Molecular Therapeutics Laboratory, Department of Surgery, Iwate Medical University School of Medicine, Morioka, Iwate, 020-8505, Japan.
Division of Biomedical Research and Development, Institute of Biomedical Science, Iwate Medical University, Morioka, Iwate, 020-8505, Japan.
Sci Rep. 2017 May 23;7(1):2262. doi: 10.1038/s41598-017-02548-9.
Drug-tolerant cancer cell subpopulations are responsible for relapse after chemotherapy. By continuously exposing the gastric cancer cell line MKN45 to 5-FU for >100 passages, we established a 5-fluorouracil (5-FU)-tolerant line, MKN45/5FU. Orthotopic xenografts of MKN45/5FU cells in the stomach of nude mice revealed that these cells had a high potential to metastasize to sites such as the liver. Levels of phosphorylated phosphatidylinositide 3-kinase (PI3K) increased both in 5-FU-tolerant subpopulations according to the 5-FU dose, and in gastric submucosal orthotopic xenografts of MKN45/5FU cells. Sequential administration of 5-FU and a PI3K inhibitor, GDC-0941, targeted the downstream ribosomal S6 kinase phosphorylation to significantly suppress 5-FU-tolerant subpopulations and tumor propagation of orthotopic MKN45/5FU xenografts. These results suggest that administration of 5-FU followed by GDC-0941 may suppress disease relapse after 5-FU-based gastric cancer chemotherapy.
耐药癌细胞亚群是化疗后复发的原因。通过连续将胃癌细胞系 MKN45 暴露于 5-FU 超过 100 代，我们建立了一个 5-氟尿嘧啶（5-FU）耐药系，MKN45/5FU。MKN45/5FU 细胞在裸鼠胃中的原位异种移植表明，这些细胞具有向肝脏等部位转移的高潜力。根据 5-FU 剂量，耐药亚群中磷酸化磷脂酰肌醇 3-激酶（PI3K）的水平增加，MKN45/5FU 细胞的胃黏膜下原位异种移植中也是如此。5-FU 和 PI3K 抑制剂 GDC-0941 的序贯给药靶向下游核糖体 S6 激酶磷酸化，可显著抑制 5-FU 耐药亚群和 MKN45/5FU 原位异种移植的肿瘤增殖。这些结果表明，5-FU 后序贯给予 GDC-0941 可能抑制基于 5-FU 的胃癌化疗后的疾病复发。
