Low dosage combination treatment with metformin and simvastatin inhibits obesity-promoted pancreatic cancer development in male KrasG12D mice.
Low dosage combination treatment with metformin and simvastatin inhibits obesity-promoted pancreatic cancer development in male KrasG12D mice.
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DOI：
10.1038/s41598-023-43498-9
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发表时间：
2023-09-26
影响因子：
4.6
通讯作者：
Eibl, Guido
中科院分区：
文献类型：
--
作者：
Teper, Yaroslav;Ye, Linda;Waldron, Richard T.;Lugea, Aurelia;Sun, Xiaoying;Sinnett-Smith, James;Hines, Oscar J.;Pandol, Stephen J.;Rozengurt, Enrique;Eibl, Guido
胰腺导管腺癌（PDAC）是一种治疗选择有限的高致死性疾病，在高危人群中，将FDA批准的药物用于预防或拦截策略可能会受益。先前的动物研究表明，使用二甲双胍和他汀类药物作为单一药物在相对高的剂量抑制PDAC的发展。在这里，在所有胰腺谱系中表达KrasG 12 D的4周龄小鼠（KC小鼠）和喂食促进早期PDAC发展的致肥胖高脂肪、高热量饮食的小鼠被随机分配到低剂量二甲双胍、辛伐他汀或两种药物联合口服给药。双重给药减轻了雄性KC小鼠的体重增加、纤维炎症和晚期PDAC前体病变（胰腺上皮内瘤[PanIN]-3）的发生，对雌性小鼠或单独给药无显著影响。双重处理的KC小鼠具有降低的PanIN细胞增殖和降低的Hippo效应物雅普和TAZ的转录活性，它们是PDAC发展的重要调节剂。二甲双胍和辛伐他汀还协同抑制胰腺癌细胞在体外的集落形成。总之，我们的数据表明，低剂量的二甲双胍和辛伐他汀联合使用可以抑制PDAC的发展，这意味着这两种药物都是有希望在临床试验中进行测试以预防胰腺癌进展的药物。
Pancreatic ductal adenocarcinoma (PDAC), a highly lethal disease with limited therapeutic options, may benefit from repurposing of FDA-approved drugs in preventive or interceptive strategies in high-risk populations. Previous animal studies demonstrated that the use of metformin and statins as single agents at relatively high doses restrained PDAC development. Here, four-week-old mice expressing KrasG12D in all pancreatic lineages (KC mice) and fed an obesogenic high fat, high calorie diet that promotes early PDAC development were randomized onto low dosage metformin, simvastatin, or both drugs in combination administered orally. Dual treatment attenuated weight gain, fibro-inflammation, and development of advanced PDAC precursor lesions (pancreatic intraepithelial neoplasia [PanIN]-3) in male KC mice, without significant effect in females or when administered individually. Dual-treated KC mice had reduced proliferation of PanIN cells and decreased transcriptional activity of the Hippo effectors, YAP and TAZ, which are important regulators of PDAC development. Metformin and simvastatin also synergistically inhibited colony formation of pancreatic cancer cells in vitro. Together, our data demonstrated that a combination of low doses of metformin and simvastatin inhibits PDAC development and imply that both drugs are promising agents for being tested in clinical trials for preventing pancreatic cancer progression.
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影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
DOI：
10.1158/1940-6207.capr-13-0065
发表时间：
2013-10
期刊：
Cancer prevention research (Philadelphia, Pa.)
影响因子：
--
作者：
Dawson DW;Hertzer K;Moro A;Donald G;Chang HH;Go VL;Pandol SJ;Lugea A;Gukovskaya AS;Li G;Hines OJ;Rozengurt E;Eibl G
通讯作者：
Eibl G
影响因子：
4.2
作者：
de Vries, Sieta T.;Denig, Petra;van Puijenbroek, Eugene P.
通讯作者：
van Puijenbroek, Eugene P.
影响因子：
5.8
作者：
Jaster, R;Brock, P;Liebe, S
通讯作者：
Liebe, S
胰腺癌细胞中Berberine和二甲双胍抑制MTORC1，ERK，DNA合成和增殖的剂量依赖性AMPK依赖性和独立机制。
影响因子：
3.7
作者：
Ming M;Sinnett-Smith J;Wang J;Soares HP;Young SH;Eibl G;Rozengurt E
通讯作者：
Rozengurt E