要饿死癌细胞?饮食疗法很可能是短期有助于癌症治疗的方案!

2020-06-03 陶然 健康界

"Dietary Approaches to Cancer Therapy”一文,综述了癌症治疗中的饮食疗法,探讨了饮食调节脂肪、碳水化合物和蛋白质的治疗潜力。

我们该吃什么以及健康的话题一直经久不衰。希腊人和罗马人曾提倡将适度饮食作为长寿之道。在过去的100年里,无数的饮食专家主张所有可以想到的营养输入变化用来治疗肥胖和包括癌症在内的许多疾病。营养选择可以影响患某些恶性肿瘤的风险,尽管这些关联背后的机制基础目前尚不清楚。另外,饮食改变可以提高对癌症治疗的反应,这一概念对许多癌症患者来说极具吸引力。

2020年5月14日Cancer cell在线发表“Dietary Approaches to Cancer Therapy”一文,综述了癌症治疗中的饮食疗法,探讨了饮食调节脂肪、碳水化合物和蛋白质的治疗潜力,特别关注选择性地剥夺个别氨基酸的饮食,将这些饮食与其他疗法相结合以最大限度地提高疗效,并讨论了肿瘤微环境和全身对营养干预的反应的重要性。

图1 Cancer cell在线发表“Dietary Approaches to Cancer Therapy”一文(图源:Cancer cell

癌症代谢复杂但可利用

大约一个世纪前,Warburg等人首次注意到伴随肿瘤恶性发展的代谢变化,但为什么癌症表现出代谢的改变,这是恶性表型的必要条件,或者仅是改变致癌转化的一个副产品?不同的癌症表现出广泛的代谢活动,尽管代谢转化具有其复杂性,但越来越多的证据表明,促进致癌进展的一些代谢变化可能会存在选择性弱点,可针对这些弱点靶向进行癌症的预防或治疗。

受组织起源、微环境和遗传学等因素的影响,癌症表现出不同的代谢需求。肿瘤细胞也会影响周围基质细胞的行为,癌症善于利用和操纵周围环境来提供营养支持。因此,饮食调节将需要与癌症和治疗的具体特征相匹配,这是一种精确的方法,需要对决定每种癌症代谢弱点的机制有详细的了解。

大多数国家癌症组织提供了饮食指南,强调癌症患者的健康饮食和足够的营养摄入,癌症患者被鼓励保持热量摄入,特别是采用高蛋白饮食。

进食限制热量可以作为替代治疗目标

各种癌症治疗的饮食干预正在进行临床试验,其中最直接的包括通过禁食或模仿禁食的饮食(FMD)来消除(或接近消除)食物摄入。这些方法包括慢性热量限制(往往会导致体重下降)和急性间歇性禁食或短期禁食(允许恢复正常饮食,从而帮助保持体重和增加依从性)。

禁食的作用机制可能反映一系列反应,包括系统反应,如循环葡萄糖、胰岛素和IGF-1与增加的IGF结合蛋白(IGFBPs)协同在正常细胞中诱导保护性反应,如增殖抑制、AMPK的诱导、抗氧化剂和自噬。有充分的证据表明热量限制可以加强癌症治疗,间歇性禁食已被证明是一种很好的耐受性方法。

虽然热量限制模拟和自噬诱导可以促进抗肿瘤反应,但最近的一项研究也表明,宿主自噬通过提供循环精氨酸在支持癌症生长方面发挥着重要作用。所以应考虑更有针对性的方法,在不限制热量的情况下限制选择性营养物质,作为替代治疗目标。

生酮饮食可通过葡萄糖代谢的改变来发挥作用

生酮饮食的低糖成分与上述FMD相似,这可以部分解释它们对癌症治疗的协同作用。然而,与FMD不同的是,生酮饮食不需要热量限制或低蛋白摄入。

①生酮饮食的一种反应是降低循环葡萄糖和较低的循环胰岛素和IGF-1水平,这有助于限制肿瘤中胰岛素受体下游的致癌信号通路的异常激活。

②葡萄糖的限制会迫使细胞使用线粒体代谢,这是一种代谢开关,可以增加活性氧(ROS)到一些高糖酵解癌细胞的毒性水平,尽管其他肿瘤可能通过降低肿瘤氧化应激来响应生酮饮食。

③氧化还原应激在某些情况下也可能有助于生酮饮食的反应。

需要注意的是,生酮饮食不太可能作为一个独立的治疗方案,但可以配合特定的疗法,使适合该疗法的癌症患者受益。

蛋白质限制极具抑癌效力

限制蛋白质饮食也可以限制癌症发展,对蛋白质限制的各种反应可以解释这一现象,包括IGF-1水平的调节和PI3K/AKT/mTOR信号传导的限制自噬的激活和循环FGF21水平的诱导也被认为是对蛋白质摄入量减少的反应,尽管这些可能对限制或促进癌症发展的作用尚不清楚。

图4 丝氨酸合成途径的调控与治疗机会(图源:Cancer cell

膳食蛋白质(而非碳水化合物)的适度减少已被证明可诱导癌细胞内质网应激的激活,促进抗肿瘤T细胞反应的诱导。有趣的是,高水平的动物蛋白似乎比植物蛋白更有害健康,这表明饮食中的特定氨基酸含量可能比总体蛋白质水平更重要。

总结与思考

在预测饮食干预和药理学治疗之间的治疗协同作用的模型开发已经取得了重大进展,尽管关于如何更好地利用饮食调节来支持传统和靶向治疗仍存在许多问题。我们对外源性营养水平如何影响癌细胞生长的理解,在一定程度上受到了广泛使用的细胞培养基的阻碍,这种培养基不能反映癌细胞在体内遇到的环境。

为了保持抗肿瘤的功能免疫反应,避免恶病质的发生,应该从整体上考虑限制饮食的影响,重要的是要记住饮食控制的癌症治疗很可能只是短期的协调治疗方案。

参考资料:Myle` ne Tajan and Karen H. Vousde. Dietary Approaches to Cancer Therapy. Cancer Cell 37, June 8, 2020. https://doi.org/10.1016/j.ccell.2020.04.005

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    2020-06-05 yxch36

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