Dataset Information

Flavonoids modulate multidrug resistance through wnt signaling in P-glycoprotein overexpressing cell lines.

ABSTRACT:

Background

Wnt signaling has been linked with P-glycoprotein (P-gp) overexpression and which was mainly mediated by ?-catenin nuclear translocation. Flavonoids have already been reported as modulators of the Wnt/?-catenin pathway and hence they may serve as promising agents in the reversal of P-gp mediated cancer multi drug resistance (MDR).

Methods

In this study, we screened selected flavonoids against Wnt/?-catenin signaling molecules. The binding interaction of flavonoids (theaflavin, quercetin, rutin, epicatechin 3 gallate and tamarixetin) with GSK 3? was determined by molecular docking. Flavonoids on P-gp expression and the components of Wnt signaling in drug-resistant KBCH^R8-5 cells were analyzed by western blotting and qRT-PCR. The MDR reversal potential of these selected flavonoids against P-gp mediated drug resistance was analyzed by cytotoxicity assay in KBCH^R8-5 and MCF7/ADR cell lines. The chemosensitizing potential of flavonoids was further analyzed by observing cell cycle arrest in KBCH^R8-5 cells.

Results

In this study, we observed that the components of Wnt/?-catenin pathway such as Wnt and GSK 3? were activated in multidrug resistant KBCH^R8-5 cell lines. All the flavonoids selected in this study significantly decreased the expression of Wnt and GSK 3? in KBCH^R8-5 cells and subsequently modulates P-gp overexpression in this drug-resistant cell line. Further, we observed that these flavonoids considerably decreased the doxorubicin resistance in KBCH^R8-5 and MCF7/ADR cell lines. The MDR reversal potential of flavonoids were found to be in the order of theaflavin > quercetin > rutin > epicatechin 3 gallate > tamarixetin. Moreover, we observed that flavonoids pretreatment significantly induced the doxorubicin-mediated arrest at the phase of G2/M. Further, the combinations of doxorubicin with flavonoids significantly modulate the expression of drug response genes in KBCH^R8-5 cells.

Conclusion

The present findings illustrate that the studied flavonoids significantly enhances doxorubicin-mediated cell death through modulating P-gp expression pattern by targeting Wnt/?-catenin signaling in drug-resistant KBCH^R8-5 cells.

SUBMITTER: Mohana S

PROVIDER: S-EPMC6260573 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Publications

Flavonoids modulate multidrug resistance through wnt signaling in P-glycoprotein overexpressing cell lines.

Mohana S S Ganesan M M Rajendra Prasad N N Ananthakrishnan D D Velmurugan D D

BMC cancer 20181126 1

<h4>Background</h4>Wnt signaling has been linked with P-glycoprotein (P-gp) overexpression and which was mainly mediated by β-catenin nuclear translocation. Flavonoids have already been reported as modulators of the Wnt/β-catenin pathway and hence they may serve as promising agents in the reversal of P-gp mediated cancer multi drug resistance (MDR).<h4>Methods</h4>In this study, we screened selected flavonoids against Wnt/β-catenin signaling molecules. The binding interaction of flavonoids (thea ...[more]

PMID: 30477461

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Project description:To investigate the therapeutic efficacy and mechanism of β-cells with insulin receptor (IR) overexpression on diabetes mellitus (DM), rat insulinoma (INS-1) cells were engineered to stably express human insulin receptor (INS-IR cells), and subsequently transplanted into streptozotocin- induced diabetic rats. Compared with INS-1 cells, INS-IR cells showed improved β-cell function, including the increase in glucose utilization, calcium mobilization, and insulin secretion, and exhibited a higher rate of cell proliferation, and maintained lower levels of blood glucose in diabetic rats. These results were attributed to the increase of β-catenin/PPARγ complex bindings to peroxisome proliferator response elements in rat glucokinase (GK) promoter and the prolongation of S-phase of cell cycle by cyclin D1. These events resulted from more rapid and higher phosphorylation levels of insulin-signaling intermediates, including insulin receptor substrate (IRS)-1/IRS-2/phosphotylinositol 3 kinase/v-akt murine thymoma viral oncogene homolog (AKT) 1, and the consequent enhancement of β-catenin nuclear translocation and Wnt responsive genes including GK and cyclin D1. Indeed, the higher functionality and proliferation shown in INS-IR cells were offset by β-catenin, cyclin D1, GK, AKT1, and IRS-2 gene depletion. In addition, the promotion of cell proliferation and insulin secretion by Wnt signaling activation was shown by 100 nM insulin treatment, and to a similar degree, was shown in INS-IR cells. In this regard, this study suggests that transferring INS-IR cells into diabetic animals is an effective and feasible DM treatment. Accordingly, the method might be a promising alternative strategy for treatment of DM given the adverse effects of insulin among patients, including the increased risk of modest weight gain and hypoglycemia. Additionally, this study demonstrates that the novel mechanism of cross-talk between insulin and Wnt signaling plays a primary role in the higher therapeutic efficacy of IR-overexpressing β-cells.

Project description:Background:Multidrug resistance transporters (MDRs) are transmembrane proteins that efflux metabolites and xenobiotics. They are highly conserved in sequence and function in bacteria and eukaryotes and play important roles in cellular homeostasis, as well as in avoidance of antibiotics and cancer therapies. Recent evidence also documents a critical role in reproductive health and in protecting the ovary from environmental toxicant effects. The most well understood MDRs are MDR-1 (P-glycoprotein (P-gp) also known as ABCB1) and BCRP (breast cancer resistance protein) and are both expressed in the ovary. We have previously shown that MDR-1 mRNA steady state expression changes throughout the murine estrous cycle, but expression appears to increase in association with the surge in estradiol during proestrus. Methods:Here we test the model that MDR-1 and BCRP are regulated by estrogen, the major hormonal product of the ovary. This was performed by administering 6-week-old female mice either sesame oil (vehicle control) or oral ethinyl estradiol at 1 ?g, 10 ?g, and 100 ?g or PROGESTERONE at 0.25mg, 0.5 mg or 1 mg or a combination of both for 5 days. The mice were then sacrificed, and the ovaries were removed and cleaned. Ovaries were used for qPCR, immunoblotting, and immnunolabeling. Results:We found that oral ethinyl estradiol did not influence the steady state mRNA of MDR-1 or BCRP. Remarkably, the effect on mRNA levels neither increased or decreased in abundance upon estrogen exposures. Conversely, we observed less MDR-1 protein expression in the groups treated with 1 ?g and 10 ?g, but not 100 ?g of ethinyl estradiol compared to controls. MDR-1 and BCRP are both expressed in pre-ovulatory follicles. When we tested progesterone, we found that MDR-1 mRNA increased at the dosages of 0.25 mg and 0.5 mg, but protein expression levels were not statistically significant. Combined oral ethinyl estradiol and progesterone significantly lowered both MDR-1 mRNA and protein. Conclusions:Progesterone appears to influence MDR-1 transcript levels, or steady state levels. This could have implications for better understanding how MDR-1 can be modulated during times of toxic exposure. Understanding the normal physiology of MDR-1 in the ovary will expand the current knowledge in cancer biology and reproduction.

Dataset Information

Flavonoids modulate multidrug resistance through wnt signaling in P-glycoprotein overexpressing cell lines.

Background

Methods

Results

Conclusion

Publications

Flavonoids modulate multidrug resistance through wnt signaling in P-glycoprotein overexpressing cell lines.

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