Curcumin partly ameliorates irinotecan-induced diarrhea and synergistically promotes apoptosis in colorectal cancer through mediating oxidative stress

Abstract

OBJECTIVE Development of treatment resistance and adverse toxicity limits the gains made by irinotecan in patients with colorectal cancer. According to our previous studies, we found that curcumin could enhance the efficacy of irinotecan-induced apoptosis of colorectal tumor cells in vitro. This study aims to examine the effectiveness of a combination treatment regimen of irinotecan and curcumin in the colorectal cancer xenograft model. RESULTS Curcumin or irinotecan alone reduced the tumor volume, and the combination had the strongest anticancer effects. Oxidative stress was induced in tumor (MDA: P < 0.01, GPx: P < 0.05, PRDX4: P < 0.01), while was reduced in intestinal tissue (MDA: P < 0.01, SOD: P < 0.05, GPx: P < 0.01). The apoptosis in tumor was accompanied by up-regulation of apoptotic proteins (caspase-3: P < 0.01, Bax: P < 0.01), but down-regulation of anti-apoptotic proteins (pro-caspase-3: P < 0.01, Bcl-2: P < 0.01). Besides, the combination treatment alleviated diarrhea and intestine injury, and also restored the autophagy (PGC-1α: P < 0.05, Atg-7: P < 0.05, and LC3B: P < 0.05) and mitochondrial dynamics (Mfn-1: P < 0.01, Mfn-2: P < 0.01, Drp-1: P < 0.01, Fis-1: P < 0.05) in intestinal tissue. MATERIALS AND METHODS Nude mice were implanted with LoVo colorectal cancer cells before randomization into the following treatment groups: control; curcumin only; irinotecan only; curcumin + irinotecan. After a 9-day treatment, we compared the tumor weight, tumor volume, morphological change of intestine, and oxidative stress factors (LDH, MDA, SOD, GPx). In addition, we detected the oxidative stress (PRDX4, MnSOD, and p53), apoptosis (Bax, Bcl-2, pro-caspase-3, cleaved-caspase-3) and autophagy (PGC-1α, Atg-7, and LC3B) signaling. CONCLUSIONS Curcumin could enhance the efficacy of irinotecan-induced apoptosis of colorectal cancer in vivo, while restore the irinotecan-induced autophagy of small intestinal epithelium.