Gambogic Acid Induces Apoptosis in Imatinib-Resistant Chronic Myeloid Leukemia Cells via Inducing Proteasome Inhibition and Caspase-Dependent Bcr-Abl Downregulation
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- Xianping Shi
- Authors' Affiliations: 1Protein Modification and Degradation Lab, Departments of Pathophysiology and Biochemistry, Guangzhou Medical University, Guangdong; 2Department of Hematology, The People's Hospital of Guangxi Autonomous Region, Nanning, Guangxi, China; 3Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, South Dakota; and 4The Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, Michigan
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- Xin Chen
- Authors' Affiliations: 1Protein Modification and Degradation Lab, Departments of Pathophysiology and Biochemistry, Guangzhou Medical University, Guangdong; 2Department of Hematology, The People's Hospital of Guangxi Autonomous Region, Nanning, Guangxi, China; 3Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, South Dakota; and 4The Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, Michigan
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- Xiaofen Li
- Authors' Affiliations: 1Protein Modification and Degradation Lab, Departments of Pathophysiology and Biochemistry, Guangzhou Medical University, Guangdong; 2Department of Hematology, The People's Hospital of Guangxi Autonomous Region, Nanning, Guangxi, China; 3Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, South Dakota; and 4The Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, Michigan
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- Xiaoying Lan
- Authors' Affiliations: 1Protein Modification and Degradation Lab, Departments of Pathophysiology and Biochemistry, Guangzhou Medical University, Guangdong; 2Department of Hematology, The People's Hospital of Guangxi Autonomous Region, Nanning, Guangxi, China; 3Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, South Dakota; and 4The Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, Michigan
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- Chong Zhao
- Authors' Affiliations: 1Protein Modification and Degradation Lab, Departments of Pathophysiology and Biochemistry, Guangzhou Medical University, Guangdong; 2Department of Hematology, The People's Hospital of Guangxi Autonomous Region, Nanning, Guangxi, China; 3Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, South Dakota; and 4The Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, Michigan
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- Shouting Liu
- Authors' Affiliations: 1Protein Modification and Degradation Lab, Departments of Pathophysiology and Biochemistry, Guangzhou Medical University, Guangdong; 2Department of Hematology, The People's Hospital of Guangxi Autonomous Region, Nanning, Guangxi, China; 3Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, South Dakota; and 4The Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, Michigan
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- Hongbiao Huang
- Authors' Affiliations: 1Protein Modification and Degradation Lab, Departments of Pathophysiology and Biochemistry, Guangzhou Medical University, Guangdong; 2Department of Hematology, The People's Hospital of Guangxi Autonomous Region, Nanning, Guangxi, China; 3Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, South Dakota; and 4The Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, Michigan
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- Ningning Liu
- Authors' Affiliations: 1Protein Modification and Degradation Lab, Departments of Pathophysiology and Biochemistry, Guangzhou Medical University, Guangdong; 2Department of Hematology, The People's Hospital of Guangxi Autonomous Region, Nanning, Guangxi, China; 3Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, South Dakota; and 4The Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, Michigan
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- Siyan Liao
- Authors' Affiliations: 1Protein Modification and Degradation Lab, Departments of Pathophysiology and Biochemistry, Guangzhou Medical University, Guangdong; 2Department of Hematology, The People's Hospital of Guangxi Autonomous Region, Nanning, Guangxi, China; 3Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, South Dakota; and 4The Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, Michigan
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- Wenbin Song
- Authors' Affiliations: 1Protein Modification and Degradation Lab, Departments of Pathophysiology and Biochemistry, Guangzhou Medical University, Guangdong; 2Department of Hematology, The People's Hospital of Guangxi Autonomous Region, Nanning, Guangxi, China; 3Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, South Dakota; and 4The Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, Michigan
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- Ping Zhou
