期刊
BRITISH JOURNAL OF CANCER
卷 101, 期 8, 页码 1290-1297出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.bjc.6605311
关键词
hypoxia; apoptosis; DNA damage; oxaliplatin; tumour spheroids; bioavailability
类别
资金
- CR-UK [C84/A4394, C147/A6058]
- MRC [G0500366]
- Medical Research Council [G0500366] Funding Source: researchfish
- MRC [G0500366] Funding Source: UKRI
BACKGROUND: Hypoxia is as an indicator of poor treatment outcome. Consistently, hypoxic HCT116 colorectal cancer cells are resistant to oxaliplatin, although the mechanistic basis is unclear. This study sought to investigate the relative contribution of HIF-1 (hypoxia-inducible factor-1)-mediated gene expression and drug penetrance to oxaliplatin resistance using three-dimensional spheroids. METHODS: Hypoxia-inducible factor-1 alpha function was suppressed by the stable expression of a dominant-negative form in HCT116 cells (DN). Cells were drug exposed as monolayer or multicellular spheroid cultures. Cells residing at differing oxygenation status were isolated from Hoechst 33342-treated spheroids using flow cytometry. Sub-populations were subjected to clonogenic survival assays and to Inductively-Coupled Plasma Mass Spectroscopy to determine oxaliplatin uptake. RESULTS: In spheroids, a sensitivity gradient (hypoxic < aerobic) was revealed by survival assays and this correlated with levels of platinum-bound DNA. The resistance of hypoxic sub-populations exceeded relative changes in adduct levels, implicating factors other than drug penetrance in cell response. Dominant-negative monolayer cells showed no resistance to oxaliplatin in hypoxia and spheroids; the relative resistance of hypoxic compared with aerobic sub-populations was reduced compared with those from controls. CONCLUSION: Overall, data show that drug penetration, DNA damage levels and HIF-1-dependent processes, all contribute to the resistance of hypoxic cells to oxaliplatin. British Journal of Cancer ( 2009) 101, 1290-1297. doi:10.1038/sj.bjc.6605311 www.bjcancer.com Published online 15 September 2009 (C) 2009 Cancer Research UK
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据