Geldanamycin and its anti-cancer activities.
Geldanamycin is a benzoquinone ansamycin antibiotic that manifests anti-cancer activity through the inhibition of HSP90-chaperone function. The HSP90 molecular chaperone is expressed at high levels in a wide variety of human cancers including melanoma, leukemia, and cancers in colon, prostate, lung, and breast. In cancer cells dependent upon mutated and/or over-expressed oncogene proteins, HSP90 is thought to have a critical role in regulating the stability, folding, and activity of HSP90-associated proteins, so-called "client proteins". These client proteins include the growth-stimulating proteins and kinases that support malignant transformation. Recently, oncogenic activating BRAF mutants have been identified in variety of cancers where constitutive activation of the MEK/ERK MAPK signaling pathway is the key for tumorigenesis, and they have been shown to be client proteins for HSP90. Accordingly, HSP90 inhibition can suppress certain cancer-causing client proteins and therefore represents an important therapeutic target. The molecular mechanism underlying the anti-cancer effect of HSP90 inhibition is complicated. Geldanamycin and its derivatives have been shown to induce the depletion of mutationally-activated BRAF through several mechanisms. In this review, we will describe the HSP90-inhibitory mechanism, focusing on recent progress in understanding HSP90 chaperone structure-function relationships, the identification of new HSP90 client proteins and the development of HSP90 inhibitors for clinical applications.
Fukuyo
Yayoi
Y
Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63108, United States.
Hunt
Clayton R
CR
Horikoshi
Nobuo
N
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016227:Benzoquinones / Q000494:pharmacology*; D018841:HSP90 Heat-Shock Proteins / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy*; D015398:Signal Transduction / Q000187:drug effects*
D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C001277:geldanamycin