The limited treatment option for recurrent prostate cancer and the eventual resistance to conventional chemotherapy drugs has fueled continued interest in finding new anti-neoplastic agents of natural product origin.
We previously reported anti-proliferative activity of deoxypodophyllotoxin (DPT) on human prostate cancer cells. Using the PC-3 cell model of human prostate cancer, the present study reveals that DPT induced apoptosis via a caspase-3-dependent pathway that is activated due to dysregulated mitochondrial function. DPT-treated cells showed accumulation of the reactive oxygen species (ROS), intracellular Ca(i) (2+) surge, increased mitochondrial membrane potential (MMP, ΔΨ(m) ), Bax protein translocation to mitochondria and cytochrome c release to the cytoplasm. This resulted in caspase-3 activation, which in turn induced apoptosis. The antioxidant N-acetylcysteine (NAC) reduced ROS accumulation, MMP and Ca(i) (2+) surge, on the other hand the Ca(2+) chelator BAPTA inhibited the Ca(i) (2+) overload and MMP without affecting the increase of ROS, indicating that the generation of ROS was occurred prior to Ca(2+) flux. This suggested that both ROS and Ca(i) (2+) signaling play roles in the increased MMP via Ca(i) (2+) -dependent and/or -independent mechanisms, since ΔΨ(m) elevation was reversed by NAC and BAPTA. This study provides the first evidence for the involvement of both ROS- and Ca(i) (2+) -activated signals in the disruption of mitochondrial homeostasis and the precedence of ROS production over the failure of Ca(2+) flux homeostasis.
Written by:
Kim KY, Cho HJ, Yu SN, Kim SH, Yu HS, Park YM, Mirkheshti N, Kim SY, Song CS, Chatterjee B, Ahn SC Are you the author?
Department of Microbiology & Immunology, Pusan National University School of Medicine, Yangsan 626-870, Republic of Korea
Reference: J Cell Biochem. 2012 Nov 28(Epub ahead of print)
doi: 10.1002/jcb.24455
PubMed Abstract
PMID: 23192945
