Heat-shock protein 90 inhibitors in cancer therapy: 17AAG and beyond.
Heat-shock protein 90 (HSP90) has diverse functions in mammalian cells. It acts as molecular chaperone, together with several co-chaperone molecules (such as Hop, Hip, p23, cdc37, Aha, and immunophilins). HSP90 binds to its client proteins (such as steroid receptors, AKT, Bcr-Abl, Apaf-1, survivin, cyclin dependent kinases which are involved in signal transduction that regulate cell cycle, survival, and death, and promote their proper protein folding, assembly, and transportation across different cellular compartments. Failure of Hsp90 chaperone activity leads to misfolding of client proteins, which leads to ubiquitination and proteasome degradation, and this deregulating cellular homeostasis. Since tumor cells frequently overexpress the active form of HSP90, which is more susceptible to inhibition by small molecules such as geldanamycin and its analogs, HSP90 became an attractive target for cancer therapy. This paper will review the recent advances in HSP90-biology and will discuss the emerging role of the HSP90 inhibitors such as 17-allylamino-17 demethoxy-geldanamycin and other HSP-90-directed small molecules in cancer therapy.
The University of Texas, Department of Lymphoma and Myeloma, MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
Georgios V
GV
Georgakis
Anas
A
Younes
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D016227:Benzoquinones; D002453:Cell Cycle; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic; D018832:Molecular Chaperones; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015398:Signal Transduction
D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018832:Molecular Chaperones; D017828:Rifabutin; C112765:tanespimycin; D017346:Protein Serine-Threonine Kinases