Natural Proteasome Inhibitors for Battling Cancer
Pp. 272-308 (37)
Huanjie Yang, Kristin R. Landis-Piwowar, Di Chen, Vesna Milacic and Q. Ping Dou
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).
Though successful in improving clinical outcomes when Bortezomib was used in
hematological malignancies, relapse often occurs in those patients who responded
initially. Recently, several second-generation of proteasome inhibitors (including
carfilzomib, marizomib, and MLN9708) have been applied in clinics. Furthermore,
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 tumorsensitizers
to conventional radiotherapy and chemotherapy. In this eBook chapter, we
will summarize the structure 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.
Ubiqutin, proteasome, ptoteasomal chymotrypsin-like activity, cell
cycle arrest, apoptosis, proteasome inhibitor, nucleophilic suceptibility,
bortezomib, natural products, β-lactone, tea polyphenols, isoflavonoids,
triterpenes, anti-proliferation, anti-tumor, cancer prevention, cancer treatment,
clinical trials, chemosensitization, drug resistance.
Barbara Ann Karmanos Cancer Institute, and the Department of Oncology School of Medicine, Wayne State University, 540.1 HWCRC, 4100 John R. Road, Detroit, Michigan 48201, USA.