Lin Peiyu, Yang Xiyue, Wang Linghui, Zou Xin, Mu Lingli, Xu Cangcang, Yang Xiaoping
Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha 410000, Hunan, China.
Korean J Physiol Pharmacol. 2024 May 1;28(3):219-227. doi: 10.4196/kjpp.2024.28.3.219.
Bladder cancer remains the 10th most common cancer worldwide. In recent years, metformin has been found to have potential anti-bladder cancer activity while high concentration of IC at millimolar level is needed, which could not be reached by regular oral administration route. Thus, higher efficient agent is urgently demanded for clinically treating bladder cancer. Here, by conjugating artesunate to metformin, a novel artesunate-metformin dimer triazine derivative AM2 was designed and synthesized. The inhibitory effect of AM2 on bladder cancer cell line T24 and the mechanism underlying was determined. Anti-tumor activity of AM2 was assessed by MTT, cloning formation and wound healing assays. Decreasing effect of AM2 on lipogenesis was determined by oil red O staining. The protein expressions of Clusterin, SREBP1 and FASN in T24 cells were evaluated by Western blotting. The results show that AM2 significantly inhibited cell proliferation and migration at micromolar level, much higher than parental metformin. AM2 reduced lipogenesis and down-regulated the expressions of Clusterin, SREBP1 and FASN. These results suggest that AM2 inhibits the growth of bladder cancer cells T24 by inhibiting cellular lipogenesis associated with the Clusterin/SREBP1/FASN signaling pathway.
膀胱癌仍然是全球第十大常见癌症。近年来，已发现二甲双胍具有潜在的抗膀胱癌活性，然而需要毫摩尔水平的高浓度药物，而常规口服给药途径无法达到这一浓度。因此，临床上迫切需要更高效的药物来治疗膀胱癌。在此，通过将青蒿琥酯与二甲双胍偶联，设计并合成了一种新型青蒿琥酯-二甲双胍二聚体三嗪衍生物AM2。测定了AM2对膀胱癌细胞系T24的抑制作用及其潜在机制。通过MTT、克隆形成和伤口愈合试验评估AM2的抗肿瘤活性。通过油红O染色测定AM2对脂肪生成的降低作用。通过蛋白质免疫印迹法评估T24细胞中Clusterin、SREBP1和FASN的蛋白表达。结果表明，AM2在微摩尔水平上显著抑制细胞增殖和迁移，远高于母体二甲双胍。AM2减少脂肪生成并下调Clusterin、SREBP1和FASN的表达。这些结果表明，AM2通过抑制与Clusterin/SREBP1/FASN信号通路相关的细胞脂肪生成来抑制膀胱癌细胞T24的生长。
