Molecular chemotherapeutic potential of butein: A concise review

Jayasooriya, Rajapaksha Gedara Prasad Tharanga,Molagoda, Ilandarage Menu Neelaka,Park, Cheol,Jeong, Jin-Woo,Choi, Yung Hyun,Moon, Dong-Oh,Kim, Mun-Ock,Kim, Gi-Young Elsevier 2018 Food and chemical toxicology Vol.112 No.-

<P><B>Abstract</B></P> <P>Butein is a biologically active flavonoid isolated from the bark of <I>Rhus verniciflua</I> Stokes, which is known to have therapeutic potential against various cancers. Notably, butein inhibits cancer cell growth by inducing G<SUB>2</SUB>/M phase arrest and apoptosis. Butein-induced G<SUB>2</SUB>/M phase arrest is associated with increased phosphorylation of ataxia telangiectasia mutated (ATM) and Chk1/2, and consequently, with reduced cdc25C levels. In addition, butein-induced apoptosis is mediated through the activation of caspase-3, which is associated with changes in the expression of Bcl-2 and Bax proteins. Intriguingly, butein sensitizes cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis via ERK-mediated Sp1 activation, which promotes the transcription of specific death receptor 5. Butein also inhibits the migration and invasion of human cancer cells by suppressing nuclear factor-κB- and extracellular signal-regulated kinases 1/2-mediated expression of matrix metalloproteinase-9 and vascular endothelial growth factor. Additionally, butein downregulates the expression of human telomerase reverse transcriptase and causes a concomitant decrease in telomerase activity. These findings provide the basis for the pharmaceutical development of butein. The aim of this review is to provide an update on the mechanisms underlying the anticancer activity of butein, with a special focus on its effects on different cellular signaling cascades.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Butein induces apoptosis by activating Bax-caspase-3-PARP axis by PI3K/Akt-NF-κB axis through the inhibition of ROS generation. </LI> <LI> Butein induces G<SUB>2</SUB>/M phase cell cycle arrest by inhibiting ROS-mediated ATM-Chk1/2-Cdc25c-cdc2/cyclin B axis. </LI> <LI> Butein enhances TRAIL-mediated apoptosis by increasing DR5 expression through ERK-mediated Sp1 activation. </LI> <LI> Butein suppresses telomerase activity by inhibiting TERT expression and phosphorylation via c-Myc and PI3K/Akt. </LI> <LI> Butein attenuates angiogenesis, invasion/metastasis, and inflammation by suppressing the NF-κB signal pathway. </LI> </UL> </P>

Inhibition of adipocyte inflammation and macrophage chemotaxis by butein

Wang, Z.,Lee, Y.,Eun, J.S.,Bae, E.J. North-Holland ; Elsevier Science Ltd 2014 european journal of pharmacology Vol.738 No.-

Adipose tissue inflammation has been proposed as a therapeutic target for the treatment of obesity and metabolic disorders such as insulin resistance and type 2 diabetes. Butein, a polyphenol of vegetal origin, exhibits anti-inflammatory effects in macrophages but it was not reported whether butein prevents adipocyte inflammation. Here, we investigated the effects of butein on adipocyte inflammation in 3T3-L1 cells and performed functional macrophage migration assays. Butein opposed the stimulation of inducible nitric oxide synthase (iNOS) protein expression and of nitric oxide production by simultaneous treatment of adipocytes with tumor necrosis factor alpha (TNFα), lipopolysaccharide (LPS), and interferon gamma (TLI). In addition, butein inhibited mRNA expression of pro-inflammatory genes and chemokines in adipocytes stimulated with TLI or conditioned medium from RAW 264.7 macrophages treated with LPS. These effects were associated with suppression of inhibitor of kappa B alpha degradation induced by TNFα and with nuclear factor-kappa B (NF-κB) p65 phosphorylation and acetylation. Moreover, butein prevented phosphorylation of extracellular signal-regulated kinases, c-Jun N-terminal kinase, and the mitogen-activated protein kinase (MAPK) p38. These results suggest that butein suppresses adipocyte inflammation by inhibiting NF-κB/MAPK-dependent transcriptional activity. Furthermore, conditioned media from adipocytes stimulated macrophage chemotaxis, whereas media from adipocytes treated with butein blocked macrophage migration, an effect that was consistent with suppression of MCP-1 secretion by adipocytes treated with butein. In addition, macrophages treated with butein exhibited a reduced ability to migrate toward adipocyte CM. In conclusion, butein may represent a therapeutic agent to prevent adipose tissue inflammation and the obesity-linked insulin resistance.

