title: 5-Phenylselenyl- and 5-methylselenyl-methyl-2'-deoxyuridine induce oxidative stress, DNA damage, and caspase-2-dependent apoptosis in cancer cells.
abstract: In the present study, we investigated the signaling pathways implicated in the induction of apoptosis by two modified nucleosides, 5-phenylselenyl-methyl-2'-deoxyuridine (PhSe-T) and 5-methylselenyl-methyl-2'-deoxyuridine (MeSe-T), using human cancer cell lines. The induction of apoptosis was associated with proteolytic activation of caspase-3 and -9, PARP cleavage, and decreased levels of IAP family members, including c-IAP-1 and c-IAP-2, but had no effect on XIAP and survivin. PhSe-T and MeSe-T also enhanced the activities of caspase-2 and -8, Bid cleavage, and the conformational activation of Bax. Additionally, nucleoside derivative-induced apoptosis was inhibited by the selective inhibitors of caspase-2, -3, -8, and -9 and also by si-RNAs against caspase-2, -3, -8, and -9; however, inhibition of caspase-2 and -3 was more effective at preventing apoptosis than inhibition of caspase-8 and -9. Moreover, the inhibition of caspase-2 activation by the pharmacological inhibitor z-VDVAD-fmk or by the knockdown of protein expression using siRNA suppressed nucleoside derivative-induced caspase-3 activation, but not vice versa. PhSe-T and MeSe-T also induced a Δψ(m) loss via a CsA-insensitive mechanism, ROS production, and DNA damage, including strand breaks. Moreover, ROS scavengers such as NAC, tiron, and quercetin inhibited nucleoside derivative-induced ROS generation and apoptosis by blocking the sequential activation of caspase-2 and -3, indicating the role of ROS in caspase-2-mediated apoptosis. Taken together, these results indicate that caspase-2 acts upstream of caspase-3 and that caspase-2 functions in response to DNA damage in both PhSe-T- and MeSe-T-induced apoptosis. Our results also suggest that ROS are critical regulators of the sequential activation of caspase-2 and -3 in nucleoside derivative-treated cancer cells.
authors: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, 215-4 Gongneung-dong, Nowon-Gu, Seoul, 139-706, Korea.
authors: Byeong Mo
authors: BM
authors: Kim
authors: Ambadas B
authors: AB
authors: Rode
authors: Eun Jong
authors: EJ
authors: Han
authors: In Seok
authors: IS
authors: Hong
authors: Sung Hee
authors: SH
authors: Hong
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D053143:Caspase 2 / Q000235:genetics / Q000378:metabolism*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D003857:Deoxyuridine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D009369:Neoplasms / Q000378:metabolism*; D009842:Oligopeptides / Q000008:administration & dosage; D016566:Organoselenium Compounds / Q000008:administration & dosage*; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C558288:5-methylselenylmethyl-2'-deoxyuridine; C558289:5-phenylselenylmethyl-2'-deoxyuridine; D061945:Caspase Inhibitors; D009842:Oligopeptides; D016566:Organoselenium Compounds; D017382:Reactive Oxygen Species; C427308:benzoylcarbonyl-valyl-aspartyl-valyl-alanyl-aspartyl-fluoromethyl ketone; D053143:Caspase 2; D053148:Caspase 3; D003857:Deoxyuridine