidant effects and toxicity of Croton campestris in Drosophila melanogaster

Júnior

Macedo

Zemolin

et al. 2016

Pharmaceutical Biology

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Context: Croton campestris A.St.-Hil. (Euphorbiaceae) is a species native to Northeast Brazil used by traditional communities for the treatment of a variety of health problems. However, potential toxicological effects of this plant are unknown. Objective: The potential toxicity of the hydroalcoholic extract of C. campestris leaves on Drosophila melanogaster insect model, additionally with phytochemical constitution and cellular mechanisms mediating the action of extract were analysed in this study. Materials and methods: Constituents of the extract were evaluated by HPLC. In vitro antioxidant potential of extract was analysed by DPPH, ABTS and FRAP. Flies injected culture medium mixed with extract (0.1-50 mg/mL) for 72 h. After, ROS production was evaluated by DCF-DA oxidation. Phosphorylation of MAPK signalling pathway was investigated by Western blotting method. Activity of antioxidant enzymes was analysed in homogenates.Results: Major components of the extract include quercetin (38.11 ± 0.06 mg/g), caffeic acid (20.06 ± 0.17 mg/g) and kaempferol (15.45 ± 0.05 mg/g). Consumption of the extract impaired locomotor performance and induced fly death of flies (LC 50 of 26.51 mg/mL). Augmented ROS formation and SOD, CAT and GST activity were observed from 0.1 mg/mL. JNK and p38 kinases phosphorylation was modulated and Paraquat-induced toxicity was augmented by extract. Discussion and conclusion: Our data show important toxicological effects of C. campestris leading to increased mortality and impaired locomotor performance accompanied by induction of cell stress markers in flies. The study draws attention to the indiscriminate use of plant extracts. ARTICLE HISTORY

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“…For instance, it was reported that Quer may either decrease [36] or increase [37, 38] ROS production in HL60 cells, and ROS increase mediated apoptosis induction [38]. For these reasons, we evaluated possible alterations in intracellular ROS accumulation after short treatments (3 h) with Quer and 2-DG, alone and in combination, using the ROS-sensitive fluorescent probe H 2 DCFDA.…”

Section: Resultsmentioning

confidence: 99%

Selected polyphenols potentiate the apoptotic efficacy of glycolytic inhibitors in human acute myeloid leukemia cell lines. Regulation by protein kinase activities

et al. 2016

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BackgroundThe glycolysis inhibitor 2-deoxy-d-glucose (2-DG) is a safe, potentially useful anti-tumour drug, but its efficacy is normally low when used alone. Recent studies indicated that 2-DG stimulates the PI3K/Akt and MEK/ERK defensive pathways, which limits the apoptotic efficacy in tumour cell lines. We hypothesized that co-treatment with selected polyphenols could improve 2-DG-provoked apoptosis by preventing defensive kinase activation.MethodsCell proliferation was measured by cell counting or the MTT assay. Cell cycle, apoptosis and necrosis were determined by propidium iodide staining and/or annexin V labeling followed by flow cytometry. Mitochondria pore transition and depolarization were determined by calcein-ATM or rhodamine 123 labeling followed flow cytometry. Intracellular reactive oxygen species and GSH were determined by dichlorodihydrofluorescein diacetate or monochlorobimane labeling followed by flow cytometry or fluorimetry. Expression and phosphorylation of protein kinases were analyzed by the Western blot.Results(i) 2-DG-provoked apoptosis was greatly potentiated by co-treatment with the sub-lethal concentrations of the flavonoid quercetin in human HL60 acute myeloblastic leukemia cells. Allowing for quantitative differences, apoptosis potentiation was also obtained using NB4 promyelocytic and THP-1 promonocytic cells, using curcumin or genistein instead of quercetin, and using lonidamine instead of 2-DG, but not when 2-DG was substituted by incubation in glucose-free medium. (ii) Quercetin and 2-DG rapidly elicited the opening of mitochondria pore transition, which preceded the trigger of apoptosis. (iii) Treatments did not affect GSH levels, and caused disparate effects on reactive oxygen species generation, which did not match the changes in lethality. (iv) 2-DG and lonidamine stimulated defensive Akt and ERK phosphorylation/activation, while glucose starvation was ineffective. Polyphenols prevented the stimulation of Akt phosphorylation, and in some cases also ERK phosphorylation. In addition, quercetin and 2-DG stimulated GSK-3α,β phosphorylation/inactivation, although with different isoform specificity. The use of pharmacologic inhibitors confirmed the importance of these kinase modifications for apoptosis.ConclusionsThe present in vitro observations suggest that co-treatment with low concentrations of selected polyphenols might represent a manner of improving the poor anti-tumour efficacy of some glycolytic inhibitors, and that apoptosis potentiation may be at least in part explained by the regulation of defensive protein kinase activities.Electronic supplementary materialThe online version of this article (doi:10.1186/s12935-016-0345-y) contains supplementary material, which is available to authorized users.

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Quercetin induces mitochondrial-derived apoptosis via reactive oxygen species-mediated ERK activation in HL-60 leukemia cells and xenograft

Cited by 86 publications

References 45 publications

The role of quercetin and vitamin C in Nrf2-dependent oxidative stress production in breast cancer cells

The role of quercetin and vitamin C in Nrf2-dependent oxidative stress production in breast cancer cells

Oxidant effects and toxicity of Croton campestris in Drosophila melanogaster

Selected polyphenols potentiate the apoptotic efficacy of glycolytic inhibitors in human acute myeloid leukemia cell lines. Regulation by protein kinase activities

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