Butein Synergizes with Statin to Upregulate Low-Density Lipoprotein Receptor Through HNF1α-Mediated PCSK9 Inhibition in HepG2 Cells

황진택,김효진,최효경,박재호,정상원,정민유 한국식품영양과학회 2020 Journal of medicinal food Vol.23 No.10

Downregulation of the low-density lipoprotein (LDL) receptor (LDLR) can lead to hypercholesterolemia and related conditions, including cardiovascular diseases. Statins are a class of LDL cholesterol-lowering agents and are best-selling medications for patients at high risk of developing cardiovascular diseases. Indeed, statins upregulate LDLR and proprotein convertase subtilisin/kexin type 9a (PCSK9), leading to LDLR lysosomal degradation, which interferes with the attenuation of hypercholesterolemia. In the present study, butein was found to decrease extracellular PCSK9 levels by reducing its mRNA expression, which was attributable to butein-mediated downregulation of HNF1α in HepG2 cells. Butein-mediated PCSK9 inhibition further reversed LDLR protein synthesis inhibition, which possibly occurred through butein-mediated inhibition of LDLR degradation. When treated as a combination of butein and a statin, butein reduced statin-mediated enhancement of PCSK9 protein expression. This resulted in a synergistic enhancement of LDLR protein expression, whereas butein alone marginally increased LDLR protein expression. These findings suggest that butein, a novel PCSK9 inhibitor, may be a potential alternative or adjunct to statin treatment.

p53 causes butein-mediated apoptosis of chronic myeloid leukemia cells

WOO, SANG-MI,CHOI, YOUN KYNUG,KIM, AH JEONG,CHO, SUNG-GOOK,KO, SEONG-GYU D.A. Spandidos 2016 MOLECULAR MEDICINE REPORTS Vol.13 No.2

<P>Progression of chronic myeloid leukemia, marked by the oncogenic <I>Bcr</I>-<I>Abl</I> mutation, is tightly associated with an alteration of the p53 pathway. It is known that butein extracted from various plants represses cancer growth. Although the anticancer effects of butein are widely accepted, the mechanisms by which butein induces apoptosis of chronic myeloid leukemia cells remains to be elucidated. The present study demonstrated that butein-induced apoptosis was mediated by p53. KBM5 chronic myeloid leukemia (CML) cells expressing wild-type p53 were more sensitive to butein compared with p53-null K562 CML cells in terms of apoptotic cell death. In addition, butein arrested KBM5 cells at S-phase and altered the expression levels of certain cyclins and the p53-downstream targets, MDM2 and p21. In addition, while butein reduced the protein expression of MDM2 in the KBM5 and K562 cells, it resulted in proteasome-independent MDM2 degradation in p53-expressing KBM5 cells, however, not in p53-null K562 cells. Therefore, the present study suggested that p53 causes the butein-mediated apoptosis of leukemic cells.</P>

