title: The combination of proteasome inhibitors bortezomib and gambogic acid triggers synergistic cytotoxicity in vitro but not in vivo.
abstract: The proteasome inhibitor-based combinational therapy has been reported to be an efficient cancer treatment. Our recent studies demonstrated that the natural compound gambogic acid (GA) is a tissue-specific proteasome inhibitor, comparable to bortezomib (Bor), and sensitizes malignant cells to the proteasome inhibitor MG132/MG262 both in vitro and in vivo. The aim of this study was to further extend our investigation by combining GA with the clinically used proteasome inhibitor Bor to test their combined efficacy against human hepatoma HepG2 and mouse hepatoma H22 cells. GA and Bor synergistically induced cytotoxicity and cell death in human HepG2 and mouse H22 cells, and accelerated proteasome inhibition, endoplasmic reticulum (ER) stress and caspase activation in HepG2 cancer cells. However, unexpectedly, GA did not enhance or even antagonized Bor-induced tumor growth inhibition in H22 allograft and HepG2 xenograft tumor models. These findings demonstrated that GA increased Bor activity in vitro but limited the efficacy of Bor in vivo. We suggest that the combination of GA and Bor be avoided when administering these drugs to patients.
authors.affiliation: Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangzhou 510182, Guangdong, People's Republic of China; Guangzhou Research Institute of Cardiovascular Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, Guangdong, People's Republic of China.
authors.forename: Ningning
authors.initials: N
authors.lastname: Liu
authors.affiliation: Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangzhou 510182, Guangdong, People's Republic of China.
authors.forename: Hongbiao
authors.initials: H
authors.lastname: Huang
authors.affiliation: Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangzhou 510182, Guangdong, People's Republic of China; Department of Hematology, The People's Hospital of GuangXi Autonomous Region, Nanning 530021, Guangxi, People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Xu
authors.affiliation: Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangzhou 510182, Guangdong, People's Republic of China.
authors.forename: Xianliang
authors.initials: X
authors.lastname: Hua
authors.affiliation: Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangzhou 510182, Guangdong, People's Republic of China.
authors.forename: Xiaofen
authors.initials: X
authors.lastname: Li
authors.affiliation: Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangzhou 510182, Guangdong, People's Republic of China.
authors.forename: Shouting
authors.initials: S
authors.lastname: Liu
authors.affiliation: Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangzhou 510182, Guangdong, People's Republic of China.
authors.forename: Changshan
authors.initials: C
authors.lastname: Yang
authors.affiliation: Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangzhou 510182, Guangdong, People's Republic of China.
authors.forename: Canguo
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangzhou 510182, Guangdong, People's Republic of China.
authors.forename: Chong
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangzhou 510182, Guangdong, People's Republic of China; Guangzhou Key Lab of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, Guangdong, People's Republic of China.
authors.forename: Shujue
authors.initials: S
authors.lastname: Li
authors.affiliation: Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangzhou 510182, Guangdong, People's Republic of China; The Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, MI 48201-2013, USA.
authors.forename: Q Ping
authors.initials: QP
authors.lastname: Dou
authors.affiliation: Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangzhou 510182, Guangdong, People's Republic of China. Electronic address: jliu@gzhmc.edu.cn.
authors.forename: Jinbao
authors.initials: J
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects*; D011719:Pyrazines / Q000494:pharmacology*; D044004:Xanthones / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D044004:Xanthones; D000069286:Bortezomib; C052659:gambogic acid; D020169:Caspases; D046988:Proteasome Endopeptidase Complex
keywords: Apoptosis; Bortezomib; Gambogic acid; Hepatocarcinoma