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Research ArticleOncologyTherapeutics
Open Access | 
10.1172/jci.insight.160606
1Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
2Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, and
3National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China.
4School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
5China Institute of Pharmaceutical Industry, Shanghai, China.
6Department of Chemistry and Biochemistry, College of Liberal Arts, and
7Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi, USA.
8Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, The Cancer Hospital of the University of Chinese Academy of Sciences (CAS), Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China.
Address correspondence to: Weidong Zhang or Xin Luan, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Phone: 86.021.51322428; Email: wdzhangy@hotmail.com (WZ); Phone: 86.021.51322775; Email: luanxin@shutcm.edu.cn (XL). Or to: Shuyang Sun, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. Phone: 86.021.23271699; Email: sunshuyang@sjtu.edu.cn.
Authorship note: JJ, Yaping Wu, and Z. Zhao contributed equally to this work.
Find articles by Jin, J. in: JCI | PubMed | Google Scholar
1Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
2Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, and
3National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China.
4School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
5China Institute of Pharmaceutical Industry, Shanghai, China.
6Department of Chemistry and Biochemistry, College of Liberal Arts, and
7Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi, USA.
8Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, The Cancer Hospital of the University of Chinese Academy of Sciences (CAS), Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China.
Address correspondence to: Weidong Zhang or Xin Luan, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Phone: 86.021.51322428; Email: wdzhangy@hotmail.com (WZ); Phone: 86.021.51322775; Email: luanxin@shutcm.edu.cn (XL). Or to: Shuyang Sun, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. Phone: 86.021.23271699; Email: sunshuyang@sjtu.edu.cn.
Authorship note: JJ, Yaping Wu, and Z. Zhao contributed equally to this work.
Find articles by Wu, Y. in: JCI | PubMed | Google Scholar
1Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
2Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, and
3National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China.
4School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
5China Institute of Pharmaceutical Industry, Shanghai, China.
6Department of Chemistry and Biochemistry, College of Liberal Arts, and
7Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi, USA.
8Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, The Cancer Hospital of the University of Chinese Academy of Sciences (CAS), Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China.
Address correspondence to: Weidong Zhang or Xin Luan, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Phone: 86.021.51322428; Email: wdzhangy@hotmail.com (WZ); Phone: 86.021.51322775; Email: luanxin@shutcm.edu.cn (XL). Or to: Shuyang Sun, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. Phone: 86.021.23271699; Email: sunshuyang@sjtu.edu.cn.
Authorship note: JJ, Yaping Wu, and Z. Zhao contributed equally to this work.
Find articles by Zhao, Z. in: JCI | PubMed | Google Scholar
1Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
2Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, and
3National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China.
4School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
5China Institute of Pharmaceutical Industry, Shanghai, China.
6Department of Chemistry and Biochemistry, College of Liberal Arts, and
7Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi, USA.
8Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, The Cancer Hospital of the University of Chinese Academy of Sciences (CAS), Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China.
Address correspondence to: Weidong Zhang or Xin Luan, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Phone: 86.021.51322428; Email: wdzhangy@hotmail.com (WZ); Phone: 86.021.51322775; Email: luanxin@shutcm.edu.cn (XL). Or to: Shuyang Sun, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. Phone: 86.021.23271699; Email: sunshuyang@sjtu.edu.cn.
Authorship note: JJ, Yaping Wu, and Z. Zhao contributed equally to this work.
Find articles by Wu, Y. in: JCI | PubMed | Google Scholar
1Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
2Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, and
3National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China.
4School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
5China Institute of Pharmaceutical Industry, Shanghai, China.
6Department of Chemistry and Biochemistry, College of Liberal Arts, and
7Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi, USA.
8Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, The Cancer Hospital of the University of Chinese Academy of Sciences (CAS), Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China.
Address correspondence to: Weidong Zhang or Xin Luan, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Phone: 86.021.51322428; Email: wdzhangy@hotmail.com (WZ); Phone: 86.021.51322775; Email: luanxin@shutcm.edu.cn (XL). Or to: Shuyang Sun, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. Phone: 86.021.23271699; Email: sunshuyang@sjtu.edu.cn.
Authorship note: JJ, Yaping Wu, and Z. Zhao contributed equally to this work.
Find articles by Zhou, Y. in: JCI | PubMed | Google Scholar
1Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
2Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, and
3National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China.
4School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
5China Institute of Pharmaceutical Industry, Shanghai, China.
6Department of Chemistry and Biochemistry, College of Liberal Arts, and
7Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi, USA.
8Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, The Cancer Hospital of the University of Chinese Academy of Sciences (CAS), Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China.
Address correspondence to: Weidong Zhang or Xin Luan, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Phone: 86.021.51322428; Email: wdzhangy@hotmail.com (WZ); Phone: 86.021.51322775; Email: luanxin@shutcm.edu.cn (XL). Or to: Shuyang Sun, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. Phone: 86.021.23271699; Email: sunshuyang@sjtu.edu.cn.
Authorship note: JJ, Yaping Wu, and Z. Zhao contributed equally to this work.
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1Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
2Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, and
3National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China.
4School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
5China Institute of Pharmaceutical Industry, Shanghai, China.
6Department of Chemistry and Biochemistry, College of Liberal Arts, and
7Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi, USA.
8Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, The Cancer Hospital of the University of Chinese Academy of Sciences (CAS), Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China.
Address correspondence to: Weidong Zhang or Xin Luan, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Phone: 86.021.51322428; Email: wdzhangy@hotmail.com (WZ); Phone: 86.021.51322775; Email: luanxin@shutcm.edu.cn (XL). Or to: Shuyang Sun, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. Phone: 86.021.23271699; Email: sunshuyang@sjtu.edu.cn.
Authorship note: JJ, Yaping Wu, and Z. Zhao contributed equally to this work.
Find articles by Sun, Q. in: JCI | PubMed | Google Scholar
1Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
2Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, and
3National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China.
4School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
5China Institute of Pharmaceutical Industry, Shanghai, China.
6Department of Chemistry and Biochemistry, College of Liberal Arts, and
7Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi, USA.
8Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, The Cancer Hospital of the University of Chinese Academy of Sciences (CAS), Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China.
Address correspondence to: Weidong Zhang or Xin Luan, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Phone: 86.021.51322428; Email: wdzhangy@hotmail.com (WZ); Phone: 86.021.51322775; Email: luanxin@shutcm.edu.cn (XL). Or to: Shuyang Sun, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. Phone: 86.021.23271699; Email: sunshuyang@sjtu.edu.cn.
Authorship note: JJ, Yaping Wu, and Z. Zhao contributed equally to this work.
Find articles by Yang, G. in: JCI | PubMed | Google Scholar
1Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
2Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, and
3National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China.
4School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
5China Institute of Pharmaceutical Industry, Shanghai, China.
6Department of Chemistry and Biochemistry, College of Liberal Arts, and
7Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi, USA.
8Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, The Cancer Hospital of the University of Chinese Academy of Sciences (CAS), Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China.
Address correspondence to: Weidong Zhang or Xin Luan, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Phone: 86.021.51322428; Email: wdzhangy@hotmail.com (WZ); Phone: 86.021.51322775; Email: luanxin@shutcm.edu.cn (XL). Or to: Shuyang Sun, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. Phone: 86.021.23271699; Email: sunshuyang@sjtu.edu.cn.
Authorship note: JJ, Yaping Wu, and Z. Zhao contributed equally to this work.
Find articles by Lin, J. in: JCI | PubMed | Google Scholar
1Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
2Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, and
3National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China.
4School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
5China Institute of Pharmaceutical Industry, Shanghai, China.
6Department of Chemistry and Biochemistry, College of Liberal Arts, and
7Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi, USA.
8Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, The Cancer Hospital of the University of Chinese Academy of Sciences (CAS), Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China.
Address correspondence to: Weidong Zhang or Xin Luan, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Phone: 86.021.51322428; Email: wdzhangy@hotmail.com (WZ); Phone: 86.021.51322775; Email: luanxin@shutcm.edu.cn (XL). Or to: Shuyang Sun, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. Phone: 86.021.23271699; Email: sunshuyang@sjtu.edu.cn.
Authorship note: JJ, Yaping Wu, and Z. Zhao contributed equally to this work.
Find articles by
Nagle, D.
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1Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
2Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, and
3National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China.
4School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
5China Institute of Pharmaceutical Industry, Shanghai, China.
6Department of Chemistry and Biochemistry, College of Liberal Arts, and
7Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi, USA.
8Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, The Cancer Hospital of the University of Chinese Academy of Sciences (CAS), Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China.
Address correspondence to: Weidong Zhang or Xin Luan, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Phone: 86.021.51322428; Email: wdzhangy@hotmail.com (WZ); Phone: 86.021.51322775; Email: luanxin@shutcm.edu.cn (XL). Or to: Shuyang Sun, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. Phone: 86.021.23271699; Email: sunshuyang@sjtu.edu.cn.
