Inhibition of P-glycoprotein by flavonoid derivatives in adriamycin-resistant human myelogenous leukemia (K562/ADM) cells

Ikegawa, Tomomi; Ohtani, Hisakazu; Koyabu, Noriko; Ju‐ichi, Motoharu; Iwase, Yukiko; Ito, Chihiro; Furukawa, Hiroshi; Naito, Mikihiko; Tsuruo, Takashi; Sawada, Yasufumi

doi:10.1016/s0304-3835(01)00761-3

Cited by 54 publications

(38 citation statements)

References 8 publications

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“…PMQ has been shown to have anti-cancer, anti-cardiac hypertrophy and anti-apoptosis pharmacological properties [32,33]. Very recently, several studies described the metabolismregulating properties of PMQ, including glucose-lowering effects and upregulation of adiponectin production [21,22].…”

Section: Discussionmentioning

confidence: 99%

Pentamethylquercetin generates beneficial effects in monosodium glutamate-induced obese mice and C2C12 myotubes by activating AMP-activated protein kinase

Shen

Han

et al. 2012

Diabetologia

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Aims/hypothesis Pentamethylquercetin (PMQ) has recently been shown to have glucose-lowering properties. Here, we aimed to characterise the effectiveness and underlying mechanisms of PMQ for ameliorating metabolic disorders in vivo and vitro. Methods We generated a mouse model of obesity by neonatal administration of monosodium glutamate (MSG) and used it to assess the properties of PMQ as a treatment for metabolic disorders. We also investigated the possible underlying mechanisms of PMQ in the prevention of metabolic disorders. Results Compared with normal mice, MSG mice had metabolic disorders, including central obesity, hyperinsulinaemia, insulin resistance, hyperglycaemia, hyperlipidaemia, decreased phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC), and downregulated levels of GLUT4 in gastrocnemius muscles. In MSG mice, PMQ treatment (5, 10, 20 mg/kg daily) reduced body weight gain, waist circumference, adipose tissue mass, serum glucose, triacylglycerol and total cholesterol, while improving insulin resistance, activating AMPK and increasing ACC phosphorylation and GLUT4 abundance. In C2C12 myotubes, PMQ (10 μmol/l) increased glucose consumption by ∼65%. PMQ treatment (1-10 μmol/l) also activated AMPK, increased ACC phosphorylation and GLUT4 abundance, and upregulated the expression of some key genes involved in fatty acid oxidation. Conclusions/interpretation These findings suggest that PMQ can ameliorate metabolic disorders at least in part via stimulation of AMPK activity.

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Section: Discussionmentioning

confidence: 99%

Pentamethylquercetin generates beneficial effects in monosodium glutamate-induced obese mice and C2C12 myotubes by activating AMP-activated protein kinase

Shen

Han

et al. 2012

Diabetologia

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“…These inhibitory potencies for P-gp were more potent than typical P-gp inhibitors, cyclosporine A and verapamil (97). Flavonoid derivatives such as nobiletin, tangeretin and 3,30,40,5,6,7,8-heptamethoxyflavone increase the cellular uptake of vincristine in multidrug-resistant tumor cells by inhibiting the function of P-gp (74).…”

Section: Reversal Of Multi-drug Resistancementioning

confidence: 92%

Emerging Significance of Flavonoids as P-Glycoprotein Inhibitors in Cancer Chemotherapy

Bansal¹,

Jaggi²,

Khar³

et al. 2009

J Pharm Pharm Sci

208

161

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Chemotherapy forms the mainstay of cancer treatment particularly for patients who do not respond to local excision or radiation treatment. However, cancer treatment by drugs is seriously limited by P-glycoprotein (P-gp) associated multi-drug resistance (MDR) in various tumor cells. On the other hand, it is now widely recognized that P-gp also influences drug transport across various biological membranes. P-gp transporter is widely present in the luminal surface of enterocytes, biliary canalicular surface of hepatocytes, apical surface of proximal tubular cells of kidney, endothelial cells of blood brain barrier, etc. thus affecting absorption, distribution, metabolism and excretion of xenobiotics. Clinical significance of above mentioned carrier is appreciated from the fact that more than fifty percent of existing anti-cancer drugs undergo inhibitable and saturable P-gp mediated efflux. Consequently, there is an increasing trend to optimize pharmacokinetics, enhance antitumour activity and reduce systemic toxicity of existing anti-cancer drugs by inhibiting P-gp mediated transport. Although a wide variety of P-gp inhibitors have been discovered, research efforts are underway to identify the most appropriate one. Flavonoids (polyphenolic herbal constituents) form the third generation, non-pharmaceutical category of P-gp inhibitors. The effects produced by some of these components are found to be comparable to those of well-known P-gp inhibitors verapamil and cyclosporine. Identification of effective P-gp modulator among herbal compounds have an added advantage of being safe, thereby making them ideal candidates for bioavailability enhancement, tissue-penetration (e.g. blood brain barrier (BBB)), decreasing biliary excretion and multi-drug resistance modulating agents. The dual effects, i.e. P-gp modulation and antitumor activity, of these herbal derivatives may synergistically act in cancer chemotherapy. This paper presents an overview of the investigations on the feasibility and application of flavonoids as P-gp modulators for improved efficacy of anti-cancer drugs like taxanes, anthracyclines, epipodophyllotoxins, camptothecins and vinca alkaloids. The review also focuses on flavonoid-drug interactions as well as the reversal activity of flavonoids useful against MDR. In addition, the experimental models which could be used for investigation on P-gp mediated efflux are also discussed.

