Gambogic acid induces apoptosis in imatinib-resistant chronic myeloid leukemia cells via inducing proteasome inhibition and caspase-dependent bcr-abl downregulation AC

Xianping Shi, Xin Chen, Xiaofen Li, Xiaoying Lan, Chong Zhao, Shouting Liu, Hongbiao Huang, Ningning Liu, Siyan Liao, Wenbin Song, Ping Zhou, Shunqing Wang, Li Xu, Xuejun Wang, Q. Ping Dou, Jinbao Liu

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Abstract

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. 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. 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. 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.

Original languageEnglish (US)
Pages (from-to)151-163
Number of pages13
JournalClinical Cancer Research
Volume20
Issue number1
DOIs
StatePublished - Jan 1 2014

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Myeloid Cells
Proteasome Endopeptidase Complex
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Caspases
Down-Regulation
Apoptosis
Heterografts
bcr-abl Fusion Proteins
Imatinib Mesylate
gambogic acid
Neoplasms
Phase II Clinical Trials
K562 Cells
United States Food and Drug Administration
Growth
Nude Mice
Protein-Tyrosine Kinases
Monocytes
Signal Transduction
Cell Survival

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Gambogic acid induces apoptosis in imatinib-resistant chronic myeloid leukemia cells via inducing proteasome inhibition and caspase-dependent bcr-abl downregulation AC. / Shi, Xianping; Chen, Xin; Li, Xiaofen; Lan, Xiaoying; Zhao, Chong; Liu, Shouting; Huang, Hongbiao; Liu, Ningning; Liao, Siyan; Song, Wenbin; Zhou, Ping; Wang, Shunqing; Xu, Li; Wang, Xuejun; Dou, Q. Ping; Liu, Jinbao.

In: Clinical Cancer Research, Vol. 20, No. 1, 01.01.2014, p. 151-163.

Research output: Contribution to journalArticle

Shi, X, Chen, X, Li, X, Lan, X, Zhao, C, Liu, S, Huang, H, Liu, N, Liao, S, Song, W, Zhou, P, Wang, S, Xu, L, Wang, X, Dou, QP & Liu, J 2014, 'Gambogic acid induces apoptosis in imatinib-resistant chronic myeloid leukemia cells via inducing proteasome inhibition and caspase-dependent bcr-abl downregulation AC', Clinical Cancer Research, vol. 20, no. 1, pp. 151-163. https://doi.org/10.1158/1078-0432.CCR-13-1063
Shi, Xianping ; Chen, Xin ; Li, Xiaofen ; Lan, Xiaoying ; Zhao, Chong ; Liu, Shouting ; Huang, Hongbiao ; Liu, Ningning ; Liao, Siyan ; Song, Wenbin ; Zhou, Ping ; Wang, Shunqing ; Xu, Li ; Wang, Xuejun ; Dou, Q. Ping ; Liu, Jinbao. / Gambogic acid induces apoptosis in imatinib-resistant chronic myeloid leukemia cells via inducing proteasome inhibition and caspase-dependent bcr-abl downregulation AC. In: Clinical Cancer Research. 2014 ; Vol. 20, No. 1. pp. 151-163.
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T1 - Gambogic acid induces apoptosis in imatinib-resistant chronic myeloid leukemia cells via inducing proteasome inhibition and caspase-dependent bcr-abl downregulation AC

AU - Shi, Xianping

AU - Chen, Xin

AU - Li, Xiaofen

AU - Lan, Xiaoying

AU - Zhao, Chong

AU - Liu, Shouting

AU - Huang, Hongbiao

AU - Liu, Ningning

AU - Liao, Siyan

AU - Song, Wenbin

AU - Zhou, Ping

AU - Wang, Shunqing

AU - Xu, Li

AU - Wang, Xuejun

AU - Dou, Q. Ping

AU - Liu, Jinbao

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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. 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. 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. 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.

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