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 in to cells and reduced by cellular reductants to the potential DNA damaging s pecies Cr(V), (TV), and (III). Reactive oxygen species and carbon-based rad icals may also be produced during Cr reduction. We previously found that Cd blocks Cr-induced apoptosis, which could allow a larger proportion of gene tically damaged cells to escape and become transformed. This study helped d efine the mechanisms of Cd-induced suppression of apoptosis. Chinese hamste r ovary (CHO K1-BH4) cells were treated with either Cd (5-20 mu M), Cr(VI) (350 mu M), or Cd (5-20 mu M) plus Cr(VI) (350 mu M) for 3 h and then cultu red in metal-free media for an additional 48 h at which time DNA was extrac ted or nuclei were examined to determine apoptosis. Cd markedly reduced Cr- induced DNA fragmentation and reduced the number of Cr-induced apoptotic ce ll nuclei to control levels. Additional study investigated the biokinetics and cellular metabolism of Cr. Cd did not alter the cellular Cr accumulatio n and there were no differences in the levels of reduced glutathione, a com pound possibly important in Cr reduction and reflective of the cellular red ucing environment. The antiapoptotic effect of Cd was not due to diminished cellular reduction of Cr(VI) as assessed by electron-spin resonance determ ination of the Levels of Cr(V). Thus, Cd suppression of Cr-induced apoptosi s is not based on altered Cr toxicokinetics or metabolism. In addition to C r, Cd also inhibited apoptosis induced by hygromycin B and actinomycin D. C d was a very effective inhibitor of caspase-3 activity, a central mediator of apoptosis, with nontoxic levels of Cd resulting in up to similar to 60% inhibition. These results indicate that Cd may have a generalized inhibitor y effect on apoptosis, possibly by inhibiting caspase-3. Inhibition of apop tosis by Cd may allow a greater portion of genetically damaged cells to sur vive, or give selective growth advantages, and has implications as a potent ial nongenotoxic mechanism of Cd carcinogenesis.