Research Papers:

Two birds, one stone: hesperetin alleviates chemotherapy-induced diarrhea and potentiates tumor inhibition

Yaping Yu, Ren Kong, Huojun Cao, Zheng Yin, Jiyong Liu, Xiang Nan, Alexandria T. Phan, Tian Ding, Hong Zhao _ and Stephen T.C. Wong

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Oncotarget. 2018; 9:27958-27973. https://doi.org/10.18632/oncotarget.24563

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Yaping Yu1,2,*, Ren Kong1,3,*, Huojun Cao1,4, Zheng Yin1, Jiyong Liu1,5, Xiang Nan1,6, Alexandria T. Phan7, Tian Ding1, Hong Zhao1 and Stephen T.C. Wong1,8

1Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Weill Cornell Medicine, Houston, TX, 77030, USA

2Department of Gynecology and Obstetrics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P.R. China

3Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou, Jiangsu, 213001, P.R. China

4Iowa Institute for Oral Health Research, College of Dentistry, The University of Iowa, Iowa City, IA, 52246, USA

5Department of Pharmacy, Changhai Hospital, Shanghai, 200433, P.R. China

6Center for Biomedical Engineering, Department of Electronic Science and Technology, University of Science and Technology of China, Hefei, Anhui, 230026, P.R. China

7Cancer Treatment Centers of America at South Eastern Regional Center, Atlanta, GA, 30265, USA

8Houston Methodist Cancer Center, Houston Methodist Hospital, Houston, TX, 77030, USA

*These authors have contributed equally to this work

Correspondence to:

Hong Zhao, email: [email protected]

Stephen T.C. Wong, email: [email protected]

Keywords: chemotherapy-induced diarrhea; hesperetin; human intestinal carboxylesterase (CES2); STAT3; macrophage

Received: October 12, 2017     Accepted: October 30, 2017     Epub: February 23, 2018     Published: June 15, 2018


Chemotherapy-induced diarrhea (CID), with clinical high incidence, adversely affects the efficacy of cancer treatment and patients’ quality of life. Our study demonstrates that the citrus flavonoid hesperetin (Hst) has a superior potential as a new agent to prevent and alleviate CID. In the animal model for irinotecan (CPT-11) induced CID, Hst could selectively inhibit intestinal carboxylesterase (CES2) and thus reduce the local conversion of CPT-11 to cytotoxic SN-38 which causes intestinal toxicity. Oral administration of Hst manifested an excellent anti-diarrhea efficacy, prohibiting 80% of severe and 100% of mild diarrhea in the CPT-11 administered tumor-bearing mice. In addition, a significant attenuation of intestinal inflammation contributed to the anti-diarrhea effect of Hst. Moreover, Hst was found to work synergistically with CPT-11 in tumor inhibition by suppressing the tumor’s STAT3 activity and recruiting tumoricidal macrophages into the tumor microenvironment. The anti-intestinal inflammation and anti-STAT3 properties of Hst would contribute its broad benefits to the management of diarrhea caused by other chemo or targeted agents, and more importantly, enhance and reinforce the anti-tumor effects of these agents, to improve patient outcomes.

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