Taxifolin Resensitizes Multidrug Resistance Cancer Cells via Uncompetitive Inhibition of P-Glycoprotein Function

Chen, Hsiu-Ju; Chung, Yun-Lung; Chang, Ying-Tzu; Wang, Charles C.N.; Lee, Hsiang-Yen; Lin, Hui‐Yi; Hung, Chin‐Chuan

doi:10.3390/molecules23123055

Cited by 36 publications

(19 citation statements)

References 31 publications

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“…Catechin had a weak effect on both the ATPase and the transport activity of Pgp, in agreement with a previous report [61]. In addition, in our current experiments, we also tested epicatechin, a stereoisomer of catechin, and found it completely ineffective.…”

Section: Discussionsupporting

confidence: 93%

Effects of Polyphenols on P-Glycoprotein (ABCB1) Activity

et al. 2021

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P-glycoprotein (Pgp, ABCB1) is a member of one of the largest families of active transporter proteins called ABC transporters. Thanks to its expression in tissues with barrier functions and its broad substrate spectrum, it is an important determinant of the absorption, metabolism and excretion of many drugs. Pgp and/or some other drug transporting ABC proteins (e.g., ABCG2, MRP1) are overexpressed in nearly all cancers and cancer stem cells by which cancer cells become resistant against many drugs. Thus, Pgp inhibition might be a strategy for fighting against drug-resistant cancer cells. Previous studies have shown that certain polyphenols interact with human Pgp. We tested the effect of 15 polyphenols of sour cherry origin on the basal and verapamil-stimulated ATPase activity of Pgp, calcein-AM and daunorubicin transport as well as on the conformation of Pgp using the conformation sensitive UIC2 mAb. We found that quercetin, quercetin-3-glucoside, narcissoside and ellagic acid inhibited the ATPase activity of Pgp and increased the accumulation of calcein and daunorubicin by Pgp-positive cells. Cyanidin-3O-sophoroside, catechin, naringenin, kuromanin and caffeic acid increased the ATPase activity of Pgp, while they had only a weaker effect on the intracellular accumulation of fluorescent Pgp substrates. Several tested polyphenols including epicatechin, trans-ferulic acid, oenin, malvin and chlorogenic acid were ineffective in all assays applied. Interestingly, catechin and epicatechin behave differently, although they are stereoisomers. We also investigated the effect of quercetin, naringenin and ellagic acid added in combination with verapamil on the transport activity of Pgp. In these experiments, we found that the transport inhibitory effect of the tested polyphenols and verapamil was additive or synergistic. Generally, our data demonstrate diverse interactions of the tested polyphenols with Pgp. Our results also call attention to the potential risks of drug–drug interactions (DDIs) associated with the consumption of dietary polyphenols concurrently with chemotherapy treatment involving Pgp substrate/inhibitor drugs.

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Section: Discussionsupporting

confidence: 93%

Effects of Polyphenols on P-Glycoprotein (ABCB1) Activity

et al. 2021

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“…A few flavonoids, including naringin (Zhu et al, 2018) and taxifolin (Chen et al, 2018), have been identified as substrates of P-gp. The cellular uptake of 40 flavonoids was measured in parental human mouth epidermal carcinoma (KB) cells and KB/MDR cells with or without elacridar.…”

Section: Traditional Chinese Medicine Modulation Of P-gpmentioning

confidence: 99%

“…Silychristin A modulates MDR by the direct inhibition of P-gp, whereas anhydrosilychristin and isosilychristin modulate MDR by downregulating the expression of P-gp (Viktorova et al, 2019). Chen et al (2018) evaluated the effects of some natural flavonoids on P-gp activity, including taxifolin, luteolin, (2)gallocatechin, and (2)-catechin. They found that taxifolin could significantly resensitize MDR cancer cells in combination with chemotherapeutic agents and enhance the efficacy.…”

Section: Traditional Chinese Medicine Modulation Of P-gpmentioning

confidence: 99%

The Effects of Traditional Chinese Medicine on P-Glycoprotein–Mediated Multidrug Resistance and Approaches for Studying the Herb–P-Glycoprotein Interactions

