Natural compounds with proteasome inhibitory activity for cancer prevention and treatment - PubMed (original) (raw)

Review

Natural compounds with proteasome inhibitory activity for cancer prevention and treatment

H Yang et al. Curr Protein Pept Sci. 2008 Jun.

Abstract

The proteasome is a multicatalytic protease complex that degrades most endogenous proteins including misfolded or damaged proteins to ensure normal cellular function. The ubiquitin-proteasome degradation pathway plays an essential role in multiple cellular processes, including cell cycle progression, proliferation, apoptosis and angiogenesis. It has been shown that human cancer cells are more sensitive to proteasome inhibition than normal cells, indicating that a proteasome inhibitor could be used as a novel anticancer drug. Indeed, this idea has been supported by the encouraging results of the clinical trials using the proteasome inhibitor Bortezomib (Velcade, PS-341), a drug approved by the US Food and Drug Administration (FDA). Several natural compounds, including the microbial metabolite lactacystin, green tea polyphenols, and traditional medicinal triterpenes, have been shown to be potent proteasome inhibitors. These findings suggest the potential use of natural proteasome inhibitors as not only chemopreventive and chemotherapeutic agents, but also tumor sensitizers to conventional radiotherapy and chemotherapy. In this review, we will summarize the structures and biological activities of the proteasome and several natural compounds with proteasome inhibitory activity, and will discuss the potential use of these compounds for the prevention and treatment of human cancers.

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Figures

Fig. (1)

Fig. (1). The Ubiquitin-Proteasome Pathway

Ubiquitin (Ub) is activated by Ub-activating (E1) enzymes through adenylation and formation of high-energy thiol ester bond and then transferred to Ub-conjugating (E2) enzymes. With the help of Ub-ligating (E3) enzymes, Ub is finally tranferred to a reactive lysine residue of a target protein. Ubiquitinated proteins are recognized by the 19S cap of the 26S proteasome and fed into its 20S catalytic core for degradation into oligopeptides. The Ub is then released and recycled.

Fig. (2)

Fig. (2)

Chemical structure of Bortezomib.

Fig. (3)

Fig. (3)

Chemical structures of lactacystin, clasto-lactacystin β-lactone and several natural polyphenols.

Fig. (4)

Fig. (4)

Chemical structures of natural triterpenes.

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