Magnetic Resonance Spectroscopic Pharmacodynamic Markers of the Heat Shock Protein 90 Inhibitor 17-Allylamino,17-Demethoxygeldanamycin (17AAG) in Human Colon Cancer Models

Abstract

Inhibition of Hsp90 by 17AAG resulted in altered phospholipid metabolism in cultured tumor cells and in tumor xenografts. The increases observed in phosphocholine and phosphomonoester levels suggest that these metabolites may have the potential to act as noninvasive pharmacodynamic markers for analyzing tumor response to treatment with 17AAG or other Hsp90 inhibitors.

Metabolic assessment of the action of targeted cancer therapeutics using magnetic resonance spectroscopy

“…As expected, inhibition of HIF-1a with PX-478 led to a trend of decreased glucose uptake and lactate production in HT-29 tumour xenografts (Jordan et al, 2005). Furthermore, inhibition of HSP90 with 17-AAG in HT-29 xenografts resulted in a moderate drop in NTPs (Chung et al, 2003), and blockade of HDAC in the same model with LAQ824 resulted in dramatic decreases in PCr, NTP and glucose levels and increased Pi. However, the effects reported, at least in the case of LAQ824, were likely to result from the induced anti-angiogenic effects and the accompanying increase in tumour necrosis .…”

Expression of heat-shock protein-90 in non-Hodgkin's lymphomas

“…[8][9][10][11][12][13][14][15][16][17][18][19][20] Increasing evidence has shown that specific inhibition of HSP90 in neoplastic cells can lead to cell cycle arrest and apoptosis. [8][9][10][11][12][13][14][15][16][17][18][19][20] No previous study, however, has systematically surveyed HSP90 expression in a variety of NHL types as defined in the WHO classification. Thus, the aim of this study was to assess for HSP90 expression in various types of B-and T-NHL, in light of the potential utility of HSP90 inhibitors in the treatment of patients with NHL.…”

“…14 Recently, in vitro studies have shown that treatment of solid tumors and hematological malignancies with a naturally occurring antibiotic, geldanamycin, and its derivative, 17-AAG, inhibits HSP90 activity through blocking ATP-binding sites of the HSP90-partner complex, with subsequent proteosomal degradation and/or dephosphorylation of client proteins. [10][11][12][13][14][15][16][17][18][19][20] These HSP inhibitors act mainly by occupying the binding site for the client protein within the HSP90-multichaperone complex and, by blocking this step, these derivatives enhance protein destabilization with subsequent shortening of protein half-life and eventual proteosomal degradation. 9 Based on the promising results of preclinical studies, [10][11][12][13][14][15][16][17][18][19][20] several phase I clinical trials with 17-AAG have been initiated in the United States and United Kingdom for patients with hematological malignancies, and solid tumors including breast, prostate and kidney cancers.…”

“…9 Via the N-terminal domain, HSP90 serves as a molecular chaperone for many client proteins that are involved in oncogenesis, for example, NF-kappa B, BCR-ABL, NPM-ALK, AKT and mutated p53. [8][9][10][11][12][13][14][15][16][17][18][19][20] As these client proteins are involved in a number of pathways that are critical to the survival of neoplastic cells, HSP90 is an attractive target for inhibition because many pathways can be blocked simultaneously. It therefore follows that HSP90 inhibitors could be active against many tumor types.…”

Changes in choline metabolism as potential biomarkers of phospholipase Cγ1 inhibition in human prostate cancer cells

“…On the other hand, treatment with heat shock protein 90 or histone deacetylase inhibitors in human colon and prostate carcinoma cells lead, interestingly, to an increase in the phosphocholine and phosphomonoester signal (43)(44)(45).…”