March 12, 2003
"Unexpectedly, we found that ritonavir activates the chymotrypsin-like activity of isolated 26S proteasomes, in strong contrast to its effect on isolated 20S proteasomes," Gaedicke and coauthors wrote. "The net effect of low micromolar concentrations of ritonavir on the chymotrypsin-like activity in cells and cell lysates was a weak inhibition, consistent with marginal alterations of polyubiquitinated proteins, marginal alterations in acid-soluble proteolytic peptide levels, and a small accumulation of the tumor suppressor protein p53, in cells treated with ritonavir."
"In contrast," the researchers noted, "we found a relatively strong accumulation of the cyclin-dependent kinase inhibitor p21 (WAF-1), a sign of deregulation of cell-cycle progression typical for apoptosis induction in transformed cells by classical proteasome inhibitors." Data showed that "p21 accumulation in the presence of ritonavir is attributable to the inhibition of proteolytic degradation. Accumulation of p21 most likely reflects a selective inhibition of proteasomes, in line with the atypical degradation of p21, which does not require ubiquitination."
Gaedicke and colleagues concluded that "selective perturbation of proteasomal protein degradation may play a role in the antitumoral activities of ritonavir." The study, "Antitumor Effect of the Human Immunodeficiency Virus Protease Inhibitor Ritonavir: Induction of Tumor-Cell Apoptosis Associated with Perturbation of Proteasomal Proteolysis" appeared in Cancer Research (2002;62(23):6901-6908).
Adapted from:
Cancer Weekly
02.04.03
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