The State Key Laboratory of Functions and Applications of Medicinal Plants & College of Pharmacy, Guizhou Medical University, University Town, Guian New District, Guiyang 550025, China.
College of Biomedical Engineering and National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu 610064, China.
Mol Pharm. 2022 Sep 5;19(9):3187-3198. doi: 10.1021/acs.molpharmaceut.2c00333. Epub 2022 Aug 8.
As the most common subtype in ovarian malignancies, high-grade serous ovarian cancer (HGSOC) made less therapeutic progress in past decades due to the lack of effective drug-able targets. Herein, an effective linoleic acid (LA) and glucosamine (GlcN) hybrid (LA-GlcN) was synthesized for the treatment of HGSOC. The GlcN was introduced to recognize the glucose transporter 1 (GLUT 1) overexpressed in tumor cells to enhance the uptake of LA-GlcN, and the unsaturated LA was employed to trigger ferroptosis by iron-dependent lipid peroxidation. Since the iron content of HGSOC was ∼5 and 2 times, respectively, higher than that of the normal ovarian cells and low-grade serous ovarian cancer cells, these excess irons make them a good target to enhance the ferroptosis of LA-GlcN. The in vitro study demonstrated that LA-GlcN could selectively kill HGSOC cells without affecting normal cells; the in vivo study revealed that LA-GlcN at the dose of 50 mg kg achieved a comparable tumor inhibition as doxorubicin hydrochloride (4 mg kg) while the overall survival of mice was extended largely due to the low toxicity, and when the dose was increased to 100 mg kg, the therapeutic outcomes could be improved further. This dietary hybrid which targets the excess endogenous iron to activate ferroptosis represents a promising drug for HGSOC treatment.
作为卵巢恶性肿瘤中最常见的亚型，由于缺乏有效的药物靶点，高等级浆液性卵巢癌（HGSOC）在过去几十年中治疗进展甚微。在此，我们合成了一种有效的亚油酸（LA）和氨基葡萄糖（GlcN）杂化物（LA-GlcN），用于治疗 HGSOC。GlcN 的引入是为了识别肿瘤细胞中过度表达的葡萄糖转运蛋白 1（GLUT 1），以增强 LA-GlcN 的摄取，不饱和 LA 则用于通过铁依赖性脂质过氧化引发铁死亡。由于 HGSOC 的铁含量分别比正常卵巢细胞和低等级浆液性卵巢癌细胞高约 5 倍和 2 倍，这些多余的铁使它们成为增强 LA-GlcN 铁死亡的良好靶点。体外研究表明，LA-GlcN 可以选择性地杀死 HGSOC 细胞，而不影响正常细胞；体内研究表明，LA-GlcN 的剂量为 50mg/kg 时，与盐酸多柔比星（4mg/kg）的肿瘤抑制效果相当，而小鼠的总生存期则大大延长，这主要是由于其毒性较低，当剂量增加到 100mg/kg 时，治疗效果可以进一步提高。这种针对内源性多余铁以激活铁死亡的饮食杂化物代表了治疗 HGSOC 的一种有前途的药物。
