Acquired resistance to the anticancer drug paclitaxel is associated with induction of cytochrome P4502C8
Acquired resistance to the anticancer drug paclitaxel is associated with induction of cytochrome P4502C8
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DOI：
10.2217/14622416.7.4.575
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发表时间：
2006-06-01
期刊：
影响因子：
2.1
通讯作者：
Agundez, Jose A. G.
中科院分区：
文献类型：
--
作者：
Garcia-Martin, Elena;Pizarro, Rosa M.;Agundez, Jose A. G.
简介：我们先前已经表明，人类结直肠癌组织能够通过细胞色素P450（CYP）2C 8和CYP 3A 4代谢来抑制抗癌药物紫杉醇。本研究的目的是评估编码这些酶的基因表达水平的变化是否与长期暴露于药物后的抗癌药物耐药性有关。研究方法：将对紫杉醇敏感的人结直肠癌细胞（Caco-2）暴露于0-250 nM浓度递增的药物中一年，以选择紫杉醇耐药细胞。随后，我们比较了原始细胞和耐药细胞对紫杉醇的敏感性以及CYP 2C 8、CYP 3A 4和CYP 3A 5基因的表达程度。结果：与原始癌细胞相比，耐药癌细胞对紫杉醇的致死剂量（LD）（50）增加了246倍（p < 0.004）。在暴露于紫杉醇的耐药细胞中观察到CYP 2C 8表达增加4.4倍（p = 0.005），多药耐药（MDR）1表达增加5.6倍（p = 0.001）。当紫杉醇从培养基中去除时，CYP 2C 8而不是MDR 1表达恢复到基础水平，并且对紫杉醇的耐药性降低了3.2倍（p = 0.005）。未观察到CYP 3A 4和CYP 3A 5表达水平的重大变化。结论：Caco-2细胞能够增加CYP 2C 8的表达水平，作为对长期暴露于紫杉醇的反应。本研究为基于抗癌代谢酶诱导的获得性抗癌治疗耐药机制提供了证据。
Introduction: We have previously shown that human colorectal cancer tissue is able to inactivate the anticancer drug paclitaxel through cytochrome P450 (CYP)2C8 and CYP3A4 metabolisms. The aim of this study was to evaluate whether changes in the expression levels of genes coding for such enzymes are related to anticancer drug resistance after long-term exposure to the drug. Methods: Human colorectal cancer cells (Caco-2) that are sensitive to paclitaxel were exposed to increasing concentrations of the drug from 0-250 nM during one year, in order to select paclitaxel-resistant cells. Subsequently, we compared the sensitivity to paclitaxel and the extent of expression of the CYP2C8, CYP3A4 and CYP3A5 genes in original and resistant cells. Results: Resistant cancer cells displayed a 246-fold increased lethal dose (LD)(50) to paclitaxel (p < 0.004) as compared with original cancer cells. A 4.4-fold (p = 0.005) enhancement of CYP2C8 expression and a 5.6-fold (p = 0.001) increase of multidrug resistance (MDR)1 expression was observed in resistant cells exposed to paclitaxel. When paclitaxel was removed from the culture medium, CYP2C8, but not MDR1 expression, reverted to basal levels and the resistance to paclitaxel decreased 3.2-fold (p = 0.005). No major changes in the expression levels of CYP3A4 and CYP3A5 were observed. Conclusions: Caco-2 cells are capable of increasing the expression levels of CYP2C8 as a response to long-term exposure to paclitaxel. This study provides evidence for a mechanism of acquired resistance to anticancer therapy based on the induction of anticancer-metabolizing enzymes.