Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China; Department of Pharmacy, The Central Hospital of Wuhan，Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, China.
Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Life Sci. 2020 Jul 1;252:117612. doi: 10.1016/j.lfs.2020.117612. Epub 2020 Apr 1.
Intestinal mucositis is the most common side effect of 5-fluorouracil (5-Fu) treatment in cancer patients. Previous research suggested that andrographolide (Andro) attenuated the intestinal injury in colitis or diarrhea in mice. The present study was aimed at investigating the protective effect of Andro against 5-Fu induced intestinal mucositis and the underlying mechanism.
BALB/C mice were injected 5-Fu at a dose of 100 mg/kg for 5 days to induce intestinal mucositis. Andro at different doses (25, 50, 100 mg/kg/day) was administered. Weight loss, diarrhea score, cellular apoptosis and proliferation were evaluated. Apoptosis related proteins were detected by Western blotting. Then, NCM460 cells were used to explore the possible mechanism in vitro. The effect of Andro on the anti-tumor efficacy of 5-Fu was investigated in H22 tumor-bearing mice.
Andro significantly ameliorated the 5-Fu induced weight loss and diarrhea. The apoptosis of intestinal cells was also attenuated by Andro treatment both in vivo and in vitro. Besides, Andro markedly down-regulated the 5-Fu-induced protein expression of caspase8/3, Bax and the phosphorylation of p38. Moreover, 5-Fu significantly reduced the viability of NCM460 cells, which was restored by the Andro pretreatment. Furthermore, asiatic acid, an agonist of p38 MAPK, reversed the anti-apoptotic effect of Andro in NCM460 cells. Andro did not weaken the anti-H22 tumor effect of 5-Fu in vivo.
We have demonstrated that p38 MAPK inhibition mediates anti-apoptotic effects of Andro against 5-Fu induced intestinal mucositis, suggesting that Andro may benefit the patients undergoing 5-Fu based chemotherapy.
氟尿嘧啶（5-Fu）治疗癌症患者时，最常见的副作用是肠道黏膜炎。先前的研究表明，穿心莲内酯（Andro）可减轻结肠炎或腹泻小鼠的肠道损伤。本研究旨在探讨穿心莲内酯对 5-Fu 诱导的肠道黏膜炎的保护作用及其潜在机制。
BALB/C 小鼠每天腹腔注射 5-Fu 100mg/kg，连续 5 天，诱导肠道黏膜炎。给予不同剂量的穿心莲内酯（25、50、100mg/kg/天）。评估体重减轻、腹泻评分、细胞凋亡和增殖。通过 Western blot 检测凋亡相关蛋白。然后，在体外使用 NCM460 细胞进行研究。在 H22 荷瘤小鼠中研究了穿心莲内酯对 5-Fu 抗肿瘤疗效的影响。
穿心莲内酯可显著改善 5-Fu 引起的体重减轻和腹泻。穿心莲内酯处理还可减轻体内和体外肠细胞的凋亡。此外，穿心莲内酯明显下调 5-Fu 诱导的 caspase8/3、Bax 蛋白表达及 p38 的磷酸化。此外，5-Fu 显著降低了 NCM460 细胞的活力，而穿心莲内酯预处理可恢复其活力。此外，p38 MAPK 的激动剂，积雪草酸，可逆转穿心莲内酯在 NCM460 细胞中的抗凋亡作用。穿心莲内酯在体内并未减弱 5-Fu 对 H22 肿瘤的抑瘤作用。
我们已经证明，p38 MAPK 抑制介导了穿心莲内酯对 5-Fu 诱导的肠道黏膜炎的抗凋亡作用，提示穿心莲内酯可能有益于接受 5-Fu 为基础的化疗的患者。