Butein의 Jurkat T 림포마 세포에서 발현되는 세포괴사 효과

김나영 한국생약학회 2008 생약학회지 Vol.39 No.2

Butein is a one of polyphenolic compound widely available in numerous plants. It has broad biological activities including antioxidant and anti-inflammatory activities, which contributed to its protective effects against cancer. Evidences that butein influence proliferation of tumor cells make it important to determine how butein affects cell death of various cancers. In this study, we show that butein, a phenolic compound, induces apoptosis in human T lymphoma jurkat cells. We found that treatment of cells with butein increased apoptosis in a dose- and time- dependent manner as determined by staining cells with Annexin V and 7AAD. There was no significant apoptotic cell death when normal lymphocytes and monocytes from healthy donor were treated with butein. We also found caspase-3 activity was increased during butein-induced apoptosis. The buteininduced apoptotic cell death was blocked by the treatment of cells with caspase-3 inhibitor. These results indicate that butein has the potential to provide an effective strategy against cancer with the advantage of being widely avalible.

Butein-Enriched Fractions of Butea monosperma (Lam.) Taub. Flower Decrease Weight Gains and Increase Energy Expenditure in High-Fat Diet-Induced Obese Mice

장재율,장서혁,송다운,송노준,한새로아름,오승준,윤의정,안지인,이석찬,구진모,박계원 한국식품영양과학회 2021 Journal of medicinal food Vol.24 No.12

Butea monosperma (Lam.) Taub. has been applied to treat inflammatory, metabolic, and infectious diseases. However, the antiobesity effects of B. monosperma (Lam.) Taub. flower (BMF) and the underlying mechanisms have not been determined. In this study, we analyzed the various extraction procedures, investigated the antiobesity effects, and identified the main chemical constituents of BMF. The BMF was subjected to acid hydrolysis in 5% H2SO4 in methanol at 50°C for 48 h and partitioned with ethyl acetate. The acid-hydrolyzed BMF ethyl acetate extracts (BMFE) strongly induced the expression of uncoupling protein 1 (Ucp1) and other thermogenic genes in C3H10T1/2 adipocytes. Daily oral administration of 70 mg/kg BMFE (BMFE70) to mice with diet-induced obesity resulted in less body weight gain, increased glucose tolerance, higher rectal temperature, and increased oxygen consumption. Qualitative and quantitative analyses along with treatments in Akt1 knockout mouse embryonic fibroblasts indicate that butein is a major active ingredient of BMFE, which stimulates Ucp1 gene expression. These data show the effects of butein-containing B. monosperma flower extract on thermogenesis and energy expenditure, further suggesting the potential role of BMFE as a functional ingredient in obesity and related metabolic diseases.

Butein에 의한 MCF-7 유방암 세포의 세포사멸에 의한 항암 효과

송바다(Ba Da Song),김순례(Sun Rye Kim),김성훈(Sung Hun Kim),신용철(Yong Cheol Shin),고성규(Seong-Gyu Ko) 한의병리학회 2010 동의생리병리학회지 Vol.24 No.3

Anti-Inflammatory Activity of Butein and Luteolin Through Suppression of NFjB Activation and Induction of Heme Oxygenase-1

성지혜,이준수 한국식품영양과학회 2015 Journal of medicinal food Vol.18 No.5

Butein and luteolin are members of the flavonoid family, which displays a variety of biological activities. In this study, we demonstrated that butein and luteolin exert anti-inflammatory activities in RAW264.7 macrophages by inducing heme oxygenase-1 (HO-1) expression. Butein and luteolin dose-dependently attenuated inducible nitric oxide synthase (iNOS) expression, leading to the suppression of iNOS-derived nitric oxide (NO) production. The inhibitory effect of butein on NO production was greater than that of luteolin. Consistent with this finding, butein also showed higher inhibitory effects on lipopolysaccharide (LPS)-induced translocation of nuclear factor jB (NFjB) and NFjB reporter gene activity in macrophages than luteolin. Furthermore, the expression of HO-1 was dose-dependently induced by butein and luteolin treatments in macrophages. Additionally, the anti-inflammatory activities of butein and luteolin involved the induction of HO-1 expression, as confirmed by the zinc protoporphyrin (ZnPP) treatment (HO-1 selective inhibitor) and HO-1 small interfering (si)RNA system. ZnPP-mediated downregulation and siRNA-mediated knockdown of HO-1 significantly abolished the inhibitory effects of butein and luteolin on the production of NO in LPS-induced macrophages. Consequently, butein and luteolin were shown to be effective HO-1 inducers capable of inhibiting macrophage-derived proinflammatory mechanisms. These findings indicate that butein and luteolin are potential therapeutic agents for the treatment of inflammatory diseases.

