Orlistat is an irreversible inhibitor of lipases in the pancreas and stomach. It is a drug for the treatment of obesity. It suppresses the action of gastrointestinal lipases, thereby impairing the metabolism of lipids in the gastrointestinal lumen, which can prevent the absorption of 30% of the lipids in dietary fat[1,2]. Orlistat is very hydrophobic and binds covalently to the active serine residues of pancreatic lipase. Orlistat passes through cell membranes sufficiently and exerts intracellular effects[3].
Orlistat(0-25µM;32h) induced a pronounced antiproliferative effect in the PC-3 cell line[4]. Orlistat inhibits Jurkat cell growth and induces a perturbation of cell cycle along with a decline of FASN activity and protein levels[6]. Orlistat-mediated(0-50µM) FASN inhibition could overcome sorafenib resistance and enhance cell killing in HCC by changing cell metabolism[7].
Orlistat(10 mg/kg/day, p.o.) alleviates colon cancer promotion in WD-driven CAC mice by suppressing inflammation, especially by inhibiting STAT3 and NF-κB activation[5].Orlistat(240 mg/kg/day;3 weeks; i.p.) prevented the growth of PC-3 tumors. Animals exhibited no outward signs of toxicity, experienced no loss of weight, nor were there any effects of Orlistat on hematocrit or WBC levels[4].
References:
[1]. Chandra P, Enespa, et,al. Microbial lipases and their industrial applications: a comprehensive review. Microb Cell Fact. 2020 Aug 26;19(1):169. doi: 10.1186/s12934-020-01428-8. PMID: 32847584; PMCID: PMC7449042.
[2]. Bansal AB, Al Khalili Y. Orlistat. 2022 Nov 2. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. PMID: 31194359.
[3]. Padwal, et,al. Drug treatments for obesity: Orlistat, sibutramine, and rimonabant. Lancet 2007, 369, 71-77.
[4]. Kridel SJ, Axelrod F, et,al. Orlistat is a novel inhibitor of fatty acid synthase with antitumor activity. Cancer Res. 2004 Mar 15;64(6):2070-5. doi: 10.1158/0008-5472.can-03-3645. PMID: 15026345.
[5]. Jin BR, Kim HJ, et,al. Anti-Obesity Drug Orlistat Alleviates Western-Diet-Driven Colitis-Associated Colon Cancer via Inhibition of STAT3 and NF-κB-Mediated Signaling. Cells. 2021 Aug 11;10(8):2060. doi: 10.3390/cells10082060. PMID: 34440829; PMCID: PMC8394553.
[6]. Cioccoloni G, Aquino A, et,al. Fatty acid synthase inhibitor orlistat impairs cell growth and down-regulates PD-L1 expression of a human T-cell leukemia line. J Chemother. 2020 Feb;32(1):30-40. doi: 10.1080/1120009X.2019.1694761. Epub 2019 Nov 28. PMID: 31775585.
[7]. Shueng PW, Chan HW, et,al. Orlistat Resensitizes Sorafenib-Resistance in Hepatocellular Carcinoma Cells through Modulating Metabolism. Int J Mol Sci. 2022 Jun 10;23(12):6501. doi: 10.3390/ijms23126501. PMID: 35742944; PMCID: PMC9223797.
奥利司他是胰脏和胃中脂肪酶的不可逆抑制剂,是治疗肥胖症的药物。它抑制胃肠道内脂肪酶的作用,从而影响胃肠道脂质的代谢,可以防止膳食脂肪的30%被吸收[1,2]。奥利司他非常疏水,与胰脏脂肪酶的活性丝氨酸残基发生共价结合。奥利司他能够充分通过细胞膜并发挥细胞内作用[3]。
奥利司他(0-25 µM; 32 h) 在 PC-3 细胞系中产生明显的抗增殖效应[4]。奥利司他抑制 Jurkat 细胞的生长并引起细胞周期紊乱,伴随着 FASN 活性和蛋白水平的下降[6]。奥利司他介导的(0-50 µM) FASN 抑制可以克服 HCC 对索拉非尼的耐药性,并通过改变细胞代谢增强细胞杀伤[7]。
奥利司他(10 mg/kg/天,p.o.) 可以通过抑制炎症,特别是通过抑制 STAT3 和 NF-κB 活化,减轻 WD 驱动的 CAC 小鼠结肠癌促进作用[5]。奥利司他(240 mg/kg/天,3 周,i.p.) 可以预防 PC-3 肿瘤的生长。动物没有外观上的毒性表现,没有体重减轻,奥利司他对红细胞压积或白细胞计数没有影响[4]。