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

Journal Article · Sun Oct 15 00:00:00 EDT 2006 · Toxicology and Applied Pharmacology

OSTI ID:20850443

Zeping, Hu ^[1]; Xiaoxia, Yang ^[1]; Suiyung, Chan ^[1]; Anlong, Xu ^[2]; Wei, Duan ^[3]; Yizhun, Zhu ^[4]; Sheu, F -S ^[5]; Boelsterli, Urs Alex ^[1]; Chan, Eli ^[1]; Qiang, Zhang ^[6]; Wang, J -C ^[6]; Ee, Pui Lai Rachel; Koh, H L ^[1]; Min, Huang ^[7]; Shufeng, Zhou ^[1]

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1. Department of Pharmacy, Faculty of Science, National University of Singapore, Science Drive 4, Singapore 117543 (Singapore)
2. Department of Biochemistry, School of Life Sciences, Sun Yat-sen University, Guangzhou (China)
3. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (Singapore)
4. Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore (Singapore)
5. Department of Biological Science, Faculty of Science, National University of Singapore (Singapore)
6. Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing (China)
7. Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou (China)

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-1{beta}, 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-1{beta}, 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-1{beta}, 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.

• OSTI ID: 20850443
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 2 Vol. 216; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
APOPTOSIS
CHEMOTHERAPY
DAMAGE
DIARRHEA
DOSES
DRUGS
EPITHELIUM
INFLAMMATION
INHIBITION
INTERFERON
INTESTINES
LABELLING
NEOPLASMS
PATIENTS
RATS
TOXICITY