Reactive oxygen species derived from xanthine oxidase interrupt dimerization of breast cancer resistance protein, resulting in suppression of uric acid excretion to the intestinal lumen

Ogura, Jiro; Kuwayama, Kaori; Sasaki, Shunichi; Kaneko, Chris R. S.; Koizumi, Takahiro; Yabe, Keisuke; Tsujimoto, Takashi; Takeno, Reiko; Takaya, Atsushi; Kobayashi, Masaki; Yamaguchi, Hiroaki; Iseki, Ken

doi:10.1016/j.bcp.2015.06.021

Cited by 30 publications

(23 citation statements)

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“…5b and c). In addition to the mitochondria, xanthine oxidase, lipoxygenase, cyclooxygenase, cytochrome p450 and NADPH oxidase are sources of cellular ROS [48–51]. However, inhibitors of these enzymes failed to block B5G9-induced ROS generation (Fig.…”

Section: Resultsmentioning

confidence: 99%

A piperazidine derivative of 23-hydroxy betulinic acid induces a mitochondria-derived ROS burst to trigger apoptotic cell death in hepatocellular carcinoma cells

Yao

Lei

et al. 2016

J Exp Clin Cancer Res

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BackgroundElevated production of reactive oxygen species (ROS) and an altered redox state have frequently been observed in hepatocellular carcinoma (HCC); therefore, selective killing of HCC cells by chemotherapeutic agents that stimulate ROS generation or impair antioxidant systems may be a feasible approach in HCC chemotherapy. Recently, betulinic acid and its derivatives have attracted attention because they showed anti-cancer effects via a ROS- and mitochondria-related mechanism. However, the source of ROS overproduction and the role of mitochondria were poorly identified, and the weak in vivo antitumour activity of these compounds limits their development as drugs.MethodsCytotoxicity was detected using MTT assays. In vivo anti-HCC effects were assessed using nude mice bearing HepG2 tumour xenografts. Cell cycle analysis, apoptosis rate and mitochondrial membrane potential were measured by flow cytometry. ROS production was detected using a microplate reader or a fluorescence microscope. Changes in gene and protein levels were measured by RT-PCR and western blotting, respectively. Other assays were performed using related detection kits.ResultsB5G9, a piperazidine derivative of 23-hydroxy betulinic acid (23-HBA), showed excellent in vivo anti-HCC effects, with a tumour growth inhibitory rate of greater than 80%, and no significant side effects. B5G9 stimulated the production of ROS, which were derived from the mitochondria, but it had no effect on various other antioxidant systems. Moreover, B5G9 induced mitochondrial dysfunction, which was characterized by morphological changes, membrane potential collapse, membrane permeabilization, and decreases in the O2 consumption rate and ATP production. Furthermore, mtDNA-depleted ρ0 HepG2 cells were less sensitive to B5G9 treatment than wt HepG2 cells, indicating the importance of mitochondria in B5G9-induced cell death.ConclusionWe discovered a piperazidine derivative of 23-HBA, B5G9, with excellent anti-HCC effects both in vivo and in vitro and no obvious toxic effects. The underlying mechanism was associated with mitochondria-derived ROS overproduction, and mitochondria played essential roles in B5G9-induced cell death. This study identified a potential agent for anti-HCC therapy and elucidated the mitochondria-related mechanism of BA and its derivatives.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0457-1) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

A piperazidine derivative of 23-hydroxy betulinic acid induces a mitochondria-derived ROS burst to trigger apoptotic cell death in hepatocellular carcinoma cells

Yao

Lei

et al. 2016

J Exp Clin Cancer Res

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“…Unlike ABC transporters, however, BCRP has only one N-terminal ATP-binding domain [28,29,30]. Reduced intestinal excretion of UA is often associated with polymorphisms of the BCRP gene [26] or with a lack of BCRP dimerization, which is due to oxidative stress [31,32]. …”

Section: Purine Metabolism and Uric Acid Physiologymentioning

confidence: 99%

Fructose Intake, Serum Uric Acid, and Cardiometabolic Disorders: A Critical Review

et al. 2017

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There is a direct relationship between fructose intake and serum levels of uric acid (UA), which is the final product of purine metabolism. Recent preclinical and clinical evidence suggests that chronic hyperuricemia is an independent risk factor for hypertension, metabolic syndrome, and cardiovascular disease. It is probably also an independent risk factor for chronic kidney disease, Type 2 diabetes, and cognitive decline. These relationships have been observed for high serum UA levels (>5.5 mg/dL in women and >6 mg/dL in men), but also for normal to high serum UA levels (5–6 mg/dL). In this regard, blood UA levels are much higher in industrialized countries than in the rest of the world. Xanthine-oxidase inhibitors can reduce UA and seem to minimize its negative effects on vascular health. Other dietary and pathophysiological factors are also related to UA production. However, the role of fructose-derived UA in the pathogenesis of cardiometabolic disorders has not yet been fully clarified. Here, we critically review recent research on the biochemistry of UA production, the relationship between fructose intake and UA production, and how this relationship is linked to cardiometabolic disorders.

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“…Uric acid excretion was analyzed as described in the previous report [22]. To analyze uric acid excretion, the bladder was cannulated with polyethylene tubing (SP45; Natsume Seisakusho) for urine collection, and 10-cm-long intestinal loops were made at the jejunum and ileum by ligating at both ends.…”

Section: Uric Acid Excretion Studymentioning

confidence: 99%

“…Therefore, BCRP has to form a homodimer, bridged by a disulfide bond, to efflux BCRP substrates [18][19][20]. We previously reported that dimerization of BCRP was influenced by oxidative stress [21,22]. Since fructose consumption induces oxidative stress by activation of Nox, it is speculated that fructose consumption may also affect the excretion of uric acid to the intestinal lumen.…”

Section: Introductionmentioning

confidence: 99%

Fructose suppresses uric acid excretion to the intestinal lumen as a result of the induction of oxidative stress by NADPH oxidase activation

Kaneko

Ogura

Sasaki

et al. 2017

Biochimica et Biophysica Acta (BBA) - General Subjects

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Reactive oxygen species derived from xanthine oxidase interrupt dimerization of breast cancer resistance protein, resulting in suppression of uric acid excretion to the intestinal lumen

Cited by 30 publications

References 46 publications

A piperazidine derivative of 23-hydroxy betulinic acid induces a mitochondria-derived ROS burst to trigger apoptotic cell death in hepatocellular carcinoma cells

A piperazidine derivative of 23-hydroxy betulinic acid induces a mitochondria-derived ROS burst to trigger apoptotic cell death in hepatocellular carcinoma cells

Fructose Intake, Serum Uric Acid, and Cardiometabolic Disorders: A Critical Review

Fructose suppresses uric acid excretion to the intestinal lumen as a result of the induction of oxidative stress by NADPH oxidase activation

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