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.
Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63108, United States.
Yayoi
Y
Fukuyo
Clayton R
CR
Hunt
Nobuo
N
Horikoshi
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