Department of Anaesthesiology, Affiliated Tumour Hospital, Xinjiang Medical University, Xinjiang, China.
Clin Exp Pharmacol Physiol. 2020 May;47(5):848-856. doi: 10.1111/1440-1681.13248. Epub 2020 Jan 22.
Aerobic glycolysis plays a crucial role in cancer progression. Ketamine is often used for cancer pain relief in clinical settings. Moreover, ketamine inhibits proliferation and induces apoptosis in many cancer cell types. However, the anti-tumour mechanism of ketamine is still poorly understood. In the present study, we survey whether and how ketamine inhibits aerobic glycolysis in colon cancer cells. Glycolysis of colon cancer cells was determined by detecting the extracellular acidification rate in HT29 and SW480 cells. Quantitative real-time PCR was employed to determine mRNA expression. Calcium levels were detected with a Fluo-3 AM fluorescence kit. Micro-positron emission tomography/computed tomography (microPET/CT) imaging was employed to assess glycolysis in the tumours of the xenograft model. Ketamine treatment inhibited colon cancer cell viability and migration in HT29 and SW480 cells. Moreover, ketamine decreased aerobic glycolysis and decreased the expression of glycolysis-related proteins in HT29 and SW480 cells. MicroPET/CT demonstrated that ketamine decreased 18F-FDG uptake in the xenograft model. In addition, ketamine inhibited c-Myc expression and CaMK II phosphorylation and decreased calcium levels. Further, dizocilpine (an NMDAR inhibitor), and KN93 (a CaMK II inhibitor), decreased CaMK II phosphorylation, c-Myc expression, and cancer cell glycolysis; these results were similar to those with ketamine treatment. Furthermore, the anti-tumour effect of ketamine was counteracted by rapastinel (an NMDAR activator). Ketamine inhibited aerobic glycolysis in colon cancer cells probably by blocking the NMDA receptor-CaMK II-c-Myc pathway, thus attenuating colon cancer cell viability and migration.
有氧糖酵解在癌症进展中起着关键作用。氯胺酮常用于临床缓解癌症疼痛。此外，氯胺酮能抑制多种癌细胞类型的增殖并诱导其凋亡。然而，氯胺酮的抗肿瘤机制仍知之甚少。在本研究中，我们调查了氯胺酮是否以及如何抑制结肠癌细胞的有氧糖酵解。通过检测 HT29 和 SW480 细胞的细胞外酸化率来确定结肠癌细胞的糖酵解。采用定量实时 PCR 测定 mRNA 表达。用 Fluo-3 AM 荧光试剂盒检测钙水平。采用微正电子发射断层扫描/计算机断层扫描（microPET/CT）成像评估异种移植模型中肿瘤的糖酵解。氯胺酮处理抑制 HT29 和 SW480 细胞中结肠癌细胞的活力和迁移。此外，氯胺酮降低 HT29 和 SW480 细胞中的有氧糖酵解和糖酵解相关蛋白的表达。microPET/CT 表明，氯胺酮降低了异种移植模型中 18F-FDG 的摄取。此外，氯胺酮抑制 c-Myc 表达和 CaMK II 磷酸化并降低钙水平。进一步的，地佐辛（NMDAR 抑制剂）和 KN93（CaMK II 抑制剂）降低 CaMK II 磷酸化、c-Myc 表达和癌细胞糖酵解；这些结果与氯胺酮处理的结果相似。此外，氯胺酮的抗肿瘤作用被拉帕司他（NMDAR 激活剂）抵消。氯胺酮可能通过阻断 NMDA 受体-CaMK II-c-Myc 通路抑制结肠癌细胞的有氧糖酵解，从而减弱结肠癌细胞的活力和迁移。
