A major challenge in cancer therapy is tumor drug resistance. To overcome it, it 
is essential to understand the mechanisms and identify the molecules involved, 
so that they can be specifically targeted in combination therapies. The 
proteasome is such a validated target: it plays a key role in cancer cell 
proliferation, inhibition of chemotherapy-induced apoptosis and drug resistance 
development. Bortezomib (Velcade, PS-341) was the first proteasome inhibitor to 
receive regulatory approval from the US Food and Drug Administration for the 
treatment of multiple myeloma. Clinical combination trials have demonstrated a 
chemo-sensitizing effect of bortezomib on conventional agents in hematological 
malignancies and some solid tumors such as androgen-independent prostate and 
ovarian cancer. Although generally well-tolerated, bortezomib still generates 
toxicity which underscores the need for less toxic proteasome inhibitors. 
Several naturally occurring products, such as green tea polyphenols and the 
antibiotic lactacystin, have been shown to be potent proteasome inhibitors. 
Significantly, green tea polyphenols, as well as several flavonoids such as 
genistein, curcumin and resveratrol, have also been shown to have 
chemo-sensitizing properties in prostate, breast, hepatic, and lung tumors. 
Further studies on natural proteasome inhibitors as chemo-sensitizers could lead 
to identification of more potent and less toxic compounds that could be used in 
combination therapies for drug-resistant tumors.