Davies Gerald F, Juurlink Bernhard H J, Harkness Troy A A
Department of Anatomy and Cell Biology, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, Canada.
Drug Des Devel Ther. 2009 Sep 21;3:79-88. doi: 10.2147/dddt.s3314.
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 (PPARgamma) inhibitor GW9662 in the nanomolar range not only demonstrated that the action of TRG on MCF/DOX was PPARgamma-independent, but indicated that PPARgamma 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.
治疗癌症的一个主要问题是耐药性的产生。我们之前证明了K562人白血病细胞中存在阿霉素（DOX）耐药性，这与乙二醛酶1（GLO-1）和组蛋白H3表达上调有关。噻唑烷二酮类药物曲格列酮（TRG）下调了这些细胞中GLO-1的表达，并进一步上调了组蛋白H3的表达及翻译后修饰，从而使细胞对DOX重新产生敏感性。鉴于表观遗传变化在癌症发展中的多效性作用，我们推测TRG可能会下调多种癌细胞中的多药耐药（MDR）表型。为了验证这一点，将MCF7人乳腺癌细胞和K562细胞在低剂量DOX存在的情况下进行培养，以建立DOX耐药细胞系（K562/DOX和MCF7/DOX）。通过对170 kDa P-糖蛋白（Pgp）药物外排泵多药耐药蛋白1（MDR-1）和乳腺癌耐药蛋白（BCRP）进行蛋白质印迹分析，证实了MDR表型。TRG显著降低了这些细胞中MDR-1和BCRP的表达，从而使细胞对DOX敏感。沉默MDR-1的表达也使MCF7/DOX细胞对DOX敏感。使用纳摩尔范围内的特异性不可逆过氧化物酶体增殖物激活受体γ（PPARγ）抑制剂GW9662，不仅证明了TRG对MCF/DOX的作用不依赖于PPARγ，还表明PPARγ可能在MDR表型中发挥作用，而TRG可拮抗这种作用。我们得出结论，TRG在化疗耐药性癌症中可能是一种有用的辅助治疗方法。