- Authors' Affiliations: 1Protein Modification and Degradation Lab, Departments of Pathophysiology and Biochemistry, Guangzhou Medical University, Guangdong; 2Department of Hematology, The People's Hospital of Guangxi Autonomous Region, Nanning, Guangxi, China; 3Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, South Dakota; and 4The Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, Michigan
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- Shunqing Wang
- Authors' Affiliations: 1Protein Modification and Degradation Lab, Departments of Pathophysiology and Biochemistry, Guangzhou Medical University, Guangdong; 2Department of Hematology, The People's Hospital of Guangxi Autonomous Region, Nanning, Guangxi, China; 3Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, South Dakota; and 4The Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, Michigan
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- Li Xu
- Authors' Affiliations: 1Protein Modification and Degradation Lab, Departments of Pathophysiology and Biochemistry, Guangzhou Medical University, Guangdong; 2Department of Hematology, The People's Hospital of Guangxi Autonomous Region, Nanning, Guangxi, China; 3Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, South Dakota; and 4The Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, Michigan
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- Xuejun Wang
- Authors' Affiliations: 1Protein Modification and Degradation Lab, Departments of Pathophysiology and Biochemistry, Guangzhou Medical University, Guangdong; 2Department of Hematology, The People's Hospital of Guangxi Autonomous Region, Nanning, Guangxi, China; 3Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, South Dakota; and 4The Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, Michigan
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- Q. Ping Dou
- Authors' Affiliations: 1Protein Modification and Degradation Lab, Departments of Pathophysiology and Biochemistry, Guangzhou Medical University, Guangdong; 2Department of Hematology, The People's Hospital of Guangxi Autonomous Region, Nanning, Guangxi, China; 3Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, South Dakota; and 4The Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, Michigan
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- Jinbao Liu
- Authors' Affiliations: 1Protein Modification and Degradation Lab, Departments of Pathophysiology and Biochemistry, Guangzhou Medical University, Guangdong; 2Department of Hematology, The People's Hospital of Guangxi Autonomous Region, Nanning, Guangxi, China; 3Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, South Dakota; and 4The Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, Michigan
抄録
<jats:title>Abstract</jats:title><jats:p>Purpose: Chronic myelogenous leukemia (CML) is characterized by the constitutive activation of Bcr-Abl tyrosine kinase. Bcr-Abl-T315I is the predominant mutation that causes resistance to imatinib, cytotoxic drugs, and the second-generation tyrosine kinase inhibitors. The emergence of imatinib resistance in patients with CML leads to searching for novel approaches to the treatment of CML. Gambogic acid, a small molecule derived from Chinese herb gamboges, has been approved for phase II clinical trial for cancer therapy by the Chinese Food and Drug Administration (FDA). In this study, we investigated the effect of gambogic acid on cell survival or apoptosis in CML cells bearing Bcr-Abl-T315I or wild-type Bcr-Abl.</jats:p><jats:p>Experimental Design: CML cell lines (KBM5, KBM5-T315I, and K562), primary cells from patients with CML with clinical resistance to imatinib, and normal monocytes from healthy volunteers were treated with gambogic acid, imatinib, or their combination, followed by measuring the effects on cell growth, apoptosis, and signal pathways. The in vivo antitumor activity of gambogic acid and its combination with imatinib was also assessed with nude xenografts.</jats:p><jats:p>Results: Gambogic acid induced apoptosis and cell proliferation inhibition in CML cells and inhibited the growth of imatinib-resistant Bcr-Abl-T315I xenografts in nude mice. Our data suggest that GA-induced proteasome inhibition is required for caspase activation in both imatinib-resistant and -sensitive CML cells, and caspase activation is required for gambogic acid–induced Bcr-Abl downregulation and apoptotic cell death.</jats:p><jats:p>Conclusions: These findings suggest an alternative strategy to overcome imatinib resistance by enhancing Bcr-Abl downregulation with the medicinal compound gambogic acid, which may have great clinical significance in imatinib-resistant cancer therapy. Clin Cancer Res; 20(1); 151–63. ©2013 AACR.</jats:p>
収録刊行物
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- Clinical Cancer Research
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Clinical Cancer Research 20 (1), 151-163, 2014-01-01
American Association for Cancer Research (AACR)