Authorship note: JJ, Yaping Wu, and Z. Zhao contributed equally to this work.
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Qin, J.
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1Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
2Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, and
3National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China.
4School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
5China Institute of Pharmaceutical Industry, Shanghai, China.
6Department of Chemistry and Biochemistry, College of Liberal Arts, and
7Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi, USA.
8Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, The Cancer Hospital of the University of Chinese Academy of Sciences (CAS), Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China.
Address correspondence to: Weidong Zhang or Xin Luan, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Phone: 86.021.51322428; Email: wdzhangy@hotmail.com (WZ); Phone: 86.021.51322775; Email: luanxin@shutcm.edu.cn (XL). Or to: Shuyang Sun, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. Phone: 86.021.23271699; Email: sunshuyang@sjtu.edu.cn.
Authorship note: JJ, Yaping Wu, and Z. Zhao contributed equally to this work.
Find articles by Zhang, Z. in: JCI | PubMed | Google Scholar
1Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
2Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, and
3National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China.
4School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
5China Institute of Pharmaceutical Industry, Shanghai, China.
6Department of Chemistry and Biochemistry, College of Liberal Arts, and
7Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi, USA.
8Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, The Cancer Hospital of the University of Chinese Academy of Sciences (CAS), Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China.
Address correspondence to: Weidong Zhang or Xin Luan, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Phone: 86.021.51322428; Email: wdzhangy@hotmail.com (WZ); Phone: 86.021.51322775; Email: luanxin@shutcm.edu.cn (XL). Or to: Shuyang Sun, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. Phone: 86.021.23271699; Email: sunshuyang@sjtu.edu.cn.
Authorship note: JJ, Yaping Wu, and Z. Zhao contributed equally to this work.
Find articles by Chen, H. in: JCI | PubMed | Google Scholar
1Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
2Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, and
3National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China.
4School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
5China Institute of Pharmaceutical Industry, Shanghai, China.
6Department of Chemistry and Biochemistry, College of Liberal Arts, and
7Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi, USA.
8Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, The Cancer Hospital of the University of Chinese Academy of Sciences (CAS), Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China.
Address correspondence to: Weidong Zhang or Xin Luan, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Phone: 86.021.51322428; Email: wdzhangy@hotmail.com (WZ); Phone: 86.021.51322775; Email: luanxin@shutcm.edu.cn (XL). Or to: Shuyang Sun, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. Phone: 86.021.23271699; Email: sunshuyang@sjtu.edu.cn.
Authorship note: JJ, Yaping Wu, and Z. Zhao contributed equally to this work.
Find articles by Zhang, W. in: JCI | PubMed | Google Scholar
1Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
2Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, and
3National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China.
4School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
5China Institute of Pharmaceutical Industry, Shanghai, China.
6Department of Chemistry and Biochemistry, College of Liberal Arts, and
7Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi, USA.
8Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, The Cancer Hospital of the University of Chinese Academy of Sciences (CAS), Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China.
Address correspondence to: Weidong Zhang or Xin Luan, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Phone: 86.021.51322428; Email: wdzhangy@hotmail.com (WZ); Phone: 86.021.51322775; Email: luanxin@shutcm.edu.cn (XL). Or to: Shuyang Sun, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. Phone: 86.021.23271699; Email: sunshuyang@sjtu.edu.cn.
Authorship note: JJ, Yaping Wu, and Z. Zhao contributed equally to this work.
Find articles by Sun, S. in: JCI | PubMed | Google Scholar
1Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
2Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, and
3National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China.
4School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
5China Institute of Pharmaceutical Industry, Shanghai, China.
6Department of Chemistry and Biochemistry, College of Liberal Arts, and
7Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi, USA.
8Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, The Cancer Hospital of the University of Chinese Academy of Sciences (CAS), Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China.
Address correspondence to: Weidong Zhang or Xin Luan, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Phone: 86.021.51322428; Email: wdzhangy@hotmail.com (WZ); Phone: 86.021.51322775; Email: luanxin@shutcm.edu.cn (XL). Or to: Shuyang Sun, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. Phone: 86.021.23271699; Email: sunshuyang@sjtu.edu.cn.
Authorship note: JJ, Yaping Wu, and Z. Zhao contributed equally to this work.
Find articles by Luan, X. in: JCI | PubMed | Google Scholar
Authorship note: JJ, Yaping Wu, and Z. Zhao contributed equally to this work.
