St. John's wort attenuates irinotecan-induced diarrhea via down-regulation of intestinal pro-inflammatory cytokines and inhibition of intestinal epithelial apoptosis

• Published in: Toxicology and applied pharmacology Vol. 216; no. 2; pp. 225 - 237
• Main Authors: Hu, Ze-Ping, Yang, Xiao-Xia, Chan, Sui Yung, Xu, An-Long, Duan, Wei, Zhu, Yi-Zhun, Sheu, Fwu-Shan, Boelsterli, Urs Alex, Chan, Eli, Zhang, Qiang, Wang, Jian-Cheng, Ee, Pui Lai Rachel, Koh, Hwee Ling, Huang, Min, Zhou, Shu-Feng
• Format: Journal Article
• Language: English
• Published: San Diego, CA Elsevier Inc 15.10.2006; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; Animals; Antineoplastic Agents, Phytogenic - adverse effects; Antineoplastic Agents, Phytogenic - antagonists & inhibitors; APOPTOSIS; Apoptosis - drug effects; Biological and medical sciences; Camptothecin - adverse effects; Camptothecin - analogs & derivatives; Camptothecin - antagonists & inhibitors; CHEMOTHERAPY; Cytokines - metabolism; DAMAGE; DIARRHEA; Diarrhea - chemically induced; Diarrhea - drug therapy; Disease Models, Animal; DOSES; Down-Regulation - drug effects; Drug Therapy, Combination; DRUGS; EPITHELIUM; General pharmacology; Hypericum; Hypericum perforatum; INFLAMMATION; INHIBITION; INTERFERON; Intestinal Mucosa - drug effects; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; INTESTINES; Irinotecan; LABELLING; Male; Medical sciences; NEOPLASMS; PATIENTS; Pharmacognosy. Homeopathy. Health food; Pharmacology. Drug treatments; Phytotherapy; Plant Extracts - therapeutic use; RATS; Rats, Sprague-Dawley; St. John's wort; TNF-α; TOXICITY; SJW; IL; CPT-11; TdT; Diarrhea; IFN; Irinotecan; Chemotherapy; TUNEL; TNF-α; ANOVA; St. John's wort; Apoptosis; Antineoplastic agent; Hypericum perforatum; Guttiferae; Medicinal plant; Isomerases; Dicotyledones; Angiospermae; Intestinal disease; Inhibition; Tumor necrosis factor α; Enzyme; DNA topoisomerase; Cytokine; Enzyme inhibitor; Inflammation; Treatment; Cell death; Plant origin; Digestive diseases; Spermatophyta
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2006.05.020

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-1β, IL-2, IL-6), interferon (IFN-γ) and tumor necrosis factor-α (TNF-α) 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-1β, IL-2, IL-6, IFN-γ and TNF-α 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-1β, IFN-γ and TNF-α 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-α 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.