Emodin reverses leukemia multidrug resistance by competitive inhibition and downregulation of P-glycoprotein

Min, Hongping; Niu, Miaomiao; Zhang, Weilin; Jia, Yan; Li, Jiachang; Tan, Xiying; Li, Bo; Su, Mengxiang; Di, Bin; Yan, Fang

doi:10.1371/journal.pone.0187971

Cited by 31 publications

(34 citation statements)

References 38 publications

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“…Emodin reversed ADR resistance in K562/ADR cells by decreasing the expression of P-gp. It can increase the accumulation of Rh123 in both K562/ADR and Caco-2 cells and, hence, inhibit P-gp efflux (Min et al, 2017). Shikonin/ paclitaxel (PTX) cotreatment led to synergistically enhanced cytotoxicity and apoptosis in PTX-resistant ovarian cancer cells, reflecting the reverse of MDR.…”

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

et al. 2020

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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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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

et al. 2020

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“…[24][25][26][27][28][29][30] Emodin possessed a synergistic growth-inhibitory effect with AZT via decreasing the expression of P-glycoprotein tightly in K562/ADM, doxorubicin-resistant variant of K562 cells. 31) Also, in our previous report, emodin reversed the resistance of K562/ADM cells to adriamycin by a decrease of P-glycoprotein protein expression and competition of the R transport site on P-glycoprotein as the potential substrate of P-glycoprotein. 32) However, there are few studies on whether emodin would inhibit resistance to imatinib in K562/G01 cells with resistant mechanism of Bcr-Abl overexpression and high tyrosine kinase activities, which is imatinib-resistant variant of K562 cells.…”

Section: Introductionmentioning

confidence: 78%

“…31) Also, in our previous report, emodin reversed the resistance of K562/ADM cells to adriamycin by a decrease of P-glycoprotein protein expression and competition of the R transport site on P-glycoprotein as the potential substrate of P-glycoprotein. 32) However, there are few studies on whether emodin would inhibit resistance to imatinib in K562/G01 cells with resistant mechanism of Bcr-Abl overexpression and high tyrosine kinase activities, which is imatinib-resistant variant of K562 cells. In the current study, we investigated the effects of emodin inhibiting imatinib-resistance in K562/G01 cells and the molecular mechanism involved with Bcr-Abl and related targets.…”

Section: Introductionmentioning

confidence: 78%

“…Recent paper showed that 3′-azido-3′-deoxythymidin cooperate with emodin in inhibiting the growth of adriamycinresistant human chronic myelogenous leukemia (K562/ADM) cells. 31) We previously reported that emodin inhibited adriamycin resistance in K562/ADM cells by inhibiting P-glycoprotein protein expression and competing the R transport site on P-glycoprotein. 32) In the current study, our data demonstrated that emodin was greatly active across imatinib-resistant K562/G01 CML cells and gave significant inhibition of resistance to imatinib in a time-and dose-dependent manner.…”

Section: Discussionmentioning

confidence: 98%

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Emodin Inhibits Resistance to Imatinib by Downregulation of Bcr-Abl and STAT5 and Allosteric Inhibition in Chronic Myeloid Leukemia Cells

Wang

Sun²,

Wang

et al. 2020

Biological & Pharmaceutical Bulletin

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Imatinib-resistance is a significant concern for Bcr-Abl-positive chronic myelogenous leukemia (CML) treatment. Emodin, the predominant compound of traditional medicine rhubarb, was reported to inhibit the multidrug resistance by downregulating P-glycoprotein of K562/ADM cells with overexpression of P-glycoprotein in our previous studies. In the present study, we found that emodin can be a potential inhibitor for the imatinib-resistance in K562/G01 cells which are the imatinib-resistant subcellular line of human chronic myelogenous leukemia cells with overexpression of breakpoint cluster region-abelson (Bcr-Abl) oncoprotein. Emodin greatly enhanced cell sensitivity to imatinib, suppressed resistant cell proliferation and increased potentiated apoptosis induced by imatinib in K562/G01 cells. After treatment of emodin and imatinib together, the levels of p-Bcr-Abl and Bcr-Abl were significantly downregulated. Moreover, Bcr-Abl important downstream target, STAT5 and its phosphorylation were affected. Furthermore, the expression of Bcr-Abl and signal transducers and activators of transcription 5 (STAT5) related molecules, including c-MYC, MCL-1, poly(ADP-ribose)polymerase (PARP), Bcl-2 and caspase-3, were changed. Emodin also decreased Src expression and its phosphorylation. More importantly, emodin simultaneously targeted both the ATP-binding and allosteric sites on Bcr-Abl by molecular docking, with higher affinity with the myristoyl-binding site for enhanced Bcr-Abl kinase inhibition. Overall, these data indicated emodin might be an effective therapeutic agent for inhibiting resistance to imatinib in CML treatment.

