Davies Gerald F, Roesler William J, Juurlink Bernhard H J, Harkness Troy A A
Department of Anatomy, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada.
Leuk Lymphoma. 2005 Aug;46(8):1199-206. doi: 10.1080/10428190500102555.
Human myeloid leukemia cells become resistant to doxorubicin (DOX) treatment and this resistance is correlated with an increased glyoxalase 1 (GLO1) expression. Troglitazone (TRG) is an anti-diabetic thiazolidinedione drug previously used to treat insulin-resistance in Type 2 diabetes. We previously showed that TRG down regulates GLO1 gene expression in a number of cell types and reasoned that TRG might be a useful adjunct therapy to overcome DOX resistance. Here we show that TRG treatment overcomes the resistance to DOX in the DOX-resistant K562 human leukemia cells. Higher doses of TRG were found to alter histone H3:H2B ratios with a decreased ratio in DOX-sensitive and increased ratio in DOX-resistant lines. Furthermore, phosphorylated H3 was seen in DOX-resistant but not in DOX-sensitive cells. We conclude that the downstream effect of TRG in DOX-resistant cells may be interference with normal cell cycle events leading to genomic instability. Our data suggest that TRG may be a useful adjunct therapy in circumventing drug resistance in K562 leukemia cells.
人髓系白血病细胞对阿霉素（DOX）治疗产生耐药性，且这种耐药性与乙二醛酶1（GLO1）表达增加相关。曲格列酮（TRG）是一种抗糖尿病噻唑烷二酮类药物，曾用于治疗2型糖尿病的胰岛素抵抗。我们之前表明，TRG在多种细胞类型中下调GLO1基因表达，并推断TRG可能是克服DOX耐药性的一种有用辅助治疗方法。在此我们表明，TRG治疗可克服DOX耐药的K562人白血病细胞对DOX的耐药性。发现较高剂量的TRG会改变组蛋白H3:H2B比例，在DOX敏感细胞系中该比例降低，在DOX耐药细胞系中该比例升高。此外，在DOX耐药细胞中可见磷酸化H3，而在DOX敏感细胞中未见。我们得出结论，TRG在DOX耐药细胞中的下游效应可能是干扰正常细胞周期事件，导致基因组不稳定。我们的数据表明，TRG可能是规避K562白血病细胞耐药性的一种有用辅助治疗方法。
