2篇最新论文!2018年,“神药”二甲双胍抗癌成果不断
2018/02/17
二甲双胍是使用最广泛的2型糖尿病药物,因其具有抗衰老、抗癌等作用被誉为“神药”。关于它在过去一年里的“抗癌业绩”,小编之前做过汇总。刚刚进入2018年,这款“神药”仍然没有“闲着”。两项抗癌新成果于近日新鲜出炉!

论文一:对抗卵巢癌


图片来源:Cancer Research(DOI: 10.1158/0008-5472.CAN-17-2460)

1月26日,一个中国科学家小组在Cancer Research上发表了题为“Metformin-induced reduction of CD39 and CD73 blocks myeloid-derived suppressor cell activity in patients with ovarian cancer”的论文。

此前,尽管有大量研究证实,二甲双胍能够发挥抗肿瘤作用,但背后的机制尚不清楚。而该研究调查了二甲双胍治疗是如何在卵巢癌患者中发挥作用的。

结果显示,二甲双胍治疗是通过下调卵巢癌患者中“单核和多核MDSC亚群”(MDSC:myeloid-derived suppressor cells,骨髓源抑制细胞)中CD39和CD73的表达和胞外酶活性(ectoenzymatic activity)来阻断MDSC的免疫抑制作用。


图片来源:网络

进一步研究发现,二甲双胍触发了AMPKα(AMP-activated protein kinase α)的激活,随后抑制了HIF-1αhypoxia-inducible factor-α)的表达。而HIF-1α对诱导MDSC中CD39/CD73的表达至关重要。

研究还证实,二甲双胍治疗与患卵巢癌的糖尿病患者“更长的总生存期”有关。分析显示,二甲双胍诱导了“循环CD39+CD73+MDSC出现率的下降”以及“循环CD8+T细胞抗肿瘤活性的增加”。

据研究人员介绍,MDSC是一群未成熟的骨髓细胞,可通过多种途径来抑制免疫系统,从而促进肿瘤的生长。功能性MDSC的积累已被证明是肿瘤诱导免疫抑制的主要“力量”。目前,许多靶向“MDSC诱导的免疫抑制”的疗法正处在临床开发中。

作者们在结论中总结道:该研究突出了二甲双胍对MDSC的直接作用;证明了在卵巢癌患者中,二甲双胍是通过抑制“CD39/CD73依赖性MDSC免疫抑制”,提高抗肿瘤T细胞免疫力,来产生临床益处的。


图片来源:Nature Communications(DOI:10.1038/s41467-017-02733-4)

论文二:对抗肝癌

除了揭秘二甲双胍抗卵巢癌背后的机制,1月31日,发表在Nature Communications上的一项研究中,来自美国的一个科学家小组还找到了借助“这一神药” 杀死肝癌细胞并抑制肿瘤生长的新方法。

该研究项目起源于伊利诺伊大学芝加哥分校的一个实验室。在那里,研究人员培养了肝癌细胞,并操纵了细胞中己糖激酶-2(hexokinase-2,一种帮助细胞代谢葡萄糖的酶)的表达,然后,用二甲双胍对细胞进行了处理。

接着,代谢通量分析专家、特拉华大学的Maciek R. Antoniewicz教授团队设计了一系列的实验,用于测量癌细胞会如何响应己糖激酶-2的缺失。

起初,研究人员怀疑,缺乏己糖激酶-2的癌细胞会被“饿死”,但令人惊讶的是,他们发现,只靶向己糖激酶-2对癌细胞生长的影响微乎其微,需要加入另一“武器”(即二甲双胍)来完成这一“任务”。

肝癌是一种目前很难治愈的疾病。美国国立卫生研究院的数据显示,超过82%的肝癌患者会在确诊5年内死亡。Antoniewicz教授认为,该论文的重要性在于,他们证明了,当利用二甲双胍同时靶向第二个补充机制时,靶向己糖激酶-2确实能够成为一种成功的抗癌策略。这一研究可能会加速肝癌新疗法的发展。

参考资料:

Metformin-induced reduction of CD39 and CD73 blocks myeloid-derived suppressor cell activity in patients with ovarian cancer

骨髓来源的抑制性细胞的研究进展

Researchers discover two-step process to thwart cancer cells

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  • Metformin-induced reduction of CD39 and CD73 blocks myeloid-derived suppressor cell activity in patients with ovarian cancer

    Metformin is a broadlyprescribed drug for type 2 diabetes that exerts antitumor activity, yet the mechanisms underlying this activity remain unclear. We show here that metformin treatment blocks the suppressive function of myeloid-derived suppressor cells (MDSC) in patients with ovarian cancer (OC) by downregulating the expression and ectoenzymatic activity of CD39 and CD73 on monocytic and polymononuclear MDSC subsets. Metformin triggered activation of AMP-activated protein kinase α (AMPKα) and subsequently suppressed hypoxia-inducible factor-α (HIF-1α), which was critical for induction of CD39/CD73 expression in MDSC. Furthermore, metformin treatment correlated with longer overall survival in diabetic patients with OC, which was accompanied by a metformin-induced reduction in the frequency of circulating CD39+CD73+MDSC and a concomitant increase in the antitumor activities of circulating CD8+T cells. Our results highlight a direct effect of metformin on MDSC and suggest that metformin may yield clinical benefit through improvement of antitumor T cell immunity by dampening CD39/CD73-dependent MDSC immunosuppression in OC patients.

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  • Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin

    Hepatocellular carcinoma (HCC) cells are metabolically distinct from normal hepatocytes by expressing the high-affinity hexokinase (HK2) and suppressing glucokinase (GCK). This is exploited to selectively target HCC. Hepatic HK2 deletion inhibits tumor incidence in a mouse model of hepatocarcinogenesis. Silencing HK2 in human HCC cells inhibits tumorigenesis and increases cell death, which cannot be restored by GCK or mitochondrial binding deficient HK2. Upon HK2 silencing, glucose flux to pyruvate and lactate is inhibited, but TCA fluxes are maintained. Serine uptake and glycine secretion are elevated suggesting increased requirement for one-carbon contribution. Consistently, vulnerability to serine depletion increases. The decrease in glycolysis is coupled to elevated oxidative phosphorylation, which is diminished by metformin, further increasing cell death and inhibiting tumor growth. Neither HK2 silencing nor metformin alone inhibits mTORC1, but their combination inhibits mTORC1 in an AMPK-independent and REDD1-dependent mechanism. Finally, HK2 silencing synergizes with sorafenib to inhibit tumor growth.

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