■核苷类似物如吉西他滨(GEM;dFdC)和阿糖胞苷(Ara-C)需要核苷转运蛋白进入细胞,平衡核苷转运蛋白1(ENT1)的缺乏可导致对这些药物的耐药性。为了促进独立于运输的吸收,开发了脂肪酸链连接到吉西他滨或阿糖胞苷核糖基团5'位置的前药(分别为CP-4126和CP-4055)。由于抗代谢物可以激活细胞生存途径,我们调查了前药或其侧链是否具有相似或降低的作用.
■将两个细胞系A549(非小细胞肺癌)和WiDr(结肠癌细胞)暴露于IC50浓度的GEM2-24小时,Ara-C,CP-4126、CP4055和反油酸(EA)浓度对应于CP-4126和CP-4055IC50。收获细胞并分析细胞存活途径中的蛋白质(p-AKT/AKT,p-ERK/ERK,p-P38/P38,GSK-3β/pGSK-3β)通过使用Western印迹。
■所有药物及其衍生物均显示出时间和细胞系依赖性作用。在A549细胞中,创业板,CP-4126和EA-4126在2和24小时降低p-AKT/AKT比率。对于p-ERK/ERK比率,创业板,EA-4126,Ara-C,CP-4045和EA-4055暴露导致A549细胞在6小时后增加。有趣的是,Ara-C,CP-4055和EA-4055在4小时后降低WiDr细胞中的p-ERK/ERK比率。在A549细胞中,暴露于Ara-C和CP-4055后,p-GSK-3β/GSK-3β比率降低,但在WiDr细胞中,24小时后增加。在用Ara-C处理的A549细胞中,CP-4055和EA-4126在6小时后降低p-P38/P38。
■研究结果表明,两种母体药物,前药,EA链影响细胞存活和信号通路。
UNASSIGNED: Nucleoside analogs such as gemcitabine (GEM; dFdC) and cytarabine (Ara-C) require nucleoside transporters to enter cells, and deficiency in equilibrative nucleoside transporter 1 (ENT1) can lead to resistance to these drugs. To facilitate transport-independent uptake, prodrugs with a fatty acid chain attached to the 5\'-position of the ribose group of gemcitabine or cytarabine were developed (CP-4126 and CP-4055, respectively). As antimetabolites can activate cellular survival pathways, we investigated whether the prodrugs or their side-chains had similar or decreased effects.
UNASSIGNED: Two cell lines A549 (non-small cell lung cancer) and WiDr (colon cancer cells) were exposed for 2-24hr to IC50 concentrations of GEM, Ara-C, CP-4126, CP4055 and elaidic acid (EA) concentrations corresponding to the CP-4126 and CP-4055 IC50. Cells were harvested and analyzed for proteins in cell survival pathways (p-AKT/AKT, p-ERK/ERK, p-P38/P38, GSK-3β/pGSK-3β) by using Western Blotting.
UNASSIGNED: All drugs and their derivatives showed time- and cell-line-dependent effects. In A549 cells, GEM, CP-4126 and EA-4126 decreased the p-AKT/AKT ratio at 2 and 24 hr. For the p-ERK/ERK ratio, GEM, EA-4126, Ara-C, CP-4045 and EA-4055 exposure led to an increase after 6 hr in A549 cells. Interestingly, Ara-C, CP-4055 and EA-4055 decreased p-ERK/ERK ratio in WiDr cells after 4 hr. In A549 cells, the p-GSK-3β/GSK-3β ratio decreased after exposure to Ara-C and CP-4055 but in WiDr cells increased after 24 hr. In A549 cells treatment with Ara-C, CP-4055 and EA-4126 decreased the p-P38/P38 after 6 hr.
UNASSIGNED: The findings suggest that both parent drugs, prodrugs, and the EA chain influence cell survival and signaling pathways.