Published November 22, 2022 - More info
Published in Volume 7, Issue 22 on November 22, 2022
AbstractThe aberrant activation of STAT3 is associated with the etiology and progression in a variety of malignant epithelial-derived tumors, including head and neck squamous cell carcinoma (HNSCC) and colorectal cancer (CRC). Due to the lack of an enzymatic catalytic site or a ligand-binding pocket, there are no small-molecule inhibitors directly targeting STAT3 that have been approved for clinical translation. Emerging proteolysis targeting chimeric (PROTAC) technology–based approach represents a potential strategy to overcome the limitations of conventional inhibitors and inhibit activation of STAT3 and downstream genes. In this study, the heterobifunctional small-molecule–based PROTACs are successfully prepared from toosendanin (TSN), with 1 portion binding to STAT3 and the other portion binding to an E3 ubiquitin ligase. The optimized lead PROTAC (TSM-1) exhibits superior selectivity, potency, and robust antitumor effects in STAT3-dependent HNSCC and CRC — especially in clinically relevant patient-derived xenografts (PDX) and patient-derived organoids (PDO). The following mechanistic investigation identifies the reduced expression of critical downstream STAT3 effectors, through which TSM-1 promotes cell cycle arrest and apoptosis in tumor cells. These findings provide the first demonstration to our knowledge of a successful PROTAC-targeting strategy in STAT3-dependent epithelial cancer.
Graphical Abstract
Introduction
The STAT family of transcription factors has 7 known members, including STAT3, a key mediator of oncogenic signal transduction (1). In contrast to the transient mode of action in normal cells, STAT3 exhibits persistent aberrant activation in a variety of malignant epithelial-derived tumors (2). This is especially the case in over 95% of patients with head and neck squamous cell carcinoma (HNSCC) and 57.4% of patients with colorectal cancer (CRC) (3–5). Despite advancements in surgery and radiotherapy, and the integration of chemotherapy into treatment regimens, clinical HNSCC and CRC phenotypes are highly malignant, and 5-year survival rates remain poor (6–8). The lack of effective targeted therapies, poor response to immunotherapy, and resistance to chemotherapeutics pose significant treatment challenges (9, 10). Thus, new molecular target identification and subsequent development of therapeutic approach are essential to improve treatment outcome (11). Aberrant STAT3 activation represents an important early event during the development and progression of HNSCC and CRC (4, 8), promoting tumor cell proliferation, differentiation, invasion, angiogenesis (12), metastasis, and the evasion of detection by the immune system (13). Because the suppression of tumor cell apoptosis further contributes to reduced treatment response, the inhibition of aberrant STAT3 activation emerges as a compelling HNSCC and CRC target (8, 14, 15).
Strategies to block STAT3 activation in tumor cells include direct binding to the SH2 domain that is responsible for STAT3 dimerization and phosphorylation, or indirect inhibition of upstream tyrosine kinases (16). The compounds that directly bind to the SH2 domain include short peptide aptamers, peptidomimetics, and nonpeptidic small molecules (17). Challenges facing peptide aptamer and peptidomimetic drug development include reduced stability and poor cell permeability that limit their bioactivity (17). Nonpeptidic tyrosine kinase–targeted inhibitors have the potential to be developed as novel phosphorylated STAT3 inhibitors. However, their efficacy is diminished because the inherent transcriptional activity of unphosphorylated STAT3 could also drive the expression of oncogenes such as MET and MRAS by binding to NF-κB (18–21). Furthermore, the inhibition of STAT3 upstream signaling alone is insufficient to overcome the activation of compensatory signaling pathways (12, 13). Therefore, a strategy that completely inhibits the activity of STAT3 makes an invaluable addition to the arsenal of antitumor agents.
Specific downregulation or knockdown of STAT3 has recently emerged as a promising therapeutic approach, with the potential to overcome the limitations associated with conventional inhibitors. Antisense oligonucleotides that target STAT3 mRNA have entered preclinical studies in patients with HNSCC and shown initial efficacy; however, rapid degradation of mRNA significantly limits its bioavailability (14). Proteolysis targeting chimeric (PROTAC) technology has been widely used to specifically flag transcription factors for degradation (22). Unlike the occupancy mode of small molecule inhibitors, which increase the risk of off-target effects, PROTAC adopts the pattern of “event-driven” pharmacology binding at any point within the structure of potential targets (23, 24). Moreover, the catalytic nature of PROTAC can achieve and maintain enhanced target degradation at low doses (23, 25).
