APS:抗精神病药五氟利多靶向PFKL抑制食管癌生长,可能具有广泛抗肿瘤效应

2022-05-25 网络 网络

2022年3月,暨南大学李斌教授团队基于“老药新用”策略,发现五氟利多(Penfluridol),一种抗精神病临床药物,可以显著抑制食管癌生长,研究成果发表在Acta Phar

2022年3月,暨南大学李斌教授团队基于“老药新用”策略,发现五氟利多(Penfluridol),一种抗精神病临床药物,可以显著抑制食管癌生长,研究成果发表在Acta Pharmaceutica Sinica B上。

图片

为了从现有药物中寻找能够治疗食管癌的药物,研究人员筛选了一个包含1320种FDA批准药物的小分子库(图1A)。利用这些化合物处理食管鳞状细胞癌(ESCC)细胞48小时,并测量细胞活力以评估小分子化合物的效果,确定了候选化合物抗精神病药五氟利多(图1B)。随后通过体内/外实验发现五氟利多可以抑制ESCC的糖酵解(图1D)并诱导细胞凋亡(图1C)。RNA-Seq结合IPA分析发现AMPK在五氟利多作用机制中的重要作用(图1E),并通过WB进行了验证(图1F)。

五氟利多

五氟利多化学结构

 

图片

图1 筛选抑制食管癌药物五氟利多

随后,研究人员使用药物亲和力响应靶稳定性DARTS技术(图2A),确定了磷酸果糖激酶(PFKL)是五氟利多的直接靶标(图2B)。随后细胞实验发现五氟利多不能在PFKL缺陷的癌细胞中表现出其抗癌特性,表明PFKL对于五氟利多的抗癌活性是必需的(图2C)。接着体内/外实验结合组织芯片发现PFKL的高表达与ESCC患者较差的生存率相关,且PFKL的沉默显著抑制了肿瘤生长。最后通过SPR(图2D)、分子对接(图2E)等技术发现五氟利多和PFKL的直接结合,并以AMPK依赖的方式抑制葡萄糖消耗、乳酸和ATP产生,导致FOXO3a的核易位和随后BIM的转录激活。

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图2 五氟利多药物靶点的确定与验证

总之,研究通过筛选1320种FDA批准的药物确定五氟利多作为一种新型抗癌药物。机制上,五氟利多与PFKL 的直接结合会抑制食管癌细胞的糖酵解并激活AMPK/FOXO3a/BIM 信号通路,从而抑制肿瘤的发生(图3),为开发五氟利多作为治疗食管癌的潜在药物提供了临床前理论基础。

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图3 五氟利多靶向PFKL抑制食管癌模式图

事实上,近年来针对Penfluridol有较多的研究,Penfluridol的另一个关键靶点为DRD2,通过这个靶点,能抑制肿瘤干细胞的干性化,从而抑制肿瘤的生长,尤其是肾细胞癌,这项研究结果也刚刚发表在Cell Death Dis上。甚至还发现它能下调HK-2,从而抑制线粒体的糖酵解活动,促进线粒体凋亡,从而对结直肠癌具有抑制作用。另外,还发现了Penfluridol对肺腺癌也具有显著的抑制作用。

梅斯认为,抗精神病类药物作用机制可能相当复杂,过往已有一些研究关注这些老药对肿瘤的影响,未来可以进一步改造出更具有特异性的治疗药物。

原始出处:

Zheng C, Yu X, Liang Y, Zhu Y, He Y, Liao L, Wang D, Yang Y, Yin X, Li A, He Q, Li B.Targeting PFKL with penfluridol inhibits glycolysis and suppresses esophageal cancer tumorigenesis in an AMPK/FOXO3a/BIM-dependent manner.Acta Pharm Sin B. 2022 Mar;12(3):1271-1287. doi: 10.1016/j.apsb.2021.09.007.

Tung MC, Lin YW, Lee WJ, Wen YC, Liu YC, Chen JQ, Hsiao M, Yang YC, Chien MH.Targeting DRD2 by the antipsychotic drug, penfluridol, retards growth of renal cell carcinoma via inducing stemness inhibition and autophagy-mediated apoptosis.Cell Death Dis. 2022 Apr 23;13(4):400. doi: 10.1038/s41419-022-04828-3

Wang NN, Zhang PZ, Zhang J, Wang HN, Li L, Ren F, Dai PF, Li H, Lv XF.Penfluridol triggers mitochondrial-mediated apoptosis and suppresses glycolysis in colorectal cancer cells through down-regulating hexokinase-2.Anat Rec (Hoboken). 2021 Mar;304(3):520-530

Xue Q, Liu Z, Feng Z, Xu Y, Zuo W, Wang Q, Gao T, Zeng J, Hu X, Jia F, Zhu Y, Xia Y, Yu L.Penfluridol: An antipsychotic agent suppresses lung cancer cell growth and metastasis by inducing G0/G1 arrest and apoptosis.Biomed Pharmacother. 2020 Jan;121:109598. doi: 10.1016/j.biopha.2019.109598

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    2022-05-27 zhouqu_8
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    2022-05-25 ms6000001791212108

    学习了,新疗效

    0

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    2022-05-25 清风徐来2022

    #老药新用##五氟利多#靶向PFKL抑制#食管癌#。不过从这篇报道来看,似乎五氟利多的真正靶点还不明确,在我印象中,也有报道它的靶点是MMPs,可以调节#肿瘤微环境#,当然,它作用于DRD2,这个#多巴胺#受体2这是没有问题的,但是这里认为它还能影响代谢,#磷酸果糖激酶#,有点令人吃惊了。

    0

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