Simultaneous modulation of multidrug resistance and antiapoptotic cellular defense by MDR1 and BCL-2 targeted antisense oligonucleotides enhances the anticancer efficacy of doxorubicin
Simultaneous modulation of multidrug resistance and antiapoptotic cellular defense by MDR1 and BCL-2 targeted antisense oligonucleotides enhances the anticancer efficacy of doxorubicin
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DOI：
10.1023/a:1022687617318
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发表时间：
2003-03-01
影响因子：
3.7
通讯作者：
Minko, T
中科院分区：
文献类型：
--
作者：
Pakunlu, RI;Cook, TJ;Minko, T
目的.通过同时抑制泵和非泵细胞阻力来增强已建立药物的抗癌功效。使用多药耐药人卵巢癌（A2780/AD）和乳腺癌（MCF-7/AD）细胞。将靶向MDR 1和BCL-2 mRNA的阿霉素（DOX）和反义寡核苷酸（阿索）以不同的组合系列组合在一个脂质体药物递送系统（LDDS）内的溶液中。进行了10个系列的实验。在每个系列中，将细胞与12至45个浓度的游离DOX和不同的脂质体制剂一起孵育6至48小时。检测细胞毒性、凋亡诱导、caspase、MDR 1、BCL-2和APAF-1基因、P-糖蛋白和BCL-2蛋白。在一个LDDS中，靶向MDR 1和BCL-2 mRNA的DOX和阿索的组合显示出DOX的抗癌作用的显著增加。由于P-gp和BCL-2蛋白合成的抑制同时抑制了泵和非泵细胞阻力，因此caspase的活化和凋亡显著增加。同时抑制多药耐药性和抗凋亡细胞防御显着增强阿霉素的抗癌活性。因此，拟议的DDS组合可能用于治疗多药耐药的卵巢癌和乳腺癌。
Purpose. To enhance the anticancer efficacy of an established drug by the simultaneous suppression of pump and nonpump cellular resistance.Methods. Multidrug resistant human ovarian (A2780/AD) and breast (MCF-7/AD) cancer cells were used. Doxorubicin (DOX) and antisense oligonucleotides (ASO) targeted to MDR1 and BCL-2 mRNA were combined in a solution within one liposomal drug delivery system (LDDS) in different combination series. Ten series of experiments were performed. In each series cells were incubated with 12 to 45 concentrations of free DOX and different liposomal formulations over a period of 6 to 48 h. Cytotoxicity, apoptosis induction, caspases, MDR1, BCL-2, and APAF-1 genes, P-glycoprotein, and BCL-2 protein were studied.Results. The combination of DOX and ASO targeted to MDR1 and BCL-2 mRNA in one LDDS exhibited a dramatic increase in the anticancer action of DOX. As a result of the simultaneous suppression of pump and nonpump cellular resistance by the inhibition of P-glycoprotein and BCL-2 protein synthesis, a significant increase in the activation of caspases and apoptosis was observed.Conclusions. The simultaneous suppression of multidrug resistance and antiapoptotic cellular defense significantly enhanced the anticancer activity of DOX. Therefore, the proposed DDS combination may potentially be used in the treatment of multidrug-resistant ovarian and breast cancers.