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

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

doi:10.1186/s12885-018-5103-1

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

BMC Cancer. 2018 Nov 26;18(1):1168. doi: 10.1186/s12885-018-5103-1.

Authors

S Mohana¹, M Ganesan¹, N Rajendra Prasad², D Ananthakrishnan³, D Velmurugan^{3

4}

Affiliations

¹ Department of Biochemistry and Biotechnology, Annamalai University, Annamalai Nagar, Tamil Nadu, 608 002, India.
² Department of Biochemistry and Biotechnology, Annamalai University, Annamalai Nagar, Tamil Nadu, 608 002, India. drprasadnr@gmail.com.
³ Bioinformatics Infrastructure Facility (BIF), University of Madras, Guindy Campus, Chennai, Tamil Nadu, India.
⁴ CAS in Crystallography and Biophysics, University of Madras, Guindy Campus, Chennai, Tamil Nadu, India.

Abstract

Background: 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).

Methods: In this study, we screened selected flavonoids against Wnt/β-catenin signaling molecules. The binding interaction of flavonoids (theaflavin, quercetin, rutin, epicatechin 3 gallate and tamarixetin) with GSK 3β 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/β-catenin pathway such as Wnt and GSK 3β 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 3β 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/β-catenin signaling in drug-resistant KBCH^R8-5 cells.

Keywords: Flavonoids; GSK 3β; Molecular docking; Multidrug resistance; P-glycoprotein; Wnt/β-catenin signaling.

Publication types

Retracted Publication

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / chemistry
ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics*
Apoptosis / drug effects
Apoptosis / genetics
Binding Sites
Cell Line, Tumor
Drug Resistance, Multiple / genetics*
Drug Resistance, Neoplasm / genetics*
Flavonoids / chemistry
Flavonoids / pharmacology*
Gene Expression*
Glycogen Synthase Kinase 3 beta / chemistry
Glycogen Synthase Kinase 3 beta / metabolism
Humans
Models, Biological
Molecular Conformation
Protein Binding
Structure-Activity Relationship
Wnt Signaling Pathway / drug effects*

Substances

ATP Binding Cassette Transporter, Subfamily B, Member 1
Flavonoids
Glycogen Synthase Kinase 3 beta

Abstract

Publication types

MeSH terms

Substances

Grants and funding