二氯醋酸钠对胶质瘤C6的疗效取决于给药方案和剂量。

Effectiveness of sodium dichloroacetate against glioma C6 depends on administration schedule and dosage.

作者信息

Fedorchuk A G, Pyaskovskaya O N, Gorbik G V, Prokhorova I V, Kolesnik D L, Solyanik G I

机构信息

R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NAS of Ukraine, Kyiv 03022, Ukraine.

出版信息

Exp Oncol. 2016 Jun;38(2):80-3.

PMID:27356574

Abstract

BACKGROUND

Anticancer action of sodium dichloroacetate (DCA) could be related to its ability to activate oxidative phosphorylation leading to enhanced generation of reactive oxygen species and induction of apoptosis. On the other hand, activation of oxidative phosphorylation could promote tumor cell survival, in particular, via increased ATP synthesis. Such ambiguous effects of DCA could influence its anticancer effectiveness, depending on biological properties of a tumor, schedule of DCA administration and its dosage. The aim of the study was to analyze anticancer effect of DCA against glioma С6 in rats under conditions of different schedules of its administration and various dosages.

MATERIALS AND METHODS

The study was carried out in Wistar rats with intracerebrally transplanted glioma С6 cells. Therapy with DCA was performed as follows: daily for 6 days starting from the second day after tumor cell transplantation (schedule І) or 7(th) day (schedule ІІ) at a dose of 1.0 g/kg, or daily for 13 days starting from the second day at doses of 1.0; 1.5 or 4.5 g/kg (schedule ІІІ). An influence of hypoxia on anticancer effect of DCA was studied using hypoxic chambers where oxygen content was maintained at a level of 12.5-13% for 3 h after DCA administration to glioma С6 bearing rats. The state of mitochondrial electron transport chain components in tumor cells was studied using electron paramagnetic resonance.

RESULTS

It has been shown that therapy with DCA using schedule I resulted in 15% decrease of animals life span (LS; < 0.05), while the use of schedule II had no effect on this index. Prolonged administration of DCA (schedule ІІІ) resulted in significant antitumor effect and increased LS of rats by 25.5% (p < 0.05). Under hypoxic conditions, treatment with DCA resulted in a significant increase of animal LS by 15-22%. Dosage of DCA had a moderate effect of its anticancer action. Maximal effect, an increase of LS by 34.5% (p < 0.05) was detected at a dose of 1.5 g/kg. It has been shown that anticancer activity of DCA under all studied conditions is not related to its influence on a functional state of tumor cell mitochondria.

CONCLUSION

Anticancer effect of DCA significantly depends on a schedule of its administration; being administered at equal total dose, but dependent on the schedule DCA could cause ambiguous effects varying from tumor growth stimulation to significant anticancer activity. Under hypoxic conditions, anticancer efficacy of DCA against glioma С6 is significantly enhanced.

摘要

背景

二氯乙酸钠（DCA）的抗癌作用可能与其激活氧化磷酸化的能力有关，氧化磷酸化的激活会导致活性氧生成增加并诱导细胞凋亡。另一方面，氧化磷酸化的激活也可能促进肿瘤细胞存活，特别是通过增加ATP合成来实现。DCA的这种模糊作用可能会影响其抗癌效果，这取决于肿瘤的生物学特性、DCA的给药方案及其剂量。本研究的目的是分析在不同给药方案和不同剂量条件下，DCA对大鼠脑胶质瘤C6的抗癌作用。

材料与方法

本研究在脑内移植了胶质瘤C6细胞的Wistar大鼠中进行。DCA治疗如下：从肿瘤细胞移植后的第二天开始每日给药6天（方案I）或第7天开始（方案II），剂量为1.0 g/kg，或者从第二天开始每日给药13天，剂量分别为1.0、1.5或4.5 g/kg（方案III）。使用缺氧舱研究缺氧对DCA抗癌作用的影响，在给荷胶质瘤C6大鼠注射DCA后，将缺氧舱内的氧气含量维持在12.5 - 13%水平3小时。使用电子顺磁共振研究肿瘤细胞中线粒体电子传递链成分的状态。

结果

结果表明，采用方案I进行DCA治疗导致动物寿命（LS）缩短15%（< 0.05），而采用方案II对该指标无影响。长期给予DCA（方案III）产生了显著的抗肿瘤作用，并使大鼠的LS增加了25.5%（p < 0.05）。在缺氧条件下，用DCA治疗导致动物LS显著增加15 - 22%。DCA的剂量对其抗癌作用有中等程度的影响。在剂量为1.5 g/kg时检测到最大效应，即LS增加34.5%（p < 0.05）。结果表明，在所有研究条件下，DCA的抗癌活性与其对肿瘤细胞线粒体功能状态的影响无关。