Back to Browse Journals » Drug Design, Development and Therapy » Volume 3

Troglitazone reverses the multiple drug resistance phenotype in cancer cells

Authors Gerald F Davies, Bernhard HJ Juurlink, Troy AA Harkness

Published Date March 2009 Volume 2009:3 Pages 79—88

DOI http://dx.doi.org/10.2147/DDDT.S3314

Published 17 March 2009

Gerald F Davies1, Bernhard HJ Juurlink2, Troy AA Harkness1

1Department of Anatomy and Cell Biology, College of Medicine, University of Saskatchewan, Saskatoon, Canada; 2College of Medicine, Alfaisal University, Riyadh, Kingdom of Saudi Arabia

Abstract: A major problem in treating cancer is the development of drug resistance. We previously demonstrated doxorubicin (DOX) resistance in K562 human leukemia cells that was associated with upregulation of glyoxalase 1 (GLO-1) and histone H3 expression. The thiazolidinedione troglitazone (TRG) downregulated GLO-1 expression and further upregulated histone H3 expression and post-translational modifications in these cells, leading to a regained sensitivity to DOX. Given the pleiotropic effects of epigenetic changes in cancer development, we hypothesized that TRG may downregulate the multiple drug resistance (MDR) phenotype in a variety of cancer cells. To test this, MCF7 human breast cancer cells and K562 cells were cultured in the presence of low-dose DOX to establish DOX-resistant cell lines (K562/DOX and MCF7/DOX). The MDR phenotype was confirmed by Western blot analysis of the 170 kDa P-glycoprotein (Pgp) drug efflux pump multiple drug resistance protein 1 (MDR-1), and the breast cancer resistance protein (BCRP). TRG markedly decreased expression of both MDR-1 and BCRP in these cells, resulting in sensitivity to DOX. Silencing of MDR-1 expression also sensitized MCF7/DOX cells to DOX. Use of the specific and irreversible peroxisome proliferator-activated receptor gamma (PPARγ) inhibitor GW9662 in the nanomolar range not only demonstrated that the action of TRG on MCF/DOX was PPARγ-independent, but indicated that PPARγ may play a role in the MDR phenotype, which is antagonized by TRG. We conclude that TRG is potentially a useful adjunct therapy in chemoresistant cancers.

Keywords: chemotherapy, doxorubicin, breast cancer resistance protein-1, multiple drug resistance, multiple drug resistance protein 1

Download Article [PDF] 

Creative Commons License This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution - Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php

Readers of this article also read:

Characterization of renal biomarkers for use in clinical trials: effect of preanalytical processing and qualification using samples from subjects with diabetes

Brott DA, Furlong ST, Adler SH, Hainer JW, Arani RB, Pinches M, Rossing P, Chaturvedi N

Drug Design, Development and Therapy 2015, 9:3191-3198

Published Date: 22 June 2015

Effects of free leucine supplementation and resistance training on muscle strength and functional status in older adults: a randomized controlled trial

Trabal J, Forga M, Leyes P, Torres F, Rubio J, Prieto E, Farran-Codina A

Clinical Interventions in Aging 2015, 10:713-723

Published Date: 13 April 2015

Effects of prolonged head-down bed rest on working memory

Liu Q, Zhou R, Zhao X, Oei TPS

Neuropsychiatric Disease and Treatment 2015, 11:835-842

Published Date: 26 March 2015

Synthesis, pharmacokinetics, and biological use of lysine-modified single-walled carbon nanotubes [Erratum]

Mulvey JJ, Feinberg EN, Alidori S, McDevitt MR, Heller DA, Scheinberg DA

International Journal of Nanomedicine 2015, 10:595-596

Published Date: 14 January 2015

Tailored antihypertensive drug therapy prescribed to older women attenuates circulating levels of interleukin-6 and tumor necrosis factor-α

Toledo JO, Moraes CF, Souza VC, Tonet-Furioso AC, Afonso LCC, Córdova C, Nóbrega OT

Clinical Interventions in Aging 2015, 10:209-215

Published Date: 9 January 2015

Green synthesis of water-soluble nontoxic polymeric nanocomposites containing silver nanoparticles

Prozorova GF, Pozdnyakov AS, Kuznetsova NP, Korzhova SA, Emel’yanov AI, Ermakova TG, Fadeeva TV, Sosedova LM

International Journal of Nanomedicine 2014, 9:1883-1889

Published Date: 16 April 2014