奥利司他（Orlistat）对子宫内膜癌基因转基小鼠模型具有抗肥胖和抗肿瘤作用。
Orlistat exerts anti-obesity and anti-tumorigenic effects in a transgenic mouse model of endometrial cancer.
发表日期：2023
作者：
Guangxu Xu, Ziyi Zhao, Weiya Z Wysham, Dario R Roque, Ziwei Fang, Wenchuan Sun, Yajie Yin, Boer Deng, Xiaochang Shen, Chunxiao Zhou, Victoria Bae-Jump
来源：
Disease Models & Mechanisms
摘要：
在所有癌症中，子宫内膜癌与肥胖之间的关联最为强烈，超过65％的子宫内膜癌与肥胖和超重相关。脂肪酸合酶（FAS）是一个关键的脂肪合成酶，其在子宫内膜癌肿瘤中表达，并与该疾病的预后不良相关。奥利司他（Orlistat）是一种经美国食品药品监督管理局批准的减肥药物，它在多种临床前癌症模型中展现出抗肿瘤活性。
在本研究中，我们使用Lkb1fl/flp53fl/fl小鼠模型，暴露于三种饮食干预措施下，包括高脂饮食（肥胖）、低脂饮食（瘦）和从高脂饮食切换到低脂饮食，然后暴露于奥利司他或安慰剂。
与低脂饮食的小鼠相比，高脂饮食的小鼠体重和肿瘤重量显著增加。与高脂饮食和低脂饮食组相比，从高脂饮食切换到低脂饮食可降低小鼠体重并抑制肿瘤生长。奥利司他有效降低肥胖小鼠的体重，并通过诱导凋亡来抑制肥胖、瘦、以及从高脂饮食切换到低脂饮食小鼠组的肿瘤生长。奥利司他在11个人类子宫内膜癌原代细胞培养中也显示出抗增殖活性。
我们的发现强有力地证明了饮食干预和奥利司他在体内具有抗肿瘤活性，并支持进一步研究奥利司他与饮食干预联合应用于子宫内膜癌的预防和治疗。Copyright © 2023 Xu, Zhao, Wysham, Roque, Fang, Sun, Yin, Deng, Shen, Zhou and Bae-Jump.
Among all cancers, endometrial cancer is most strongly associated with obesity, with more than 65% of endometrial cancers attributable to obesity and being overweight. Fatty acid synthase (FAS), a key lipogenic enzyme, is expressed in endometrial cancer tumors and is associated with a worse prognosis for this disease. Orlistat, an FAS inhibitor, is an FDA-approved weight loss medication that has demonstrated anti-tumor activity in a variety of preclinical cancer models.In this study, the Lkb1fl/flp53fl/fl mouse model of endometroid endometrial cancer was exposed to three diet interventions, including a high fat diet (obese), a low fat diet (lean) and switch from a high fat to a low fat diet, and then exposed to orlistat or placebo.The mice fed a high-fat diet had significantly increased body weight and tumor weight compared to mice fed a low-fat diet. Switching from a high-fat diet to a low fat diet led to a reduction in mouse weight and suppressed tumor growth, as compared to both the high fat diet and low fat diet groups. Orlistat effectively decreased body weight in obese mice and inhibited tumor growth in obese, lean, and the high fat diet switch to low fat diet mouse groups through induction of apoptosis. Orlistat also showed anti-proliferative activity in nine of 11 primary cultures of human endometrial cancer.Our findings provide strong evidence that dietary intervention and orlistat have anti-tumor activity in vivo and supports further investigation of orlistat in combination with dietary interventions for the prevention and treatment of endometrial cancer.Copyright © 2023 Xu, Zhao, Wysham, Roque, Fang, Sun, Yin, Deng, Shen, Zhou and Bae-Jump.