Dichloroacetate (DCA) sensitizes both wild-type and over expressing Bcl-2 prostate cancer cells in vitro to radiation
Dichloroacetate (DCA) sensitizes both wild-type and over expressing Bcl-2 prostate cancer cells in vitro to radiation
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DOI：
10.1002/pros.20788
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发表时间：
2008-08-01
期刊：
影响因子：
2.8
通讯作者：
Rosser, Charles J.
中科院分区：
文献类型：
--
作者：
Cao, Wengang;Yacoub, Saif;Rosser, Charles J.
背景资料。BCL-2可保护细胞免于凋亡，并为过度表达该癌基因的细胞提供生存优势。此外，Bcl2的过表达使细胞对放射治疗产生抵抗力。最近，二氯乙酸酯(DCA)被证明通过与Bcl2相互作用而增强了细胞的凋亡机制。在本研究中，我们研究了DCA对人前列腺癌细胞的增殖、克隆存活、细胞周期、细胞周期时相分布、线粒体膜电位、以及Bcl2、Bcl2、Bax、Bak蛋白表达的影响。结果：DCA单独作用于PC-3-Bcl2和PC-3-Neo细胞后，细胞增殖、克隆存活、细胞凋亡、细胞周期时相分布、线粒体膜电位以及Bcl2、BclxL、Bax和Bak蛋白的表达均发生显著变化。此外，DCA与细胞凋亡率的增加有关。DCA与辐射的结合使两种细胞系都对辐射的杀伤作用敏感。PC-3-Bc-2或PC-3-Neo与DCA联合照射可引起Bc-2家族各成员的显著变化。此外，DCA还引起线粒体膜电位的显著变化，从而支持DCA作用于线粒体的观点。结论首次证实DCA可通过调控Bcl2家族关键成员的表达，有效地增敏野生型和高表达的人前列腺癌细胞对辐射的敏感性。综上所述，这些发现值得进一步评估DCA和放射治疗的结合。
BACKGROUND. Bcl-2 protects cells from apoptosis and provides a survival advantage to cells over-expressing this oncogene. In addition, over expression of Bcl-2 renders cell resistant to radiation therapy. Recently, dichloroacetate (DCA) was proven to potentiate the apoptotic machinery by interacting with Bcl-2. In this study, we investigated whether treating human prostate cancer cells with DCA could modulate Bcl-2 expression and if the modulation in Bcl-2 expression could render the Bcl-2 over expressing cells more susceptible to cytotoxicity effects of radiation.METHODS. PC-3-Bcl-2 and PC-3-Neo human prostate cancer cells treated with DCA in addition to irradiation were analyzed in vitro for changes in proliferation, clonogenic survival, apoptosis, cell cycle phase distribution, mitochondrial membrane potential, and expression of Bcl-2, Bcl-xL, Bax, or Bak proteins.RESULTS. DCA alone produced significant cytotoxic effects and was associated with G1 cell cycle arrest. Furthermore, DCA was associated with an increased rate of apoptosis. The combination of DCA with irradiation sensitized both cell lines to radiation's killing effects. Treatment of PC-3-Bcl-2 or PC-3-Neo with DCA and irradiation resulted in marked changes in various members of the Bcl-2 family. In addition, DCA therapy resulted in a significant change in mitochondria membrane potential, thus supporting the notion that DCAs effect is on the mitochondria.CONCLUSIONS. This is the first study to demonstrate DCA can effectively sensitize wild-type and over expressing Bcl-2 human prostate cancer cells to radiation by modulating the expression of key members of the Bcl-2 family. Together, these findings warrant further evaluation of the combination of DCA and irradiation.