Liu Wei, Fang Yong, Wang Xiao-Tong, Liu Ju, Dan Xing, Sun Lu-Lu
Department of Pharmacy, Beijing Shijitan Hospital, Capital Medical University, Beijing, China E-mail :
Asian Pac J Cancer Prev. 2014;15(17):7037-41. doi: 10.7314/apjcp.2014.15.17.7037.
5-Fluorouracil (5-FU) is the most commonly used drug in colon cancer therapy. However, despite impressive clinical responses initially, development of drug resistance to 5-Fu in human tumor cells is the primary cause of failure of chemotherapy. In this study, we established a 5-Fu-resistant human colon cancer cell line for comparative chemosensitivity studies.
Real time PCR and Western blotting were used to determine gene expression levels. Cell viability was measured by MTT assay. Glucose uptake was assess using an Amplex Red Glucose/Glucose Oxidase assay kit.
We found that 5-Fu resistance was associated with the overexpression of Glut1 in colon cancer cells. 5-Fu treatment at low toxic concentration induced Glut1 expression. At the same time, upregulation of Glut1 was detected in 5-Fu resistant cells when compared with their parental cells. Importantly, inhibition of Glut1 by a specific inhibitor, WZB117, significantly increased the sensitivity of 5-Fu resistant cells to the drug.
This study provides novel information for the future development of targeted therapies for the treatment of chemo-resistant colon cancer patients. In particular it demonstrated that Glut1 inhibitors such as WZB117 may be considered an additional treatment options for patients with 5-Fu resistant colon cancers.
5-氟尿嘧啶（5-FU）是结肠癌治疗中最常用的药物。然而，尽管最初临床反应令人印象深刻，但人类肿瘤细胞对5-FU产生耐药性是化疗失败的主要原因。在本研究中，我们建立了一种5-FU耐药的人结肠癌细胞系用于比较化学敏感性研究。
采用实时PCR和蛋白质印迹法测定基因表达水平。通过MTT法测定细胞活力。使用Amplex Red葡萄糖/葡萄糖氧化酶检测试剂盒评估葡萄糖摄取。
我们发现5-FU耐药与结肠癌细胞中Glut1的过表达有关。低毒浓度的5-FU处理诱导了Glut1的表达。同时，与亲本细胞相比，在5-FU耐药细胞中检测到Glut1上调。重要的是，特异性抑制剂WZB117对Glut1的抑制显著增加了5-FU耐药细胞对该药物的敏感性。
本研究为未来开发针对化疗耐药结肠癌患者的靶向治疗提供了新信息。特别是它表明，诸如WZB117之类的Glut1抑制剂可能被认为是5-FU耐药结肠癌患者的额外治疗选择。
