St. John's wort attenuates irinotecan-induced diarrhea via down-regulation of intestinal pro-inflammatory cytokines and inhibition of intestinal epithelial apoptosis.
Diarrhea is a common dose-limiting toxicity associated with cancer chemotherapy, in particular for drugs such as irinotecan (CPT-11), 5-fluouracil, oxaliplatin, capecitabine and raltitrexed. St. John's wort (Hypericum perforatum, SJW) has anti-inflammatory activity, and our preliminary study in the rat and a pilot study in cancer patients found that treatment of SJW alleviated irinotecan-induced diarrhea. In the present study, we investigated whether SJW modulated various pro-inflammatory cytokines including interleukins (IL-1beta, IL-2, IL-6), interferon (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) and intestinal epithelium apoptosis in rats. The rats were treated with irinotecan at 60 mg/kg for 4 days in combination with oral SJW or SJW-free control vehicle at 400 mg/kg for 8 days. Diarrhea, tissue damage, body weight loss, various cytokines including IL-1beta, IL-2, IL-6, IFN-gamma and TNF-alpha and intestinal epithelial apoptosis were monitored over 11 days. Our studies demonstrated that combined SJW markedly reduced CPT-11-induced diarrhea and intestinal lesions. The production of pro-inflammatory cytokines such as IL-1beta, IFN-gamma and TNF-alpha was significantly up-regulated in intestine. In the mean time, combined SJW significantly suppressed the intestinal epithelial apoptosis induced by CPT-11 over days 5-11. In particular, combination of SJW significantly inhibited the expression of TNF-alpha mRNA in the intestine over days 5-11. In conclusion, inhibition of pro-inflammatory cytokines and intestinal epithelium apoptosis partly explained the protective effect of SJW against the intestinal toxicities induced by irinotecan. Further studies are warranted to explore the potential for STW as an agent in combination with chemotherapeutic drugs to lower their dose-limiting toxicities.
Hu
Ze-Ping
ZP
Department of Pharmacy, Faculty of Science, National University of Singapore, Science Drive 4, Singapore 117543, Singapore.
Yang
Xiao-Xia
XX
Chan
Sui Yung
SY
Xu
An-Long
AL
Duan
Wei
W
Zhu
Yi-Zhun
YZ
Sheu
Fwu-Shan
FS
Boelsterli
Urs Alex
UA
Chan
Eli
E
Zhang
Qiang
Q
Wang
Jian-Cheng
JC
Ee
Pui Lai Rachel
PL
Koh
Hwee Ling
HL
Huang
Min
M
Zhou
Shu-Feng
SF
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D016207:Cytokines / Q000378:metabolism; D003967:Diarrhea / Q000139:chemically induced / Q000188:drug therapy*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D004359:Drug Therapy, Combination; D020902:Hypericum; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000077146:Irinotecan; D008297:Male; D008517:Phytotherapy; D010936:Plant Extracts / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000972:Antineoplastic Agents, Phytogenic; D016207:Cytokines; D010936:Plant Extracts; D000077146:Irinotecan; D002166:Camptothecin