Active Ingredients of Hange-shashin-to, Baicalelin and 6-Gingerol, Inhibit 5-Fluorouracil-Induced Upregulation of CXCL1 in the Colon to Attenuate Diarrhea Development

Abstract

5-Fluorouracil (5-FU)is widely used as an anti cancer drug and is known to cause severe diarrhea. Recently we suggested that levels of chemokine (C-X-C motif) ligand 1 (CXCL1) and neutrophil recruitment in the colonic mucosa were drastically increased by the 5-FU administration in mice. Hange-shashin-to (HST) is prescribed in Japan for treat gastritis, stomatitis, and inflammatory diarrhea. We therefore examined the effects of HST and its active ingredients on 5-FU-induced CXCL1 upregulation in cultured colon tissue, and also examined the effects of HST on 5-FU-induced diarrhea development in the mouse. The distal colon isolated from the mouse was incubated with 5-FU and HST. Mice were given 5-FU (50 mg/kg, intraperitoneally (i.p.)) daily for four days. HST (300 mg/kg, per os ( p.o.)) was administered 30 min before mice received 5-FU. mRNA levels of CXCL1 in the colon were examined using quantitative RT-PCR. 5-FU enhanced CXCL1 mRNA in the colon but the effect by 5-FU was markedly suppressed by application of HST and its active ingredients, baicalein and 6-gingerol. Nuclear factor kappa B (NF-κB) was activated by 5-FU treatment in cultured colon tissue, which was also suppressed by HST and the combination of baicalein and 6-gingerol. Furthermore, HST reduced 5-FU-induced diarrhea development. Under such experimental condition, CXCL1 gene, protein levels of neutrophil elastase and myeloperoxidase upregulation induced by 5-FU in the colon was attenuated by HST. These findings suggest that HST, especially baicalein and 6-gingerol, prevent the development of neutrophil recruitment and diarrhea by the inhibition of NF-κB activity.

Banxia Xiexin decoction: A review on phytochemical, pharmacological, clinical and pharmacokinetic investigations

“…The findings demonstrated that BXD, particularly baicalein and 6-gingerol, decreased the mRNA expression of CXCL1 via activating NF-κB in vitro, and attenuated the development of neutrophil recruitment and 5-FU-induced diarrhea in vivo. [ 94 ]…”

Flavonoids against non-physiologic inflammation attributed to cancer initiation, development, and progression—3PM pathways

“…Harati et al (2017) documented that EGCG and silibinin represent potential candidate molecules as mild therapeutic options for patients with solid sarcomas that require palliative treatment and are not suitable for doxorubicin-based chemotherapy [207]. In another preclinical study, baicalelin and 6-gingerol reduced 5-fluorouracil-induced overexpression of CXCL1 in the colon and prevented the development of neutrophil recruitment and weakened diarrhea development by the suppression of NF-κB activity [208]. Data from another preclinical study point out to protective role of quercetin coadministered with vitamin E in the prevention of doxorubicin-induced toxicity in uterine and ovarian tissues in rats [209].…”

Efficacy of Hangeshashinto in the Prevention of Chemotherapy-Induced Diarrhea: A Systematic Review and Meta-Analysis

“…Hangeshashinto is a traditional Japanese herbal medicine used for diarrhea, anorexia, nausea, and vomiting [7][8][9][10][11][12]. This herbal medicine may cause pseudo-hyperaldosteronism and skin rash, but their frequency is low, and serious adverse events are extremely rare [13].…”