Blocking heat shock protein-90 inhibits the invasive properties and hepatic growth of human colon cancer cells and improves the efficacy of oxaliplatin in p53-deficient colon cancer tumors in vivo

Abstract

We recently showed that inhibition of heat shock protein 90 (Hsp90) decreases tumor growth and angiogenesis in gastric cancer through interference with oncogenic signaling pathways. However, controversy still exists about the antimetastatic potential of Hsp90 inhibitors. Moreover, in vitro studies suggested that blocking Hsp90 could overcome p53-mediated resistance of cancer cells to oxaliplatin. We therefore hypothesized that blocking oncogenic signaling with a Hsp90 inhibitor would impair metastatic behavior of colon cancer cells and also improve the efficacy of oxaliplatin in vivo. Human colon cancer cells (HCT116, HT29, and SW620) and the Hsp90 inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG) were used for experiments. In vitro, 17-DMAG substantially inhibited phosphorylation of epidermal growth factor receptor, c-Met, and focal adhesion kinase, overall resulting in a significant decrease in cancer cell invasiveness. Importantly, 17-DMAG led to an up-regulation of the transcription factor activating transcription factor-3, a tumor suppressor and antimetastatic factor, on mRNA and protein levels. In a cell death ELISA, 17-DMAG markedly induced apoptosis in both p53-wt and p53-deficient cells. In vivo, 17-DMAG significantly reduced tumor growth and vascularization. Furthermore, blocking Hsp90 reduced hepatic tumor burden and metastatic nodules in an experimental model of hepatic colon cancer growth. Importantly, combining oxaliplatin with 17-DMAG in vivo significantly improved growth inhibitory and proapoptotic effects on p53-deficient cells, compared with either substance alone. In conclusion, inhibition of Hsp90 abrogates the invasive properties of colon cancer cells and modulates the expression of the antimetastatic factor activating transcription factor-3. Hence, targeting Hsp90 could prove valuable for treatment of advanced colorectal cancer by effectively inhibiting colon cancer growth and hepatic metastasis and improving the efficacy of oxaliplatin.

89Zr-Bevacizumab PET of Early Antiangiogenic Tumor Response to Treatment with HSP90 Inhibitor NVP-AUY922

“…These results are comparable to the effects seen with other HSP90 inhibitors. Treatment with 17-AAG and 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG, or alvespimycin), a water-soluble geldanamycin analog, decreased MVD in gastric, colon, and hepatocellular carcinoma xenograft models (7,11,22,23). Additionally, 17-DMAG downregulated VEGF-R2 protein expression on endothelial cells, inhibited VEGF-A-induced Erk and Akt activation, and downregulated total Akt expression (24).…”

Impact of butyrate on PKM2 and HSP90β expression in human colon tissues of different transformation stages: a comparison of gene and protein data

“…Stabilization of these client proteins that are often overexpressed in tumors prevents their degradation by the proteasome and consequently contributes to tumor development and cell survival (Brown et al 2007). Blocking of HSP90 was shown to result in reduced invasiveness in vitro and in decreased tumor cell proliferation, vascularization as well as an improved efficacy of conventional therapy strategies in vivo (Moser et al 2007). Further, HSP90 expressed by cancer cells protects against apoptosis (Rashmi et al 2003), down-regulates tumorsuppressing signals such as TP53 (Lin et al 2008) and enables replicative immortality through enhanced telomerase assembly (Akalin et al 2001).…”

Crystal structure of monoaqua(tetraammine)oxalatodiplatinum(II) dinitrate, [Pt2(H2O)(C2O4)(NH3)4][NO3]2

“…Since this discovery, other platinum compounds such as Carboplatin and Oxaliplatin have become available for the treatment of cancer [2,3]. In order to improve activity and to reduce toxicity, much attention has been focused on designing Cisplatin analogues with reduced toxicity and/or broader antitumor spectrum, leading to successful developmentof several new anticancer platinum drugs including Nedaplatin, Lobaplatin and Eptaplatin.…”