TY - JOUR
T1 - Two birds, one stone
T2 - Hesperetin alleviates chemotherapyinduced diarrhea and potentiates tumor inhibition
AU - Yu, Yaping
AU - Kong, Ren
AU - Cao, Huojun
AU - Yin, Zheng
AU - Liu, Jiyong
AU - Nan, Xiang
AU - Phan, Alexandria T.
AU - Ding, Tian
AU - Zhao, Hong
AU - Wong, Stephen T.C.
PY - 2018/6/15
Y1 - 2018/6/15
N2 - 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.
AB - 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.
KW - Chemotherapy-induced diarrhea
KW - Hesperetin
KW - Human intestinal carboxylesterase (CES2)
KW - Macrophage
KW - STAT3
UR - http://www.scopus.com/inward/record.url?scp=85048607629&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85048607629&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.24563
DO - 10.18632/oncotarget.24563
M3 - Article
AN - SCOPUS:85048607629
VL - 9
SP - 27958
EP - 27973
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 46
ER -