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“…How morin mediates these effects is not fully understood. Morin has been shown to induce p21 and activate caspases (1), suppress AKT activation and induce stress kinase activation (8), abolish peroxisome proliferator-activated receptor activity (11), inhibit P-glycoprotein (12), inhibit lipooxygenase-1 (13), suppress inducible nitric oxide synthase and cyclooxygenase-2 (COX-2) expression in macrophages (14), and inhibit the release of inflammatory cytokines, such as interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF) from mast cells (15).…”

mentioning

confidence: 99%

Morin (3,5,7,2′,4′-Pentahydroxyflavone) Abolishes Nuclear Factor-κB Activation Induced by Various Carcinogens and Inflammatory Stimuli, Leading to Suppression of Nuclear Factor-κB–Regulated Gene Expression and Up-regulation of Apoptosis

Manna

Aggarwal

Sethi

et al. 2007

Clinical Cancer Research

119

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Purpose: Morin is a flavone that exhibits antiproliferative, antitumor, and anti-inflammatory effects through a mechanism that is not well understood. Because of the role of transcription factor nuclear factor-nB (NF-nB) in the control of cell survival, proliferation, tumorigenesis, and inflammation, we postulated that morin mediates its effects by modulating NF-nB activation. Experimental Design: We investigated the effect of morin on NF-nB pathway activated by inflammatory agents, carcinogens, and tumor promoters. The effect of this flavone on expression of NF-nB^regulated gene products involved in cell survival, proliferation, and invasion was also examined. Results: We showed by DNA-binding assay that NF-nB activation induced by tumor necrosis factor (TNF), phorbol 12-myristate 13-acetate, lipopolysaccharide, ceramide, interleukin-1, and H 2 O 2 was suppressed by morin; the suppression was not cell type specific. The suppression of NF-nB by morin was mediated through inhibition of InBa (inhibitory subunit of NF-nB) kinase, leading to suppression of phosphorylation and degradation of InBa and consequent p65 nuclear translocation. Morin also inhibited the NF-nB^dependent reporter gene expression activated by TNF, TNF receptor (TNFR) 1, TNFR1-associated death domain, TNFR-associated factor 2, NFnB^inducing kinase, InB kinase, and the p65 subunit of NF-nB. NF-nB^regulated gene products involved in cell survival [inhibitor of apoptosis (IAP) 1, IAP2, X chromosome-linked IAP, Bcl-xL, and survivin], proliferation (cyclin D1and cyclooxygenase-2), and invasion (matrix metalloproteinase-9) were down-regulated by morin. These effects correlated with enhancement of apoptosis induced byTNF and chemotherapeutic agents. Conclusion: Overall, our results indicate that morin suppresses the activation of NF-nB and NF-nB^regulated gene expression, leading to enhancement of apoptosis. This may provide the molecular basis for the ability of morin to act as an anticancer and anti-inflammatory agent.

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Inhibition of P-glycoprotein by flavonoid derivatives in adriamycin-resistant human myelogenous leukemia (K562/ADM) cells

Cited by 54 publications

References 8 publications

Pentamethylquercetin generates beneficial effects in monosodium glutamate-induced obese mice and C2C12 myotubes by activating AMP-activated protein kinase

Pentamethylquercetin generates beneficial effects in monosodium glutamate-induced obese mice and C2C12 myotubes by activating AMP-activated protein kinase

Emerging Significance of Flavonoids as P-Glycoprotein Inhibitors in Cancer Chemotherapy

Morin (3,5,7,2′,4′-Pentahydroxyflavone) Abolishes Nuclear Factor-κB Activation Induced by Various Carcinogens and Inflammatory Stimuli, Leading to Suppression of Nuclear Factor-κB–Regulated Gene Expression and Up-regulation of Apoptosis

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