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Abstract
The molecular co-chaperone CDC37 is over-expressed in hepatocellular carcinoma (HCC) cells, where it functions with HSP90 to regulate the activity of protein kinases in multiple oncogenic signaling pathways that contribute towards hepatocarcinogenesis. Disruption of these signaling pathways via inhibition of HSP90/CDC37 interaction is therefore a rational therapeutic approach. We evaluated the anti-tumor effects of celastrol, pristimerin, and two novel derivatives (cel-D2, and cel-D7) on HCC cell lines in vitro and on orthotopic HCC patient-derived xenografts in vivo. All four compounds preferentially inhibited viability of HCC cells in vitro,and significantly inhibited the growth of three orthotopic HCC patient-derived xenografts in vivo; with the novel derivatives cel-D2 and cel-D7 exhibiting lower toxicity. All four compounds also induced cell apoptosis; and promoted degradation and inhibited phosphorylation of protein kinases in the Raf/MEK/ERK and PI3K/AKT/mTOR signaling pathways. We demonstrated that HSP90/CDC37 antagonists are potentially broad spectrum agents that might be beneficial for treating the heterogeneous subtypes of HCC, either as monotherapy, or in combination with other chemotherapeutic agents.
Highlights
Hepatocellular carcinoma (HCC), the most common adult liver malignancy, is the seventh most common cancer and the second most frequent cause of cancer-related death worldwide [1]
The inhibition of heat shock protein 90 (HSP90) or CDC37 alone has shown encouraging anti-tumor effects in cell-based studies of multiple tumors, which are associated with enhanced degradation and decreased phosphorylation of oncogenic HSP90/CDC37 client protein kinases [11, 16, 17, 33]
Based on the established role of these client protein kinases in hepatocarcinogenesis, we hypothesized that the direct disruption of HSP90 interaction with CDC37 by the small molecule celastrol would achieve desirable anti-tumor effects
Summary
Hepatocellular carcinoma (HCC), the most common adult liver malignancy, is the seventh most common cancer and the second most frequent cause of cancer-related death worldwide [1]. Most of the burden (80%) of HCC is borne in the developing world, such as Eastern and Southeast Asia and sub-Saharan Africa, where the dominant risk factor is chronic infection with hepatitis B virus (HBV), together with exposure with aflatoxin B1. In developed countries, including North America, Europe, and Japan, the dominant risk factor is chronic infection with hepatitis C virus [2]. More than 50 drugs that target different biomarkers or signaling pathways are in clinical trials for HCC treatment [4], as yet there is no therapeutic agent superior to sorafenib, which was FDA approved as the standard of care for advanced HCC [5]. Due to recent emergence of resistance to sorafenib (7), second-line therapies targeting other key signaling pathways in HCC, such as the EGFR, WNT, and PI3KAKT-mTOR pathways [7], are highly desirable
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