Novel celastrol derivatives inhibit the growth of hepatocellular carcinoma patient-derived xenografts

// Wei Wei 1 , Song Wu 1,2 , Xiaolin Wang 1 , Chris Kin-Wai Sun 1 , Xiaoyang Yang 1 , Xinrui Yan 3 , Mei-Sze Chua 1 and Samuel So 1 1 Asian Liver Center, Department of Surgery, Stanford University School of Medicine, Stanford, CA 2 School of Pharmaceutical Sciences, Wuhan University, Wuhan, P. R. China 3 Department of Radiology, Molecular Imaging Program at Stanford University, Stanford, CA Correspondence: Mei-Sze Chua, email: // Keywords : celastrol derivatives, molecular chaperone, targeted therapy Received : April 25, 2014 Accepted : July 10, 2014 Published : July 10, 2014 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.