Butein induction of HO-1 by p38 MAPK/Nrf2 pathway in adipocytes attenuates high-fat diet induced adipose hypertrophy in mice

Wang, Z.,Ka, S.O.,Lee, Y.,Park, B.H.,Bae, E.J. North-Holland ; Elsevier Science Ltd 2017 european journal of pharmacology Vol.799 No.-

<P>Adipose tissue inflammation and oxidative stress are key components in the development of obesity and insulin resistance. Heme oxygenase (HO)-1 in adipocytes protects against obesity and adipose dysfunction. In this study, we report the identification of butein, a flavonoid chalcone, as a novel inducer of HO-1 expression in adipocytes in vitro and in vivo. Butein upregulated HO-1 mRNA and protein expression in 3T3-L1 adipocytes, accompanied by Kelch-Like ECH-Associated Protein (Keap) 1 degradation and increase in the nuclear level of nuclear factor erythroid 2-related factor 2 (Nrf2). Butein modulation of Keapl and Nrf2 as well as HO-1 upregulation was reversed by pretreatment with p38 MAPK inhibitor SB203580, indicating the involvement of p38 MAPK in butein activation of Nrf2 in adipocytes. In addition, HO-1 activation by butein led to the inhibitions of reactive oxygen species and adipocyte differentiation, as evidenced by the fact that butein repression of reactive oxygen species and adipogenesis was reversed by pretreatment with HO-1 inhibitor SnPP. Induction of HO-1 expression by butein was also demonstrated in the adipose tissue of C57BL/6 mice fed a high-fat diet administered along with butein for three weeks, and correlated with the inhibitions of adiposity and adipose tissue inflammation, which were reversed by co-administration of SnPP. Altogether, our results demonstrate that butein activates the p38 MAPK/Nrf2/H0-1 pathway to act as a potent inhibitor of adipose hypertrophy and inflammation in a diet-induced obesity model and thus has potential for suppressing obesity linked metabolic syndrome.</P>

Butein, a tetrahydroxychalcone, suppresses pro-inflammatory responses in HaCaT keratinocytes

( Won Yong Seo ),( Gi Soo Youn ),( Soo Young Choi ),( Jinseu Park ) 생화학분자생물학회 2015 BMB Reports Vol.48 No.9

Up-regulation of cell adhesion molecules and proinflammatory cytokines contributes to enhanced monocyte adhesiveness and infiltration into the skin, during the pathogenesis of various inflammatory skin diseases, including atopic dermatitis. In this study, we examined the anti-inflammatory effects of butein, a tetrahydroxychalcone, and its action mechanisms using TNF--stimulated keratinocytes. Butein significantly inhibited TNF--induced ICAM-I expression and monocyte adhesion in human keratinocyte cell line HaCaT. Butein also decreased TNF-- induced pro-inflammatory mediators, such as IL-6, IP-10 and MCP-1, in HaCaT cells. Butein decreased TNF--induced ROS generation in a dose-dependent manner in HaCaT cells. In addition, treatment of HaCaT cells with butein suppressed TNF--induced MAPK activation. Furthermore, butein suppressed TNF--induced NF-kappaB activation. Overall, our results indicate that butein has immunomodulatory activities by inhibiting expression of proinflammatory mediators in keratinocytes. Therefore, butein may be used as a therapeutic agent for the treatment of inflammatory skin diseases. [BMB Reports 2015; 48(9): 495-500]