Dichloroacetate (DCA) sensitizes both wild‐type and over expressing Bcl‐2 prostate cancer cells in vitro to radiation

Abstract

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. 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. 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. 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.