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

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.

Nanogold Particles Suppresses 5-Flurouracil-Induced Renal Injury: An Insight into the Modulation of Nrf-2 and Its Downstream Targets, HO-1 and γ-GCS

“…5-FU-induced organ toxicity is accompanied by a marked reduction in Nrf-2 along with an increase in Keap-1. Hence, studies showed that activation of Nrf-2 could be beneficial in the protection against 5-FU-induced organ injury [35,36]. Similarly, data in the present study indicated that 5-FU induced a significant decrease in renal tissue expression of Nrf-2 protein compared to both normal and AuNPs control groups.…”

Molecular basis for Poria cocos mushroom polysaccharide used as an antitumour drug in China

“…In consistent, Chai et al reported that CMP has no adverse effects on mice as well. Wang et al showed that CMP could enhance the tumour inhibition rate of 5‐FU and decrease the liver injuries simultaneously caused by 5‐FU in CT26 tumour‐bearing mice …”

Gambogic Acid Induces Pyroptosis of Colorectal Cancer Cells through the GSDME-Dependent Pathway and Elicits an Antitumor Immune Response

“…GA significantly inhibited tumor growth in CT26 cell xenograft-bearing BALB/c mice, similar to 5-fluorouracil (5-FU) [ 33 ]. However, 5-FU, which is an effective and commonly used anticancer agent for the treatment of colon cancer, has side effects that may cause damage to the liver and immunological function [ 34 , 35 ]. In our study, GA exhibited excellent anticancer activity in vivo without causing injury to the major organs or hepatorenal dysfunction; thus, GA might be a safe and effective anticancer chemotherapeutic agent for CRC treatment.…”