Hepatoprotective Effect of Carboxymethyl Pachyman in Fluorouracil-Treated CT26-Bearing Mice.

Canhong Wang,Cao Li,Guibo Sun,Xiaowei Huo,Li Gao

doi:10.3390/molecules22050756

Abstract

5-Fluorouracil (5-FU) is the chemotherapeutic agent of first choice for the treatment ofcolorectal cancer, however, treatment-related liver toxicity remains a major concern. Thereby, it is desirable to search for novel therapeutic approaches that can effectively enhance curative effects and reduce the toxic side effects of 5-FU. Carboxymethyl Pachyman (CMP) exhibits strong antitumor properties, but the antitumor and hepatoprotective effects of CMP and the molecular mechanisms behind these activities, are however poorly explored. Thereby, the purpose of the present study was to evaluate the hepatoprotective effect of CMP in 5-FU-treated CT26-bearing mice, and further explore the underlying mechanism(s) of action. Initially, a CT26 colon carcinoma xenograft mice model was established. The immune organ indexes, blood indicators, liver tissue injury, and indicators associated with inflammation, antioxidant and apoptosis were then measured. Our results showed that CMP administration increased the tumor inhibitory rates of 5-FU and, meanwhile, it reversed reduction of peripheral white blood cells (WBC) and bone marrow nucleated cells (BMNC), increase of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and decrease of superoxide dismutase (SOD), catalase (CAT), GSH-Px and glutathione(GSH) induced by 5-FU. Moreover, CMP in combination with 5-FU alleviated severe liver injury induced by 5-FU via reducing the levels of ROS, IL-1β, and IL-6, decreasing expression of p-IκB-α, NF-κB, p-NF-κB, pp38 and Bax, and elevating levels of Nrf2, GCL, HO-1 and Bcl-2. Collectively, these outcomes suggested that CMP effectively enhanced the curative effects of 5-FU and simultaneously reduced the liver injuries induced by 5-FU in CT26-bearing mice, and the mechanism may be associated with regulation of NF-κB, Nrf2-ARE and MAPK/P38/JNK pathways.

Highlights

Colorectal cancer, accompanied by intestinal microflora disorders, inflammation, metabolic dysfunction symptoms, and invasion of pathogens, remains the third most commonly diagnosed cancer and the fourth leading cause of cancer-related mortality worldwide [1,2,3]
Traditional Chinese medicines have been used for a long history to enhance physical performance [14], and in many cases natural products and their derivatives are thought to be therapeutically superior to chemically synthesized drugs [15], such as docetaxel and topotecan approved by FDA, which have been demonstrated clinical utility based on the ongoing investigations [16]
5-FU significantly inhibited CT26 carcinoma growth as indicated by decreased tumor weight when compared with the model group (p < 0.01) (Figure 1A)

Summary

Introduction

Colorectal cancer, accompanied by intestinal microflora disorders, inflammation, metabolic dysfunction symptoms, and invasion of pathogens, remains the third most commonly diagnosed cancer and the fourth leading cause of cancer-related mortality worldwide [1,2,3]. Molecules 2017, 22, 756 drug-resistant phenotypes and systemic toxicity, especially liver injury, have become severe limiting factors in 5-FU therapy [7,8,9], and thereby 5-FU alone is of limited benefits in enhancing the survival of patients with advanced colorectal cancer. The development of ideal strategies that could enhance therapeutic effectiveness of 5-FU, simultaneously reduce its toxicity to liver via regulating inflammation, oxidative stress, and hepatocyte apoptosis, without compromising its tumoricidal action is highly warranted. Traditional Chinese medicines have been used for a long history to enhance physical performance [14], and in many cases natural products and their derivatives are thought to be therapeutically superior to chemically synthesized drugs [15], such as docetaxel and topotecan approved by FDA, which have been demonstrated clinical utility based on the ongoing investigations [16]. Natural products or their combinations with currently approved chemotherapeutic drugs are well accepted as alternative remedies in anticancer therapy, especially in countries where herbal medicines are widely used [17]

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Methods

Results