Future Oncol. 2005 Apr;1(2):273-81
Heat shock protein 90 inhibitors in cancer therapy: 17AAG and
beyond.
Georgakis GV, Younes A.
The University of Texas, Department of Lymphoma and Myeloma,
MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX
77030, USA.
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. |
