很多科學(xué)家認(rèn)為，維C等抗氧化劑能夠阻止腫瘤生長的原因在于,，它們能夠奪取不穩(wěn)定的氧自由基分子以避免它們對人體DNA造成傷害,。然而，美國約翰霍普金斯大學(xué)研究人員的最新一項研究表明,，抗氧化劑的真正作用有可能在于減弱腫瘤在缺氧條件下的生存能力,。相關(guān)論文9月11日發(fā)表于《癌細(xì)胞》（Cancer Cell）上。
該項研究由約翰霍普金斯大學(xué)的腫瘤學(xué)教授Chi Dang領(lǐng)導(dǎo)完成,。他和同事將人類淋巴瘤細(xì)胞或肝癌細(xì)胞植入小鼠體內(nèi),，這兩種癌細(xì)胞能產(chǎn)生大量自由基,，而給小鼠體內(nèi)補充維C或N－乙酰半胱氨酸（NAC）等抗氧化劑能夠抑制這些自由基的產(chǎn)生,。
研究人員隨后檢測了沒有喂食抗氧化劑的小鼠的癌細(xì)胞情況，結(jié)果并沒有發(fā)現(xiàn)明顯的DNA損傷,。論文第一作者Ping Gao認(rèn)為,，如果DNA損傷并不是導(dǎo)致癌癥的原因，那么抗氧化劑所發(fā)揮的作用也應(yīng)該與DNA損傷無關(guān),。
據(jù)此,，研究人員懷疑這里面一定包含著不同的機制。他們將目標(biāo)鎖定在一種特殊的蛋白上,，這種蛋白依賴一種名為阻止缺氧誘導(dǎo)因子（HIF-1）的自由基,。他們發(fā)現(xiàn)這種蛋白在小鼠未曾處理過的癌細(xì)胞中含量豐富，而在用維C處理過的細(xì)胞中則蹤影全無,。
Dang解釋說,，當(dāng)細(xì)胞缺氧的時候，HIF-1會進(jìn)行補償,。它能幫助缺氧細(xì)胞在無氧條件下將糖轉(zhuǎn)變成能量,，并發(fā)起建造新的血管以補充新鮮氧。
一些快速生長的腫瘤會消耗足夠多的能量,，從而輕易地就將附近的氧消耗殆盡,，這時HIF-1對于它們的繼續(xù)存活就顯得至關(guān)重要。但是HIF-1只有在有大量自由基存在的情況下才能發(fā)揮作用,，一旦抗氧化劑抑制了自由基的產(chǎn)生,，它就能阻止HIF-1發(fā)揮作用，從而抑制了腫瘤的生長,。
研究人員用另外的實驗證實了這種依賴HIF-1的蛋白的重要性,，他們制造了含有遺傳變異型HIF-1的癌細(xì)胞，這種變異型HIF-1不再需要自由基就能發(fā)揮作用,。結(jié)果發(fā)現(xiàn),，在這樣的癌細(xì)胞中，抗氧化劑不再具有抑制腫瘤生長的能力。
對于此次研究的意義,，Dang表示,，抗氧化劑這種潛在的抗癌作用已經(jīng)成為許多臨床和潛伏期研究的驅(qū)動力，通過揭示抗氧化劑的作用機制,，我們就能夠?qū)⑺呐R床治療功效達(dá)到最優(yōu),。（科學(xué)網(wǎng) 梅進(jìn)/編譯）
原始出處:
Cancer Cell, Vol 12, 230-238, 11 September 2007
Article
HIF-Dependent Antitumorigenic Effect of Antioxidants In Vivo
Ping Gao,1 Huafeng Zhang,2,6 Ramani Dinavahi,1 Feng Li,1 Yan Xiang,1 Venu Raman,4,5 Zaver M. Bhujwalla,4,5 Dean W. Felsher,8 Linzhao Cheng,6 Jonathan Pevsner,3 Linda A. Lee,1 Gregg L. Semenza,1,2,4,6,7 and Chi V. Dang1,4,7,
1 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2 Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
3 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
4 Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
5 Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
6 Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
7 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
8 Departments of Medicine and Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
Corresponding author
Chi V. Dang
[email protected]
The antitumorigenic activity of antioxidants has been presumed to arise from their ability to squelch DNA damage and genomic instability mediated by reactive oxygen species (ROS). Here, we report that antioxidants inhibited three tumorigenic models in vivo. Inhibition of a MYC-dependent human B lymphoma model was unassociated with genomic instability but was linked to diminished hypoxia-inducible factor (HIF)-1 levels in a prolyl hydroxylase 2 and von Hippel-Lindau protein-dependent manner. Ectopic expression of an oxygen-independent, stabilized HIF-1 mutant rescued lymphoma xenografts from inhibition by two antioxidants: N-acetylcysteine and vitamin C. These findings challenge the paradigm that antioxidants diminish tumorigenesis primarily through decreasing DNA damage and mutations and provide significant support for a key antitumorigenic effect of diminishing HIF levels.
