Myricetin is a novel inhibitor of human inosine 5′-monophosphate dehydrogenase with anti-leukemia activity

Pan, Hui-Ling Wendy; Hu, Qian; Wang, Jing‐Yuan; Liu, Zehui; Wu, Dang; Lü, Weiqiang; Huang, Jin

doi:10.1016/j.bbrc.2016.06.158

Cited by 29 publications

(16 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Myricetin, 3,3′,4′,4,5,5′,7-hexahydroxyflavone, is a flavonoid commonly extracted from the fruits, leaves and bark of the Chinese bayberry ( Myrica rubra ) and other edible plants, including broccoli, cabbage, French beans, garlic, peppers, tomato, cashew nuts, blueberries, and green and black tea (10–13). Myricetin exhibits several bioactive properties, including antioxidative (11) anticancer (14,15), nephroprotective (16) and anti-inflammatory effects (17). However, myricetin has not been previously evaluated for its potential antiepileptic effects.…”

Section: Introductionmentioning

confidence: 99%

Myricetin attenuates the severity of seizures and neuroapoptosis in pentylenetetrazole kindled mice by regulating the of BDNF‑TrkB signaling pathway and modulating matrix metalloproteinase‑9 and GABAA

Sun

Meng

et al. 2019

Exp Ther Med

View full text Add to dashboard Cite

Currently available antiepileptic drugs are effective; however, frequently associated with adverse effects that limit their therapeutic value. Compounds that target the molecular events underlying epilepsy, with minor or no adverse effects, would be of clinical value. Matrix metalloproteinase-9 (MMP-9) and the brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling pathway may be involved in epileptogenesis. The current study investigated the effects of the plant-derived hydroxyflavone, myricetin, in a pentylenetetrazole (PTZ)-induced mouse model of epilepsy. Mice received an intraperitoneal injection of 35 mg/kg body weight PTZ on alternate days (13 injections) and were observed for 30 min following each PTZ injection. Myricetin (100 or 200 mg/kg body weight) was administered orally to the treatment groups (n=18/group) for 26 days, 30 min prior to each PTZ injection. Treatment with myricetin reduced seizure and mortality rates. Increased apoptotic cell count and elevated expression levels of apoptotic proteins caused by PTZ kindling were downregulated following treatment with myricetin. The BDNF-TrkB signaling pathway and MMP-9 expression levels were regulated by myricetin. Expression of γ-aminobutyric acid A (GABA) receptor and glutamic acid decarboxylase 65, as well as the glutamate/GABA balance, were restored following treatment with myricetin. The results of the present study indicated that myricetin may exert protective effects by regulating the molecular events associated with epileptogenesis.

show abstract

Section: Introductionmentioning

confidence: 99%

Myricetin attenuates the severity of seizures and neuroapoptosis in pentylenetetrazole kindled mice by regulating the of BDNF‑TrkB signaling pathway and modulating matrix metalloproteinase‑9 and GABAA

Sun

Meng

et al. 2019

Exp Ther Med

View full text Add to dashboard Cite

show abstract

“…We and others have reported that several natural products‐derived human IMPDH2 inhibitor. For instance, we have identified myricetin, a naturally occurring ingredients existed in berries, wine and tea, as a dual inhibitor of IMPDH1/2 (Pan et al, 2016). The direct inhibition of IMPDH1/2 by myricetin, at least in part, account for its anticancer activity in chronic myeloid leukemia.…”

Section: Discussionmentioning

confidence: 99%

Shikonin is a novel and selective IMPDH2 inhibitor that target triple‐negative breast cancer

Wang

Chen

et al. 2020

Phytotherapy Research

Self Cite

View full text Add to dashboard Cite

Triple‐negative breast cancer (TNBC) is heterogeneous disease with a poor prognosis. It is therefore important to explore novel therapeutic agents to improve the clinical efficacy for TNBC. The inosine 5′‐monophosphate dehydrogenase 2 (IMPDH2) is a rate‐limiting enzyme in the de novo synthesis of guanine nucleotides. It is always overexpressed in many types of tumors, including TNBC and regarded as a potential target for cancer therapy. Through screening a library of natural products, we identified shikonin, a natural bioactive component of Lithospermum erythrorhizon, is a novel and selective IMPDH2 inhibitor. Enzymatic analysis using Lineweaver–Burk plot indicates that shikonin is a competitive inhibitor of IMPDH2. The interaction between shikonin and IMDPH2 was further investigated by thermal shift assay, fluorescence quenching, and molecular docking simulation. Shikonin treatment effectively inhibits the growth of human TNBC cell line MDA‐MB‐231, and murine TNBC cell line, 4T1 in a dose‐dependent manner, which is impaired by exogenous supplementation of guanosine, a salvage pathway of purine nucleotides. Most importantly, IMPDH2 knockdown significantly reduced cell proliferation and conferred resistance to shikonin in TNBC. Collectively, our findings showed the natural product shikonin as a selective inhibitor of IMPDH2 with anti‐TNBC activity, impelling its further study in clinical trials.

