Targeting the ubiquitin-proteasome system for cancer treatment: discovering novel inhibitors from nature and drug repurposing

Abstract

In the past fifteen years, the proteasome has been validated as an anticancer drug target and 20S proteasome inhibitors (such as bortezomib and carfilzomib) have been approved by the FDA for the treatment of multiple myeloma and some other liquid tumors. However, there are shortcomings of clinical proteasome inhibitors, including severe toxicity, drug resistance and no effect in solid tumors. At the same time, extensive research has been conducted in the areas of natural compounds and old drug repositioning toward the goal of discovering effective, economical, low toxicity proteasome-inhibitory anticancer drugs. A variety of dietary polyphenols, medicinal molecules, metallic complexes and metal-binding compounds have been found to be able to selectively inhibit tumor cellular proteasomes and induce apoptotic cell death in vitro and in vivo, supporting the clinical success of specific 20S proteasome inhibitors bortezomib and carfilzomib. Therefore, the discovery of natural proteasome inhibitors and researching old drugs with proteasome inhibitory properties may provide an alternative strategy for improving the current status of cancer treatment and even prevention.

Proteasome and Autophagy Pathway in Corneal Epithelial Cells with Limbal Stem Cell Deficiency

“…The reaction was stopped by adding 100 µM monochloroacetate and 30mM sodium acetate pH=4. that proteasome subunit beta [5] levels were significantly decreased in LSCD-CEC, when compared to healthy control CEC, indicating a decreased proteasome activity in the ocular surface. However, autophagy's proteins microtubule-associated protein 1 light chain 3 B (MA-PLC3B) ( Figure 1B) and ATG12-ATG5 complex ( Figure 1C) expressions were found elevated in LSCD-diseased CEC, when compared to control CEC, suggesting an activation of autophagy in the ocular surface with LSCD.…”

“…Briefly, cells were grown in co-culture with mouse acterized as the "Kiss of Death" because protein substrates are tagged with ubiquitin by the ubiquitination system prior to translocation inside the proteasome catalytic chamber for degradation by beta subunits [4]. Since then, there was an explosion of publications investigating the cellular function of proteasome, and, consequently proteasome inhibitors came to the market to treat cancer and suppress tumor formation [5]. Velcade, or Bortezomib/PS341, was the first therapeutic proteasome inhibitor to be tested in humans for its activity towards hematologic malignancies.…”

RING finger protein 38 induces gastric cancer cell growth by decreasing the stability of the protein tyrosine phosphatase SHP‐1

“…The ubiquitin-proteasome system (UPS) is an important signaling for regulating the degradation or function of intracellular proteins in many diseases, including tumors [18,19]. The UPS is ATP-dependent and three classes of enzymes are required for mediating protein ubiquitination, including ubiquitin-activating enzyme E1, ubiquitinconjugating enzyme E2 and ubiquitin ligase E3 [20][21][22].…”

Overview of Targeted Drugs for Mature B-Cell Non-hodgkin Lymphomas

“…The ubiquitin-proteasome pathway is a multifaceted complex responsible for the regulation of proteins involved in neoplastic activity, such as cyclin-dependent kinases (CDK), BCL-2, and NFκB complex (162,163). The role of the proteasome is upregulation of these key pathways, making it a promising antineoplastic target (10,(164)(165)(166)(167)(168). Finding that PIs lead to cell cycle inhibition and apoptosis in tumor cells has pushed them to be developed as antineoplastic agents.…”

“…It is thought that the constellation of proteins whose degradation is inhibited by PI interrupts intracellular processes crucial for the survival of tumor cells. Some examples are (1) cell cycle interruption by inhibiting the degradation of CDK such as p21 and p27; (2) inhibition of the nuclear signal transduction pathway of the κB factor (which typically inhibits apoptosis) through the accumulation of the I-κB inhibitory protein; and (3) promoting apoptosis prolonging the function of the pro-apoptotic members of the Bcl-2 proteins, such as Noxa (10,(164)(165)(166)(167)(168).…”