Possible role of caspase-3 inhibition in cadmium-induced blockage of apoptosis.
Cadmium (Cd) and chromium (Cr) are human carcinogens. Cr(VI) is taken up into cells and reduced by cellular reductants to the potential DNA damaging species Cr(V), (IV), and (III). Reactive oxygen species and carbon-based radicals may also be produced during Cr reduction. We previously found that Cd blocks Cr-induced apoptosis, which could allow a larger proportion of genetically damaged cells to escape and become transformed. This study helped define the mechanisms of Cd-induced suppression of apoptosis. Chinese hamster ovary (CHO K1-BH4) cells were treated with either Cd (5-20 microM), Cr(VI) (350 microM), or Cd (5-20 microM) plus Cr(VI) (350 microM) for 3 h and then cultured in metal-free media for an additional 48 h at which time DNA was extracted or nuclei were examined to determine apoptosis. Cd markedly reduced Cr-induced DNA fragmentation and reduced the number of Cr-induced apoptotic cell nuclei to control levels. Additional study investigated the biokinetics and cellular metabolism of Cr. Cd did not alter the cellular Cr accumulation and there were no differences in the levels of reduced glutathione, a compound possibly important in Cr reduction and reflective of the cellular reducing environment. The antiapoptotic effect of Cd was not due to diminished cellular reduction of Cr(VI) as assessed by electron-spin resonance determination of the levels of Cr(V). Thus, Cd suppression of Cr-induced apoptosis is not based on altered Cr toxicokinetics or metabolism. In addition to Cr, Cd also inhibited apoptosis induced by hygromycin B and actinomycin D. Cd was a very effective inhibitor of caspase-3 activity, a central mediator of apoptosis, with nontoxic levels of Cd resulting in up to approximately 60% inhibition. These results indicate that Cd may have a generalized inhibitory effect on apoptosis, possibly by inhibiting caspase-3. Inhibition of apoptosis by Cd may allow a greater portion of genetically damaged cells to survive, or give selective growth advantages, and has implications as a potential nongenotoxic mechanism of Cd carcinogenesis.
Yuan
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Inorganic Carcinogenesis Section, National Cancer Institute at National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Kadiiska
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Achanzar
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Mason
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Waalkes
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MP
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D016466:CHO Cells; D002104:Cadmium / Q000008:administration & dosage / Q000494:pharmacology*; D002273:Carcinogens / Q000494:pharmacology; D053148:Caspase 3; D061945:Caspase Inhibitors; D002857:Chromium / Q000008:administration & dosage / Q000494:pharmacology; D006224:Cricetinae; D053938:DNA Fragmentation; D003609:Dactinomycin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006921:Hygromycin B / Q000494:pharmacology
D002273:Carcinogens; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D002104:Cadmium; D002857:Chromium; D003609:Dactinomycin; D006921:Hygromycin B; C505407:CASP3 protein, human; D053148:Caspase 3