Kars Meltem Demirel, Işeri Ozlem Darcansoy, Ural Ali Ugur, Gündüz Ufuk
Department of Biological Sciences, Middle East Technical University, 06531 Ankara, Turkey.
Anticancer Res. 2007 Nov-Dec;27(6B):4031-7.
Zoledronic acid is an important osteotropic compound used in combination with anticancer agents to reduce the incidence of hypercalcemia and skeletal morbidity in patients with advanced breast cancer and bone metastases. Ineffectiveness of anticancer drugs during chemotherapy is a frequently observed situation in cancer chemotherapy. The resistance of tumor cells to more than one cytotoxic drugs is defined as multidrug resistance. Drug resistance may be caused by altered gene expression levels and altered activities of proteins related to drug transport or cell death.
To investigate the potential development of zoledronic acid resistance in breast cancer, parental MCF-7 cells were selected by increasing doses of zoledronic acid. MTT cytotoxicity assays, RT-PCR and Western blot were performed. The anticancer drugs paclitaxel, docetaxel, vincristine and doxorubicin were tested in combination to assess their combined antiproliferative effects and cross-resistance profiles.
Results demonstrated that the drug-adapted cells are resistant to zoledronic acid compared to parental MCF-7 and de novo expression of resistance genes, such as BCRP and LRP, were found. Up-regulation of Bcl-2 gene expression in resistant cells was also found. Synergistic cytotoxic effects of the combination of zoledronic acid with paclitaxel, docetaxel and vincristine were confirmed by fractional inhibitory indices, and zoledronic acid resistant cells were also found to be cross-resistant to these agents.
Zoledronic acid may cause resistance in MCF-7 cells. Overexpression of BCRP and LRP genes and an increase in Bcl-2 gene expression may have roles in the development of zoledronic acid resistance in the MCF-7 cell line. On the other hand, MDR1 and MRP1 genes do not seem to contribute to the zoledronic acid resistance significantly.
唑来膦酸是一种重要的亲骨性化合物，与抗癌药物联合使用可降低晚期乳腺癌和骨转移患者高钙血症和骨骼病变的发生率。化疗期间抗癌药物无效是癌症化疗中常见的情况。肿瘤细胞对一种以上细胞毒性药物的耐药性被定义为多药耐药。耐药性可能是由与药物转运或细胞死亡相关的基因表达水平改变和蛋白质活性改变引起的。
为研究乳腺癌中唑来膦酸耐药性的潜在发展，通过增加唑来膦酸剂量筛选亲本MCF-7细胞。进行了MTT细胞毒性试验、RT-PCR和蛋白质印迹分析。联合测试抗癌药物紫杉醇、多西他赛、长春新碱和阿霉素，以评估它们的联合抗增殖作用和交叉耐药情况。
结果表明，与亲本MCF-7相比，药物适应细胞对唑来膦酸耐药，并且发现了耐药基因如BCRP和LRP的从头表达。还发现耐药细胞中Bcl-2基因表达上调。通过分数抑制指数证实了唑来膦酸与紫杉醇、多西他赛和长春新碱联合的协同细胞毒性作用，并且发现唑来膦酸耐药细胞对这些药物也有交叉耐药性。
唑来膦酸可能导致MCF-7细胞产生耐药性。BCRP和LRP基因的过表达以及Bcl-2基因表达的增加可能在MCF-7细胞系唑来膦酸耐药性的发展中起作用。另一方面，MDR1和MRP1基因似乎对唑来膦酸耐药性没有显著贡献。