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“…Traditional Chinese herbal, as a complementary and alternative medicine treatment, has been widely applied into cancer treatment. For instance, emodin can reverse the drug resistance of K562 / ADM cells by inhibiting the expression of P -glycoprotein, which suggests that emodin is still potentially effective reversal agents in the treatment of chronic myeloid leukemia resistance [13]. solanine [14]and germacrone [15]were able to MDR.…”

Section: Introductionmentioning

confidence: 99%

Exploring Molecular Mechanism of Traditional Chinese Medicine Euphorbiae Semen on Reversing of Multidrug Resistance in Leukemia Based on Network Pharmacology Strategy and Molecular Docking Technology

Song

Guo

Sun

et al. 2020

Preprint

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Background: Leukemia was listed by the World Health Organization as one of the five most intractable diseases in the world. The multi-drug resistance (MDR) of leukemia cells limits the efficacy of anti-tumor drugs and is the major reason for the chemotherapy failure and recurrence of leukemia chemotherapy. Some studies have shown that Euphorbiae semen (ES) possesses the characteristics of new therapeutic drugs for MDR. However, the molecular mechanisms and active compounds have not yet been fully clarified. Therefore, there is a need for explore its active compounds and demonstrate its mechanisms through network pharmacology and molecular docking technology.Method: First, the TCMSP database was searched and screened the active compounds of the ES, supplemented with compounds verified by literature, so as to further identify the core compounds in the active ingredient. Simultaneously, the TCMSP and Swiss database were searched to the targets of active compounds, and the targets of reverses leukemia multidrug resistance (RL-MDR) were screened in the relevant databases, such as GeneCards and DrugBank. Then, the targets of active compounds were intersected with RL-MDR targets to obtain potential targets of ES acting on MDR. The compound–target network was constructed by Cytoscape. The target protein–protein interaction network was built using STRING and Cytoscape database. Second, the R language and DAVID database were used to analyse Gene Ontology (GO) biological functions analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) signal pathways enrichment. Finally, molecular docking method was utilized to investigate the binding activity between the core targets and the active compounds of ES.Results: Compound–target network mainly contained 22 compounds and 81 corresponding targets. Finally, seven components in ES were selected and 10 core targets were identified; Key targets contained JUN, CASP3, MAOA, AR, PPARG, DRD2, ADRA2A, CHRM2, PTGS2 and MAPK14. GO enrichment analysis indicated the main biological functions of potential genes of ES in the treatment of MDR. KEGG pathway enrichment analysis showed the main pathways, mainly including apoptosis, pathways in cancer, p53 signaling pathway, VEGF signaling pathway, TNF signaling pathway and PI3K–Akt signaling pathway. Finally, we chose the top 10 common targets for molecular docking with the 7 active compounds of ES. The results of molecular docking indicated that the compounds of ES, which had good affinity with targets. Conclusion: The molecular mechanism of ES in the treatment of MDR showed the synergistic reaction of multi-compound, multi-target, and multi-pathway of traditional Chinese medicine, which provided ideas for further clinical research.

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Emodin reverses leukemia multidrug resistance by competitive inhibition and downregulation of P-glycoprotein

Cited by 31 publications

References 38 publications

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

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

Emodin Inhibits Resistance to Imatinib by Downregulation of Bcr-Abl and STAT5 and Allosteric Inhibition in Chronic Myeloid Leukemia Cells

Exploring Molecular Mechanism of Traditional Chinese Medicine Euphorbiae Semen on Reversing of Multidrug Resistance in Leukemia Based on Network Pharmacology Strategy and Molecular Docking Technology

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