Cao

Shi

Cai

et al. 2020

Drug Metabolism and Disposition

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As a member of the ATP-dependent membrane transport proteins, P-Glycoprotein (P-gp) is known to pump substrates out of cells using an ATP-dependent mechanism. The overexpression of P-gp in tumor cells reduces the intracellular drug concentrations, which decreases the efficacy of extensive antitumor drugs and leads to multidrug resistance (MDR) clinically. The combination of anticancer drugs with P-gp inhibitor has been an attractive and promising strategy to reverse MDR in cancer treatment. However, nonspecific or nonselective distribution of P-gp inhibitors to nontarget organs is one of the most fatal shortcomings in clinical application. Thus, there is an urgent need for effective and nontoxic MDR reversal agents, particularly in P-gp-mediated MDR. Traditional Chinese medicine (TCM) natural products may prove less toxic for use in P-gp inhibition to promote MDR reversal. P-gp modulatory effects have been previously demonstrated using selected TCM, including the flavonoid, alkaloid, terpenoid, coumarin, and quinonoid compounds, and some Chinese medicine extracts. Moreover, the approaches for screening active components from TCM are necessary, and these approaches face challenges. At present, the approaches to study the interaction between TCM and P-gp are divided into in vitro, in vivo, and in silico methods. This review will provide an overview and update on the role of TCM in overcoming P-gp-mediated MDR and the approaches to study the interaction between TCM and P-gp. SIGNIFICANCE STATEMENT This review summarized some traditional Chinese medicines identified to have a modulatory effect on P-gp, including flavonoids, alkaloids, terpenoids, coumarins, quinonoid compounds, and some Chinese medicine extracts, and it introduced possible mechanisms. The approaches to study the interaction between TCM and P-gp are divided into in vitro, in vivo, and in silico methods.

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“…For example, taxifolin suppressed UVB-induced phosphorylation of endothelial growth factor receptor (EGFR) and Akt, subsequently suppressing their signaling pathways; and activates the Nrf2 anti-oxidative stress pathway to inhibit EMT in skin cancer cells (14,16). Taxifolin uncompetitively inhibits P-Glycoprotein to resensitize human multidrug resistant cell lines (17). In breast cancer, taxifolin has been shown to inhibit Wnt signaling to subsequently inhibit EMT and metastasis (13), and downregulate Aryl hydrocarbon receptor (AhR)/CYP1A1 to inhibit tumor growth (18).…”

Section: Discussionmentioning

confidence: 99%

The anti-tumor effect of taxifolin on lung cancer via suppressing stemness and epithelial-mesenchymal transition in vitro and oncogenesis in nude mice

Wang¹,

Zhu²,

Wang³

et al. 2020

Ann Transl Med

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Background: Taxifolin is a natural flavonoid with anti-oxidant and anti-proliferative properties. In this study, we investigated the stemness-related inhibitory effects of taxifolin in two lung cancer cell lines, A549 and H1975, as well as in A549 xenografts.Methods: A549 and H1975 cells, as well as A549 xenograft BALB/c mice were treated with taxifolin. Cell viability, stemness, mobility and protein expression were tested with Cell counting kit-8 (CCK-8), Colony formation assay, Flow cytometry, Transwell, Western blot and Immunohistochemistry, respectively.Results: CCK-8 exhibited an obvious toxicity of taxifolin to both cell lines at higher dose. Then taxifolin of 0, 25, 50, and 100 μM/L were subsequently used. Taxifolin exhibited inhibitory effects on stemness and sphere formation, reduced protein expression of SOX2 and OCT4, and reduced CD133-positive cells. Furthermore, taxifolin decreased invasive cells, reduced N-cadherin and vimentin while increased E-cadherin expression, indicating that epithelial-mesenchymal transition (EMT) was inhibited. All of the effects observed were exhibited in a dose-dependent manner, and A549 cells proved to be more sensitive to taxifolin than H1975 cells. Taxifolin inactivated PI3K and TCF4 protein phosphorylation; however, taxifolin was not observed to have an effect on NF-κB P65 or STAT3. Taxifolin also suppressed tumor growth in A549xenograft BALB/c mice, with decreased SOX2 and OCT4 expression and inhibited PI3K and TCF4.Conclusions: In summary, taxifolin inhibited stemness and EMT in lung cancer cells possibly via the inactivation of PI3K and OCT4. Taxifolin could be a potential prodrug or serve as an adjuvant in lung cancer treatment.

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Taxifolin Resensitizes Multidrug Resistance Cancer Cells via Uncompetitive Inhibition of P-Glycoprotein Function

Cited by 36 publications

References 31 publications

Effects of Polyphenols on P-Glycoprotein (ABCB1) Activity

Effects of Polyphenols on P-Glycoprotein (ABCB1) Activity

The Effects of Traditional Chinese Medicine on P-Glycoprotein–Mediated Multidrug Resistance and Approaches for Studying the Herb–P-Glycoprotein Interactions

The anti-tumor effect of taxifolin on lung cancer via suppressing stemness and epithelial-mesenchymal transition in vitro and oncogenesis in nude mice

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