title: Interplay of reactive oxygen species, intracellular Ca2+ and mitochondrial homeostasis in the apoptosis of prostate cancer cells by deoxypodophyllotoxin.
abstract: 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 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.
authors.affiliation: Department of Microbiology and Immunology, Pusan National University School of Medicine, Yangsan 626-870, Republic of Korea.
authors.forename: Kwang-Youn
authors.initials: KY
authors.lastname: Kim
authors.forename: Hyo-Jin
authors.initials: HJ
authors.lastname: Cho
authors.forename: Sun-Nyoung
authors.initials: SN
authors.lastname: Yu
authors.forename: Sang-Hun
authors.initials: SH
authors.lastname: Kim
authors.forename: Hak-Sun
authors.initials: HS
authors.lastname: Yu
authors.forename: Yeong-Min
authors.initials: YM
authors.lastname: Park
authors.forename: Nooshin
authors.initials: N
authors.lastname: Mirkheshti
authors.forename: So Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Chung Seog
authors.initials: CS
authors.lastname: Song
authors.forename: Bandana
authors.initials: B
authors.lastname: Chatterjee
authors.forename: Soon-Cheol
authors.initials: SC
authors.lastname: Ahn
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004365:Drugs, Chinese Herbal; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D021381:Protein Transport / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D004365:Drugs, Chinese Herbal; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D004533:Egtazic Acid; C014451:deoxypodophyllotoxin; D045304:Cytochromes c; D053148:Caspase 3; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D011034:Podophyllotoxin; D002118:Calcium