title: The therapeutic potential of microbial proteasome inhibitors.
abstract: The proteasome influences cellular homeostasis through the degradation of regulatory proteins, many of which are also involved in disease pathogenesis. In particular, numerous regulatory proteins associated with tumor growth, such as cyclins, cyclin-dependent kinase inhibitors, tumor suppressors, and NF-κB inhibitors are degraded by the proteasome. Proteasome inhibitors can stabilize these regulatory proteins, resulting in the suppression of tumor development and the regulation of immune responses. Thus, proteasome inhibitors are promising candidate antitumor agents and immune-regulatory agents. Bortezomib is the first-in-class proteasome inhibitor approved for the treatment of multiple myeloma. Despite its high efficiency, however, a large proportion of patients do not attain sufficient clinical response due to toxicity and drug resistance. Therefore, the development of new proteasome inhibitors with improved pharmacological properties is needed. Natural products produced by microorganisms are a promising source of such compounds. This review provides an overview of proteasome inhibitors produced by microorganisms, with special focus on inhibitors isolated from actinomycetes.
authors.affiliation: Institute of Microbial Chemistry (BIKAKEN), Numazu, 18-24 Miyamoto, Numazu-shi, Shizuoka 410-0301, Japan. Electronic address: imomose@bikaken.or.jp.
authors.forename: Isao
authors.initials: I
authors.lastname: Momose
authors.affiliation: Institute of Microbial Chemistry (BIKAKEN), Numazu, 18-24 Miyamoto, Numazu-shi, Shizuoka 410-0301, Japan; Institute of Microbial Chemistry (BIKAKEN), Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Kawada
mesh_terms: D039903:Actinobacteria / Q000737:chemistry* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001688:Biological Products / Q000494:pharmacology / Q000627:therapeutic use*; D000069286:Bortezomib / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D042521:Burkholderiaceae / Q000737:chemistry / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use*; D058990:Molecular Targeted Therapy / Q000379:methods; D009101:Multiple Myeloma / Q000188:drug therapy*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D013098:Xylariales / Q000737:chemistry / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001688:Biological Products; D007155:Immunologic Factors; D061988:Proteasome Inhibitors; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex
keywords: Actinomycetes; Natural products; Proteasome inhibitors