show abstract

“…In human embryonic kidney HEK293 and human colon cancer HCT116 cells, p53 regulated purine metabolism through a p53-miR-34a-IMPDH pathway (miR-34a is a master regulator of tumour suppression) and consequently, miR-34a-mediated inhibition of IMPDH perturbed the GTP-dependent Ras signalling pathway [137]. Inhibition of IMPDH activity has also been shown to induce differentiation in some cancer cell lines [154,155,156,157], while apoptosis was induced in other cell lines [158,159,160,161]. Over the past 30 years, several IMPDH inhibitors have been tested on many cancer models.…”

Section: Inosine 5′-monophosphate Dehydrogenasementioning

confidence: 99%

“…Apoptotic pathways triggered by inosine 5′-monophosphate dehydrogenase (IMPDH) inhibitors. The decrease in guanylate pool can trigger apoptosis through multiple pathways: ( 1 ): downregulation of the MEK/ERK pathway with inhibition of Bcl-2 and activation of Bax and cytochrome c release [167]; ( 2 ): downregulation of Src/PI3K pathway with inhibition of Akt, with downregulation of mammalian target of rapamycin (mTOR) and activation of pro-apoptotic Bak and Bax with Apoptosis Inducing Factor (AIF) and endonuclease G (Endo G) release from mitochondria (caspase-independent apoptosis) [136,162,163]; ( 3 ): upregulation of p53 with (a) downregulation of Bcl-2 and Bcl-xL, with consequent inhibition of p27 and survivin, cytochrome c (Cyt c) release, and activation of caspase-9, caspase-3 and polyADP-ribose polymerase (PARP; intrinsic apoptotic pathway) [159,160,161,164,165], (b) upregulation of PUMA and BIM with consequent SMAC/DIABLO release from mitochondria, inhibition of Inhibitor of Apoptosis (IAPs) (a caspase-3 inhibitor) with activation of caspase-3 [164], and (c) activation of caspase-2 with cleavage of Bid into truncated Bid (t-Bid) and AIF/Endo G release from mitochondria [164]; ( 4 ): synergistic effect of IMPDH inhibitors with TRAIL through binding with death receptors (DR4 and DR5) which recruit initiator caspase-8 via the adaptor protein FADD. Activated caspase-8 stimulates apoptosis via two parallel cascades: direct cleavage and activation of caspase-3, or cleavage of Bid into t-Bid which translocates to mitochondria, inducing cytochrome c release, with sequential activation of caspase-9 and -3 (extrinsic apoptotic pathway) [164].…”

Section: Figurementioning

confidence: 99%

Purine-Metabolising Enzymes and Apoptosis in Cancer

Camici¹,

Garcia‐Gil

Pesi³

et al. 2019

Cancers

View full text Add to dashboard Cite

The enzymes of both de novo and salvage pathways for purine nucleotide synthesis are regulated to meet the demand of nucleic acid precursors during proliferation. Among them, the salvage pathway enzymes seem to play the key role in replenishing the purine pool in dividing and tumour cells that require a greater amount of nucleotides. An imbalance in the purine pools is fundamental not only for preventing cell proliferation, but also, in many cases, to promote apoptosis. It is known that tumour cells harbour several mutations that might lead to defective apoptosis-inducing pathways, and this is probably at the basis of the initial expansion of the population of neoplastic cells. Therefore, knowledge of the molecular mechanisms that lead to apoptosis of tumoural cells is key to predicting the possible success of a drug treatment and planning more effective and focused therapies. In this review, we describe how the modulation of enzymes involved in purine metabolism in tumour cells may affect the apoptotic programme. The enzymes discussed are: ectosolic and cytosolic 5′-nucleotidases, purine nucleoside phosphorylase, adenosine deaminase, hypoxanthine-guanine phosphoribosyltransferase, and inosine-5′-monophosphate dehydrogenase, as well as recently described enzymes particularly expressed in tumour cells, such as deoxynucleoside triphosphate triphosphohydrolase and 7,8-dihydro-8-oxoguanine triphosphatase.

show abstract

Myricetin is a novel inhibitor of human inosine 5′-monophosphate dehydrogenase with anti-leukemia activity

Cited by 29 publications

References 35 publications

Myricetin attenuates the severity of seizures and neuroapoptosis in pentylenetetrazole kindled mice by regulating the of BDNF‑TrkB signaling pathway and modulating matrix metalloproteinase‑9 and GABAA

Myricetin attenuates the severity of seizures and neuroapoptosis in pentylenetetrazole kindled mice by regulating the of BDNF‑TrkB signaling pathway and modulating matrix metalloproteinase‑9 and GABAA

Shikonin is a novel and selective IMPDH2 inhibitor that target triple‐negative breast cancer

Purine-Metabolising Enzymes and Apoptosis in Cancer

Contact Info

Product

Resources

About