Proteasome inhibitors (INN stem –zomib)[1] are drugs that block the action of proteasomes, cellular complexes that break down proteins. They are being studied in the treatment of cancer; three are approved for use in treating multiple myeloma.
Multiple mechanisms are likely to be involved, but proteasome inhibition may prevent degradation of pro-apoptotic factors such as the p53 protein, permitting activation of programmed cell death in neoplastic cells dependent upon suppression of pro-apoptotic pathways. For example, bortezomib causes a rapid and dramatic change in the levels of intracellular peptides.[2]
The first non-peptidic proteasome inhibitor discovered was the natural product lactacystin.[3]
PI31 acts as a 20S proteasome inhibitor used for proteostasis that occurs naturally in the human body.
Bortezomib (Velcade) was approved in 2003. This was the first proteasome inhibitor approved for use in the U.S. Its boron atom binds the catalytic site of the 26S proteasome.[13]
Carfilzomib (Kyprolis) was approved by the FDA for relapsed and refractory multiple myeloma in 2012 .[14] It irreversibly binds to and inhibits the chymotrypsin-like activity of the 20S proteasome.
Ixazomib (Ninlaro) was approved by the FDA in 2015 for use in combination with lenalidomide and dexamethasone for the treatment of multiple myeloma after at least one prior therapy. It is the first orally-available proteasome inhibitor [15]
Wickström M, Danielsson K, Rickardson L, etal. (January 2007). "Pharmacological profiling of disulfiram using human tumor cell lines and human tumor cells from patients". Biochemical Pharmacology. 73 (1): 25–33. doi:10.1016/j.bcp.2006.08.016. PMID17026967.
Cvek B, Dvorak Z (August 2008). "The value of proteasome inhibition in cancer. Can the old drug, disulfiram, have a bright new future as a novel proteasome inhibitor?". Drug Discovery Today. 13 (15–16): 716–22. doi:10.1016/j.drudis.2008.05.003. PMID18579431.
Wilson JM, Fitschen PJ, Campbell B, Wilson GJ, Zanchi N, Taylor L, Wilborn C, Kalman DS, Stout JR, Hoffman JR, Ziegenfuss TN, Lopez HL, Kreider RB, Smith-Ryan AE, Antonio J (February 2013). "International Society of Sports Nutrition Position Stand: beta-hydroxy-beta-methylbutyrate (HMB)". J. Int. Soc. Sports Nutr. 10 (1): 6. doi:10.1186/1550-2783-10-6. PMC3568064. PMID23374455. Skeletal muscle proteolysis is increased in catabolic states such as fasting, immobilization, aging, and disease [77]. HMB has been shown to decrease skeletal muscle protein degradation both in vitro[72,73] and in vivo[78].... Indeed, HMB has been shown to decrease proteasome expression [72] and activity [72,78-80] during catabolic states, thus attenuating skeletal muscle protein degradation through the ubiquitin-proteasome pathway.
Luckose F, Pandey MC, Radhakrishna K (2015). "Effects of amino acid derivatives on physical, mental, and physiological activities". Crit. Rev. Food Sci. Nutr. 55 (13): 1793–1807. doi:10.1080/10408398.2012.708368. PMID24279396. S2CID22657268. HMB, a derivative of leucine, prevents muscle damage and increases muscle strength by reducing exercise-induced proteolysis in muscles and also helps in increasing lean body mass.
Wilkinson DJ, Hossain T, Hill DS, Phillips BE, Crossland H, Williams J, Loughna P, Churchward-Venne TA, Breen L, Phillips SM, Etheridge T, Rathmacher JA, Smith K, Szewczyk NJ, Atherton PJ (June 2013). "Effects of leucine and its metabolite β-hydroxy-β-methylbutyrate on human skeletal muscle protein metabolism". J. Physiol. 591 (11): 2911–2923. doi:10.1113/jphysiol.2013.253203. PMC3690694. PMID23551944. although orally supplied HMB produced no increase in plasma insulin, it caused a depression in MPB (−57%). Normally, postprandial decreases in MPB (of ~50%) are attributed to the nitrogen-sparing effects of insulin since clamping insulin at post-absorptive concentrations (5 μU ml−1) while continuously infusing AAs (18 g h−1) did not suppress MPB (Greenhaff et al. 2008), which is why we chose not to measure MPB in the Leu group, due to an anticipated hyperinsulinaemia (Fig. 3C). Thus, HMB reduces MPB in a fashion similar to, but independent of, insulin. These findings are in-line with reports of the anti-catabolic effects of HMB suppressing MPB in pre-clinical models, via attenuating proteasomal-mediated proteolysis in response to LPS (Eley et al. 2008).