The PROTAC molecule SD-36 (26), developed by the Wang group with structure-based design, can effectively simulate the degradation of STAT3 protein in leukemia cells. Apart from the lengthy target-based drug discovery (TDD) design process, this method is envisioned as a feasible way to accelerate the development of a STAT3 degrader through a more phenotypic drug discovery (PDD) strategy (27, 28). Inspired by the chemical structure diversity and biological activity of natural products (29), it was proposed that PROTAC molecules should be designed based on natural molecules as a new strategy to effectively target STAT3, especially exploring the application of STAT3 degrader in solid tumors. Herein, PROTAC-based STAT3 degraders were successfully designed by coupling a small molecule toosendanin (TSN) that specifically binds STAT3 with an E3 ubiquitin ligase–targeted component to generate the chimeric molecule, referred to as TSM-1. The therapeutic potential and mechanisms of action of the PROTAC molecule TSM-1 in STAT3-dependent epithelial cancers (HNSCC and CRC) were systematically assessed in vitro and in vivo, and especially with the patient-derived xenografts (PDX) and patient-derived organoids (PDO) during the discovery of PROTAC molecules, which further indicated that TSM-1, as the first PROTAC molecule, may serve as a promising proteolytic enhancer for STAT3-dependent epithelial cancer.
ResultsExpression of STAT3 and its clinical significance. To establish the connection between STAT3 expression and disease stages, a bioinformatic-based approach was employed to analyze clinical sample–derived data deposited in the widely used GSE databases (30, 31). Analysis of the GSE database revealed that tumor samples expressed significantly higher levels of STAT3 in HNSCC (Figure 1, A and D) and CRC (Figure 1, B and E), in comparison with normal tissues. Examination of HNSCC and CRC (Figure 1, C, F, and G) patient biopsy specimens by IHC confirmed that the levels of STAT3 protein were significantly higher in tumors. Taken together, these results suggest that increased STAT3 expression and activation were highly associated with HNSCC and CRC progression and may serve as prognostic biomarkers and potential therapeutic targets.
Figure 1Expression of STAT3 and its clinical significance. (A and D) STAT3 expression was significantly increased in patients with HNSCC (GSE30784 database). (B and E) STAT3 expression was increased in patients with CRC according to the GSE21815 database. (C, F, and G) Increased expression of STAT3 protein was observed in biopsy samples from patients with HNSCC and patients with CRC (n = 3 patients). ***P < 0.001 when compared with the control group. P values are from 2-tailed paired t tests (D–G).
Rational design of TSM-1 as a potent degrader of STAT3 protein. Following extensive literature-based research and multiple rounds of screening from our own library, the triterpenoid TSN, isolated from the traditional Chinese medicinal plant Melia toosendan, was selected as the STAT3 target warhead. TSN had demonstrated antitumor activity by targeting STAT3 regulation (32, 33), thus providing a valid foundation for this investigation. Molecular docking studies suggested that 3 hydrogen bonds were formed between TSN and Glu638 or Ser613 on STAT3 (Figure 2A). To verify the docking results, MST assay was used to determine the direct binding between TSN and STAT3, and a Kd value of 296 nM was obtained (Figure 2H). Western blot analysis revealed that TSN had no effect on total STAT3 protein levels in HNSCC and CRC cells (Supplemental Figure 1, A–D; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.160606DS1). Next, an appropriate site for tethering TSN to lenalidomide was identified for the design of STAT3 degraders (Figure 2B). Determination of the linkers was geometrically optimized using MOE software. Inspection of the docking simulation of the STAT3/TSN complex revealed solvent-exposed regions suitable for a linker attachment and PROTAC conversion. Therefore, several linkers based on succinic acid and different spacers were constructed from the most active TSN hydroxy moiety by conjugation to the cereblon (CRBN) ligand (lenalidomide) (Figure 2C). According to the above method, a set of degraders with different physicochemical properties (TSM-1 to TSM-6) were designed and synthesized. Details regarding the preparation and structures of the other PROTAC derivatives (TSM-2 to TSM-6) were shown in the Supplemental data (Supplemental Scheme II–V within Supplemental Methods). We then sought to investigate the antitumor efficacy of TSMs in CAL33 cells. Among them, TSM-1 (Figure 2C) containing single azetidine exhibited the best antitumor activity (Supplemental Figure 2). Next, we replaced the E3 ubiquitin ligase of TSM-1 with Von Hippel-Lindau (VHL) and found that the conjugation of VHL with TSN seriously decreased its solubility, resulting in poor effi
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