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We previously reported anti\u2010proliferative activity of deoxypodophyllotoxin (DPT) on human prostate cancer cells. Using the PC\u20103 cell model of human prostate cancer, the present study reveals that DPT induced apoptosis via a caspase\u20103\u2010dependent pathway that is activated due to dysregulated mitochondrial function. DPT\u2010treated cells showed accumulation of the reactive oxygen species (ROS), intracellular Ca<jats:inline-graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"graphic\/tex2gif-stack-1.gif\" xlink:title=\"urn:x-wiley:07302312:media:JCB24455:tex2gif-stack-1\"\/> surge, increased mitochondrial membrane potential (MMP, \u0394\u03a8<jats:sub>m<\/jats:sub>), Bax protein translocation to mitochondria and cytochrome <jats:italic>c<\/jats:italic> release to the cytoplasm. This resulted in caspase\u20103 activation, which in turn induced apoptosis. The antioxidant <jats:italic>N<\/jats:italic>\u2010acetylcysteine (NAC) reduced ROS accumulation, MMP and Ca<jats:inline-graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"graphic\/tex2gif-stack-2.gif\" xlink:title=\"urn:x-wiley:07302312:media:JCB24455:tex2gif-stack-2\"\/> surge, on the other hand the Ca<jats:sup>2+<\/jats:sup> chelator BAPTA inhibited the Ca<jats:inline-graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"graphic\/tex2gif-stack-3.gif\" xlink:title=\"urn:x-wiley:07302312:media:JCB24455:tex2gif-stack-3\"\/> overload and MMP without affecting the increase of ROS, indicating that the generation of ROS occurred prior to Ca<jats:sup>2+<\/jats:sup> flux. This suggested that both ROS and Ca<jats:inline-graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"graphic\/tex2gif-stack-4.gif\" xlink:title=\"urn:x-wiley:07302312:media:JCB24455:tex2gif-stack-4\"\/> signaling play roles in the increased MMP via Ca<jats:inline-graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"graphic\/tex2gif-stack-5.gif\" xlink:title=\"urn:x-wiley:07302312:media:JCB24455:tex2gif-stack-5\"\/>\u2010dependent and\/or \u2010independent mechanisms, since \u0394\u03a8<jats:sub>m<\/jats:sub> elevation was reversed by NAC and BAPTA. This study provides the first evidence for the involvement of both ROS\u2010 and Ca<jats:inline-graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"graphic\/tex2gif-stack-6.gif\" xlink:title=\"urn:x-wiley:07302312:media:JCB24455:tex2gif-stack-6\"\/>\u2010activated signals in the disruption of mitochondrial homeostasis and the precedence of ROS production over the failure of Ca<jats:sup>2+<\/jats:sup> flux homeostasis. J. Cell. Biochem. 114: 1124\u20131134, 2013. \u00a9 2012 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/jcb.24455","type":"journal-article","created":{"date-parts":[[2012,11,29]],"date-time":"2012-11-29T01:34:04Z","timestamp":1354152844000},"page":"1124-1134","source":"Crossref","is-referenced-by-count":45,"title":["Interplay of reactive oxygen species, intracellular Ca<sup>2+<\/sup> and mitochondrial homeostasis in the apoptosis of prostate cancer cells by 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