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: Byeong Mo Kim, Ambadas B Rode, Eun Jong Han, In Seok Hong, Sung Hee Hong
• Journal: Apoptosis : an international journal on programmed cell death (Apoptosis) Vol. 17 Issue 2 Pg. 200-16 (Feb 2012) ISSN: 1573-675X [Electronic] Netherlands
• PMID: 22002103 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5-methylselenylmethyl-2'-deoxyuridine
• 5-phenylselenylmethyl-2'-deoxyuridine
• Caspase Inhibitors
• Oligopeptides
• Organoselenium Compounds
• Reactive Oxygen Species
• benzoylcarbonyl-valyl-aspartyl-valyl-alanyl-aspartyl-fluoromethyl ketone
• Caspase 2
• Caspase 3
• Deoxyuridine

Topics

• Apoptosis (drug effects, genetics)
• Caspase 2 (genetics, metabolism)
• Caspase 3 (genetics, metabolism)
• Caspase Inhibitors
• Cell Line, Tumor
• DNA Damage (drug effects)
• Deoxyuridine (administration & dosage, analogs & derivatives)
• Enzyme Activation (drug effects)
• Humans
• Neoplasms (metabolism)
• Oligopeptides (administration & dosage)
• Organoselenium Compounds (administration & dosage)
• Oxidative Stress (drug effects)
• Reactive Oxygen Species (metabolism)
• Signal Transduction