Heat Shock Protein 90 - A Potential Target in the Treatment of Human Acute Myelogenous Leukemia
Pp. 3-53 (51)
H. Reikvam, R.B. Forthun, A. Brenner, E. Ersvær, K.J. Hatfield and Ø. Bruserud
Heat shock proteins (HSPs) are molecular chaperones that stabilize folding
and conformation of normal as well as oncogenic proteins. These chaperones thereby
prevent the formation of protein aggregates. HSPs are often overexpressed in human
malignancies, including AML. HSP90 is the main chaperon required for the
stabilization of multiple oncogenic kinases involved in the development of acute
myelogenous leukemia (AML). HSP90 client proteins are involved in the regulation of
apoptosis, proliferation, autophagy and cell cycle progression; several of these proteins
are in addition considered as possible therapeutic targets for the treatment of AML.
HSP90 inhibition thereby offers the possibility to modulate several of the intracellular
regulatory pathways through targeting of a single molecule. Several inhibitors of HSP90
have been developed, and they are classified into four groups: geldanamycin
derivatives, radicicol derivates, synthetic inhibitors and a final group of others. The
HSP90 activity is in addition regulated by posttranscriptional modulation; HSP90
inhibition can thereby be indirectly achieved through increased acetylation caused by
histone deacetylase inhibitors. Many of these agents have entered clinical trials, and the
results from these initial studies have documented that HSP90 inhibition can mediate
antileukemic effects in vivo. However, one would expect immunosuppressive side
effects because HSP90 inhibitors have both direct and indirect inhibitory effects on T
cell activation. Thus, future clinical studies are needed to clarify the efficiency and
toxicity of HSP90 inhibitors in the treatment of human AML, including studies where
HSP90 inhibitors are combined with conventional chemotherapy.
Acute myelogenous leukemia, apoptosis, chaperone, client proteins,
heat shock protein, heat shock protein 90 inhibitors.
Medical Department, Haukeland University Hospital, N-5021 Bergen, Norway.