Synergistic Antipancreatic Tumor Effect by Simultaneously Targeting Hypoxic Cancer Cells With HSP90 Inhibitor and Glycolysis Inhibitor (original) (raw)

2008, Clinical Cancer Research

We sought to examine the synergistic antipancreatic cancer effect by simultaneously targeting hypoxic cancer cells with heat-shock protein 90 (HSP90) inhibitor and blockade of energy production. Experimental Design: The anticancer effects of an HSP90 inhibitor (geldanamycin) in pancreatic cells were investigated in hypoxia and normoxia. A hexokinase II inhibitor, 3-broma-pyruvate (3BrPA), was evaluated for selective glycolysis inhibition in hypoxia as a sensitizer of HSP90 inhibitor against pancreatic cancer. The HSP90 client protein degradation was monitored by Western blot. The synergistic antitumor effect of geldanamycin and 3BrPA was evaluated in a xenograft pancreatic cancer model and monitored by a noninvasive dynamic contrast-enhanced magnetic resonance imaging. Results: Hypoxia enhanced HIF-1aexpression by 11-fold in pancreatic cancer cells, and HSP90 inhibitor exhibited a seven-to eightfold higher anticancer effect in hypoxia compared with normoxia via HSP90 client protein degradation. 3BrPA selectively inhibited glycolysis and sensitized geldanamycin against pancreatic cancer cells by 17-to 400-fold through HSP90 client protein degradation. The synergistic anticancer effect of reduced doses of geldanamycin and 3-BrPA was confirmed in xenograft models in vivo by more than 75% tumor growth inhibition. Conclusions:The combination of HSP90 inhibitors and glycolysis inhibitors provides preferential inhibition of cancer cells in hypoxia through HSP90 client protein degradation and selective glycolysis inhibition. This may provide a new therapeutic regimen to battle chemotherapyresistant pancreatic cancers, by enhancing the synergistic therapeutic efficacy and reducing dose-limiting toxicity. Pancreatic cancer is the fourth leading cause of cancer death in the United States (1). The high mortality rate is mostly due to the high rate of metastasis and severe resistance to both chemotherapy and radiation. Recently, the combination of gemcitabine and monoclonal antibody against VEGF, EGFR, and Her-2 has been evaluated in several clinical trials in pancreatic cancers (2-4). However, the response and survival rates of treated patients have remained at low levels. A number of biochemical and genetic abnormalities contribute to this low response rate of target-specific therapeutic strategies. First, mutations in both oncogenes (such as K-Ras) and tumor-suppressor genes (such as P53) have been identified in pancreatic cancers. Second, overexpression of growth factors (such as VEGF) and growth factor receptors (such as EGFR), have also been linked to the metastasis and disease progression (5). In addition, the hypoxic microenvironment, induced by hypovascular system in pancreatic tumors, further exacerbates the high rate of metastasis and drug resistance in pancreatic cancer therapy (6). Due to the complexity of pancreatic cancer, a single drug targeting a particular oncogene is unlikely to be entirely effective for pancreatic cancer therapy. The ansamycin antibiotic geldanamycin provides new therapeutic schemes for pancreatic cancer by inhibiting the molecular chaperone function of heatshock protein 90 (HSP90), which can downregulate multiple oncogenic proteins simultaneously via proteasomal degradation (7). Most of those proteins, such as hypoxia-inducible factor 1-a (HIF-1a), AKT, K-Ras, v-Src, Raf-1, Bcr-Abl, ErbB2, mutant P53, and EGFR (8), are involved in the regulatory pathways of pancreatic tumor development progress. Thus, HSP90 inhibitors might be able to provide more favorable strategies for pancreatic tumor therapy through simultaneously downregulated multiple targets, especially under hypoxia. Geldanamycin and 17-AAG have been shown to have antitumor activity against breast cell culture and xenograft animal models. Geldanamycin derivative 17-(allylamino)-17demethoxygeldanamycin (17-AAG) and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) was