Yousefi Bahman, Azimi Ako, Majidinia Maryam, Shafiei-Irannejad Vahid, Badalzadeh Reza, Baradaran Behzad, Zarghami Nosratollah, Samadi Nasser
1 Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
2 Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
Tumour Biol. 2017 Oct;39(10):1010428317716501. doi: 10.1177/1010428317716501.
Multidrug resistance in tumor cells is still a big challenge in cancer treatment. Therefore, identification ofsafe and effective multidrug resistance-reversing compounds with minimal side effects is an important approach in cancer treatment. Here, we investigated the role and potential mechanisms of peroxisome proliferator-activated receptor γ in doxorubicin-resistant human myelogenous leukemia (K562/DOX) cells. The effect of doxorubicin on cell viability following treatment with balaglitazone, a peroxisome proliferator-activated receptor γ agonist, was evaluated using trypan blue and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. Rhodamine123 assay was used to determine the activity of two common drug efflux membrane transporters P-glycoprotein and multidrug resistance protein-1. P-glycoprotein, multidrug resistance protein-1, and phosphatase and tensin homolog deleted on chromosome 10 messenger RNA/protein expression levels were measured by quantitative reverse transcription polymerase chain reaction and western blot analyses. Annexin V/fluorescein isothiocyanate assay was also employed to investigate apoptosis. We showed that balaglitazone considerably enhanced the cytotoxicity of doxorubicin. Balaglitazone also significantly downregulated P-glycoprotein expression and activity in K562/DOX cells and reduced multidrug resistance through elevation of intracellular doxorubicin in cells. Furthermore, upon balaglitazone treatment, phosphatase and tensin homolog deleted on chromosome 10 expression could be restored in K562/DOX cells in a peroxisome proliferator-activated receptor γ-dependent manner. We concluded that peroxisome proliferator-activated receptor γ agonist, balaglitazone, could reverse multidrug resistance by inducing phosphatase and tensin homolog deleted on chromosome 10 and peroxisome proliferator-activated receptor/ phosphatase and tensin homolog deleted on chromosome 10 signaling pathway. These findings suggest that targeting peroxisome proliferator-activated receptor γ might serve as an effective approach for circumventing multidrug resistance in chemotherapy of cancerous patients.
肿瘤细胞中的多药耐药性仍是癌症治疗中的一大挑战。因此，鉴定出安全有效且副作用最小的多药耐药逆转化合物是癌症治疗的重要途径。在此，我们研究了过氧化物酶体增殖物激活受体γ在多柔比星耐药的人髓性白血病（K562/DOX）细胞中的作用及潜在机制。使用台盼蓝和3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐试验评估了过氧化物酶体增殖物激活受体γ激动剂巴格列酮处理后多柔比星对细胞活力的影响。使用罗丹明123试验来测定两种常见的药物外排膜转运蛋白P-糖蛋白和多药耐药蛋白-1的活性。通过定量逆转录聚合酶链反应和蛋白质印迹分析来检测P-糖蛋白、多药耐药蛋白-1以及10号染色体缺失的磷酸酶和张力蛋白同源物的信使核糖核酸/蛋白质表达水平。还采用膜联蛋白V/异硫氰酸荧光素试验来研究细胞凋亡。我们发现巴格列酮显著增强了多柔比星的细胞毒性。巴格列酮还显著下调了K562/DOX细胞中P-糖蛋白的表达和活性，并通过提高细胞内多柔比星水平降低了多药耐药性。此外，经巴格列酮处理后，K562/DOX细胞中10号染色体缺失的磷酸酶和张力蛋白同源物的表达可通过过氧化物酶体增殖物激活受体γ依赖性方式得以恢复。我们得出结论，过氧化物酶体增殖物激活受体γ激动剂巴格列酮可通过诱导10号染色体缺失的磷酸酶和张力蛋白同源物以及过氧化物酶体增殖物激活受体/10号染色体缺失 的磷酸酶和张力蛋白同源物信号通路来逆转多药耐药性。这些发现表明，靶向过氧化物酶体增殖物激活受体γ可能是规避癌症患者化疗中多药耐药性的有效方法。
Cell Mol Biol (Noisy-le-grand). 2015-12-30
Med Sci Monit. 2020-8-24
Cell Commun Signal. 2023-2-9
Cancer Cell Int. 2022-12-29
Cancer Cell Int. 2022-1-29
Front Oncol. 2021-9-23
Int J Clin Exp Pathol. 2021-5-15
Zotero 插件