School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu 211198, P.R. China.
Department of General Surgery, Rui Jin Hospital, Research Institute of Pancreatic Diseases, School of Medicine, Shanghai JiaoTong University, Shanghai 200025, P.R. China.
Int J Oncol. 2020 Nov;57(5):1223-1233. doi: 10.3892/ijo.2020.5120. Epub 2020 Sep 8.
Pancreatic cancer is one of the most lethal solid malignancies, with a poor prognosis and a high mortality rate. Pancreatic cancer cells exhibit enhanced glycolysis to maintain their rapid growth. Canagliflozin (CANA) is a sodium‑glucose co‑transporter 2 inhibitor used for the clinical treatment of diabetes. Recent studies have demonstrated the potential ability of CANA to suppress hepatocellular carcinoma, whereas its therapeutic effects on and mechanisms in pancreatic cancer have rarely been reported. In the present study, the antitumor effects of CANA on pancreatic cancer were investigated. The data obtained indicated that pancreatic cancer growth was effectively suppressed by CANA in a dose‑dependent manner, with peak inhibition rates of 54.3 and 57.6% in cultured Capan‑1 and PANC‑1 cells respectively. The tumor inhibitory rate reached 45.2% in nude mice with PANC‑1‑derived tumors, suggesting its effective antitumor activity against pancreatic cancer in vitro and/or in vivo. In addition, the combined treatment of Capan‑1 and PANC‑1 cells with gemcitabine and CANA exhibited a greater efficacy compared with that of treatment with gemcitabine alone. Moreover, glucose uptake and lactate production were decreased, and the mRNA levels of the glycolysis‑associated genes, including glucose transporter‑1 and lactate dehydrogenase A were decreased, indicating the inhibitory effects caused by the combination treatment on the metabolism of glucose in pancreatic cancer cells. Furthermore, CANA induced apoptosis, notably early apoptosis, and decreased the protein levels of PI3K, p‑AKT, p‑mTOR and HIF‑1α, which indicated that the PI3K/AKT/mTOR signaling pathway was involved in the glycolytic process. These results demonstrated that pancreatic cancer growth was effectively inhibited by CANA via the suppression of glycolysis. This was mediated primarily by the PI3K/AKT/mTOR signaling pathway, revealing the underlying role and potential of this pathway for the clinical treatment of pancreatic cancer. Novel applications for the existing drug CANA can be explored, which could reduce the cost and time required for drug development in the field of drug discovery.
胰腺癌是最致命的实体恶性肿瘤之一，预后不良，死亡率高。胰腺癌细胞表现出增强的糖酵解以维持其快速生长。卡格列净（CANA）是一种用于临床治疗糖尿病的钠-葡萄糖协同转运蛋白 2 抑制剂。最近的研究表明，CANA 具有抑制肝细胞癌的潜在能力，而其在胰腺癌中的治疗效果和机制很少有报道。在本研究中，研究了 CANA 对胰腺癌的抗肿瘤作用。数据表明，CANA 以剂量依赖性方式有效抑制胰腺癌细胞生长，在培养的 Capan-1 和 PANC-1 细胞中分别达到 54.3%和 57.6%的峰值抑制率。在具有 PANC-1 衍生肿瘤的裸鼠中，肿瘤抑制率达到 45.2%，表明其对体外和/或体内胰腺癌具有有效的抗肿瘤活性。此外，与单独使用吉西他滨相比，Capan-1 和 PANC-1 细胞联合使用吉西他滨和 CANA 治疗具有更大的疗效。此外，葡萄糖摄取和乳酸产量减少，糖酵解相关基因（包括葡萄糖转运蛋白-1 和乳酸脱氢酶 A）的 mRNA 水平降低，表明联合治疗对胰腺癌细胞葡萄糖代谢的抑制作用。此外，CANA 诱导细胞凋亡，特别是早期凋亡，并降低 PI3K、p-AKT、p-mTOR 和 HIF-1α 的蛋白水平，表明 PI3K/AKT/mTOR 信号通路参与了糖酵解过程。这些结果表明，CANA 通过抑制糖酵解有效抑制胰腺癌生长。这主要是通过 PI3K/AKT/mTOR 信号通路介导的，揭示了该通路在胰腺癌临床治疗中的潜在作用和潜力。可以探索现有药物 CANA 的新应用，这可以降低药物发现领域药物开发的成本和时间。
