2. Academic Validation
  3. Sabutoclax, pan-active BCL-2 protein family antagonist, overcomes drug resistance and eliminates cancer stem cells in breast cancer

Sabutoclax, pan-active BCL-2 protein family antagonist, overcomes drug resistance and eliminates cancer stem cells in breast cancer

  • Cancer Lett. 2018 Jun 1:423:47-59. doi: 10.1016/j.canlet.2018.02.036.
Yunhui Hu 1,  Ernesto Yagüe 2,  Jing Zhao 3,  Luyao Wang 4,  Jingchao Bai 5,  Qianxi Yang 6,  Teng Pan 7,  Hui Zhao 8,  Jingjing Liu 9,  Jin Zhang 10
Affiliations

Affiliations

  • 1 The 3rdDepartment of Breast Cancer, China Tianjin Breast Cancer Prevention, Treatment and Research Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Huan Hu Xi Road, Ti Yuan Bei, He Xi District, Tianjin, 300060, PR China. Electronic address: yunhuihu200408@163.com.
  • 2 Cancer Research Center, Division of Cancer, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK. Electronic address: ernesto.yague@imperial.ac.uk.
  • 3 Department of Lymphoma, Tianjin Medical University Cancer Hospital, Sino-uS Center for Lymphoma and Leukemia, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, PR China. Electronic address: sherry4601@126.com.
  • 4 Center for Research and Development of Anti Tumor Drugs, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin 300020, PR China. Electronic address: wangluyao_1106@163.com.
  • 5 The 3rdDepartment of Breast Cancer, China Tianjin Breast Cancer Prevention, Treatment and Research Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Huan Hu Xi Road, Ti Yuan Bei, He Xi District, Tianjin, 300060, PR China. Electronic address: baijingchao001@126.com.
  • 6 The 3rdDepartment of Breast Cancer, China Tianjin Breast Cancer Prevention, Treatment and Research Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Huan Hu Xi Road, Ti Yuan Bei, He Xi District, Tianjin, 300060, PR China. Electronic address: 1042844953@qq.com.
  • 7 The 3rdDepartment of Breast Cancer, China Tianjin Breast Cancer Prevention, Treatment and Research Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Huan Hu Xi Road, Ti Yuan Bei, He Xi District, Tianjin, 300060, PR China. Electronic address: 2570758402@qq.com.
  • 8 The 3rdDepartment of Breast Cancer, China Tianjin Breast Cancer Prevention, Treatment and Research Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Huan Hu Xi Road, Ti Yuan Bei, He Xi District, Tianjin, 300060, PR China. Electronic address: 564831828@qq.com.
  • 9 The 3rdDepartment of Breast Cancer, China Tianjin Breast Cancer Prevention, Treatment and Research Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Huan Hu Xi Road, Ti Yuan Bei, He Xi District, Tianjin, 300060, PR China. Electronic address: ljj1983yida@hotmail.com.
  • 10 The 3rdDepartment of Breast Cancer, China Tianjin Breast Cancer Prevention, Treatment and Research Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Huan Hu Xi Road, Ti Yuan Bei, He Xi District, Tianjin, 300060, PR China. Electronic address: zhangjin@tjmuch.com.
PMID: 29496539 DOI: 10.1016/j.canlet.2018.02.036
Abstract

Misregulation of Bcl-2 Family of proteins renders a survival signal to withstand cytotoxic Anticancer drugs and is often found in drug resistant cells. The drug resistance phenotype is also associated with an enhancement of Cancer stem cell-like (CSC) characteristics. Thus, inhibition of anti-apoptotic Bcl-2 Family proteins has been proposed as a possible antineoplastic strategy, and Bcl-2 inhibitors are currently being clinically trailed in patients with leukemia, lymphoma or non-small cell lung Cancer. However, the effects of Bcl-2 inhibitors on drug resistant breast Cancer have not yet been elucidated. In the present study, the effect of sabutoclax, a pan-active Bcl-2 protein family antagonist, on two chemoresistant breast Cancer cell lines was assessed. We found that sabutoclax showed a significant cytotoxic activity on chemoresistant breast Cancer cells both in vitro and in vivo. When chemotherapeutic agents were combined with sabutoclax, strong synergistic antiproliferative effects were observed. Sabutoclax induced the blockage of Bcl-2, Mcl-1, Bcl-xL and Bfl-1, which in turn led to Caspase-3/7 and caspase-9 activation and modulation of Bax, Bim, PUMA and Survivin expression. Furthermore, sabutoclax effectively eliminated the CSC subpopulation and reduced sphere formation of drug-resistant cells through down-regulation of the IL-6/STAT3 signaling pathway. A similar effect was observed in a small panel of nine breast tumors ex vivo. Our findings indicate that sabutoclax partially overcomes the drug resistance phenotype of breast Cancer cells by reactivation of Apoptosis, mediated by the inhibition of several anti-apoptotic Bcl-2 Family proteins, and eliminates CSCs by abolition of the IL-6/STAT3 pathway. This offers a strong rationale to explore the therapeutic strategy of using sabutoclax alone or in combination for chemotherapy-nonresponsive breast Cancer patients.

Keywords

BCL-2; Breast cancer; Cancer stem cells; Drug resistance; Sabutoclax.

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