A novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex against pancreatic cancer cells

Abstract

Pancreatic cancer is an aggressive disease with multiple biochemical and genetic alterations. Thus, a single agent to hit one molecular target may not be sufficient to treat this disease. The purpose of this study is to identify a novel Hsp90 inhibitor to disrupt protein-protein interactions of Hsp90 and its cochaperones for down-regulating many oncogenes simultaneously against pancreatic cancer cells. Here, we reported that celastrol disrupted Hsp90-Cdc37 interaction in the superchaperone complex to exhibit antitumor activity in vitro and in vivo. Molecular docking and molecular dynamic simulations showed that celastrol blocked the critical interaction of Glu 33 (Hsp90) and Arg 167 (Cdc37). Immunoprecipitation confirmed that celastrol (10 Mmol/L) disrupted the Hsp90-Cdc37 interaction in the pancreatic cancer cell line Panc-1. In contrast to classic Hsp90 inhibitor (geldanamycin), celastrol (0.1-100 Mmol/L) did not interfere with ATP binding to Hsp90. However, celastrol (1-5 Mmol/L) induced Hsp90 client protein degradation (Cdk4 and Akt) by 70% to 80% and increased Hsp70 expression by 12-fold. Celastrol induced apoptosis in vitro and significantly inhibited tumor growth in Panc-1 xenografts. Moreover, celastrol (3 mg/kg) effectively suppressed tumor metastasis by more than 80% in RIP1-Tag2 transgenic mouse model with pancreatic islet cell carcinogenesis. The data suggest that celastrol is a novel Hsp90 inhibitor to disrupt Hsp90-Cdc37 interaction against pancreatic cancer cells.

Targeting the oncogene and kinome chaperone CDC37

“…Future strategies for Cdc37 drug design and selection would likely aim at the inhibition of either: (1) the Cdc37-client interaction or (2) Cdc37-Hsp90 association (Fig 1). Indeed recent studies using the triterpine drug celastrol indicate cancer cell growth reduction through mechanism (2) the inhibition of Hsp90-Cdc37 interaction 39 . These natural plant products cause pleiotropic changes in cancer cells and can lead to tumor regression 39 .…”

“…Indeed recent studies using the triterpine drug celastrol indicate cancer cell growth reduction through mechanism (2) the inhibition of Hsp90-Cdc37 interaction 39 . These natural plant products cause pleiotropic changes in cancer cells and can lead to tumor regression 39 . However, the cellular responses to celastrol resemble those provoked by Hsp90 inhibitors, and include client protein destruction and HSF1 activation and may not provide a radical departure from current treatments.…”

ATF2 contributes to cisplatin resistance in non‐small cell lung cancer and celastrol induces cisplatin resensitization through inhibition of JNK/ATF2 pathway

“…13 In several cancer models, both in vitro and in vivo, Celastrol showed promising anticancer activity. It induces apoptosis in different cancer cells [14][15][16][17][18][19] and inhibits the growth of glioma, melanoma and prostate cancer in nude mice. 15,20,21 In addition, it synergistically enhances the cytotoxicity of ionizing radiation, gambogic acid, TRAIL/APO-2L and temozolomide.…”

“…Celastrol affects several biological processes through the inhibition of ATF2, nuclear factor-KB, inducible NOS, VEGF receptors, HSP90, potassium/calcium channel and eventually increases the reactive oxygen species (ROS) in cancer cells, thus in turn activating apoptosis pathways. 16,22,[25][26][27][28][29] In the present study, we investigated whether ATF2 could contribute to primary and/or acquired drug resistance in NSCLC. We demonstrated that high expression levels of ATF2, at transcript and protein levels, are detected in NSCLC and ATF2 protein activation correlates with worse outcome in advanced NSCLC patients cisplatin-treated.…”

Molecular Chaperones and Co-chaperones as Therapeutic Targets for Cancer

“…More soluble and less toxic compounds like 17-AAG, KOS-953, have shown promise in cancer treatment [21]. Celastrol interferes with Hsp90/Cdc37 complex inhibiting growthregulating pathway and is considered a promising candidate for prostate cancer treatment [22]. Drug 'gedunin' binds to P23 and restores the apoptotic pathways of malignant cells [23].…”