RETRACTED ARTICLE:Flavonoids modulate multidrug resistance through wnt signaling in P-glycoprotein overexpressing cell lines
Authors: N Rajendra Prasad
S Mohana
M Ganesan
D Velmurugan
D Ananthakrishnan
Journal: BMC Cancer (2018)
Discipline: CLINICAL MEDICINE
Keywords: Flavonoids; GSK 3β; Molecular docking; Multidrug resistance; P-glycoprotein
Affiliations: Department of Biochemistry and Biotechnology, Annamalai University, Annamalai Nagar, Tamil Nadu, 608 002, India., Department of Biochemistry and Biotechnology, Annamalai University, Annamalai Nagar, Tamil Nadu, 608 002, India. ., Bioinformatics Infrastructure Facility (BIF), University of Madras, Guindy Campus, Chennai, Tamil Nadu, India., 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 KBCHR8-5 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 KBCHR8-5 and MCF7/ADR cell lines. The chemosensitizing potential of flavonoids was further analyzed by observing cell cycle arrest in KBCHR8-5 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 KBCHR8-5 cell lines. All the flavonoids selected in this study significantly decreased the expression of Wnt and GSK 3β in KBCHR8-5 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 KBCHR8-5 and MCF7/ADR cell lines. The MDR reversal potential of flavonoids were found to be in the order of theaflavin &gt; quercetin &gt; rutin &gt; epicatechin 3 gallate &gt; 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 KBCHR8-5 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 KBCHR8-5 cells. 

Retracted: Yes

PubPeer comments:
 Figure 2: The FZD1 blots in panels E (Rutin experiment) and F (Epicatechin experiment) look unexpectedly similar. Shown with red boxes. ![file] , 
 Figure 4. Some panels appear to show unexpected similarities. Shown with blue, pink (mirrored similarities), and green boxes. Note that heights are not identical, but distribution of peaks is very similar. ![file] , 
 Figure 5. These 5 graphs look unexpectedly similar, in particular regarding to the lower three lines. The aqua-colored line is showing the same experiment, but the other lines represent different treatments. Could the authors please check? ![file] , 
 Figure 6. These 5 graphs look unexpectedly similar. The aqua-colored line is showing the same experiment, but the other lines represent different treatments. Could the authors please check? ![file] , 
 2021 retraction. https: bmccancer.biomedcentral.com articles 10.1186 s12885-021-07827-3 Retraction Note: Flavonoids modulate multidrug resistance through wnt signaling in P-glycoprotein overexpressing cell lines S. Mohana, M. Ganesan, N. Rajendra Prasad, D. Ananthakrishnan D. Velmurugan BMC Cancer volume 21, Article number: 151 (2021) Cite this article 13 Accesses Metricsdetails The original article was published in BMC Cancer 2018 18:1168 Retraction Note: BMC Cancer 18, 1168 (2018) https: doi.org 10.1186 s12885-018-5103-1 The editor has retracted this article [1]. Concerns were raised regarding a number of figures, specifically: Figure 2: the FZD1 blots in panels e (Rutin experiment) and f (Epicatechin experiment) appear to be identical. Figure 4b and c appear to be identical. Figure 4d and f appear to be very similar. Figure 4i and l appear to be very similar. The data reported in this article are therefore unreliable. M. Ganesan, N. Rajendra Prasad, D. Ananthakrishan and D. Velmurugan agree with this retraction. S. Mohana has not responded to correspondence regarding this retraction. Reference 1. Mohana S, Ganesan M, Rajendra Prasad N, et al. Flavonoids modulate multidrug resistance through wnt signaling in P-glycoprotein overexpressing cell lines. BMC Cancer. 2018;18:1168. https: doi.org 10.1186 s12885-018-5103-1. ,