(CELL) 高劑量Vitamin C有助於TET2基因缺陷癌治療: myelodysplastic syndrome (MDS)/ acute myeloid leukemia (AML)

美國研究：維他命C有助對抗血癌 08月22日(二)美國研究人員發現，注射維他命C可能有助戰勝血癌。小鼠實驗表明，這種營養物質能「告訴」在我們骨髓中有毛病的幹細胞停止分裂和死亡。包括急性和慢性白血病在內的一些血癌，通常涉及影響TET2基因的突變。該基因能確保某種幹細胞成熟為白細胞，然後死亡。但TET2基因突變會導致這些細胞分裂不受控制，最終導致癌症。紐約大學醫學院的奇米諾（Luisa Cimmino）和尼爾（Benjamin Neel）及同事利用基因剪接技術培育了TET2功能可控的小鼠。結果發現，減少TET2活性50%就足以引發血癌，但如果要讓該疾病持續發展，TET2的活性也要維持在較低水準。「如果我們恢復TET2，那麼它將阻止不健康的複製，並殺死多餘的細胞。」奇米諾說。接着，研究小組將目光轉向維他命C，因為它能影響胚胎幹細胞，從而啟動TET2，令細胞複製受到控制。研究人員每天為TET2活性較低的小鼠注射非常高劑量的維他命C，並持續24周，結果發現這令白血病的發展被拖慢了。到後期，研究人員不再為控制組注射維他命C，結果顯示小鼠體內的白血球是同伴的3倍。當研究小組將人類白血病細胞暴露在一種抗癌藥物中，結果發現當添加了維他命C時，藥物效果更好。尼爾希望，高劑量的維他命C最終能結合到相關癌症治療方案中。但大量攝取維他命C不大可能預防癌症。在每次注射中，小鼠得到100毫克的維他命C，相當於兩個橙子。但一般人的體重是老鼠的3000倍，由於人體在吸收了500毫克的維他命C後會停止攝入，因此需要進行靜脈注射。維他命C是一種抗氧化劑，含有豐富維他命C的水果和蔬菜包括甜椒、深綠色蔬菜、水蜜桃、西蘭花、橙、奇異果、番茄、青豆和木瓜。

Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression. Cell. 2017 Aug 16. S0092-8674(17)30868-1. Loss-of-function mutations in TET2 occur frequently in patients with clonal hematopoiesis, myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML) and are associated with a DNA hypermethylation phenotype. To determine the role of TET2 deficiency in leukemia stem cell maintenance, we generated a reversible transgenic RNAi mouse to model restoration of endogenous Tet2 expression. Tet2 restoration reverses aberrant hematopoietic stem and progenitor cell (HSPC) self-renewal in vitro and in vivo. Treatment with vitamin C, a co-factor of Fe2+ and α-KG-dependent dioxygenases, mimics TET2 restoration by enhancing 5-hydroxymethylcytosine formation in Tet2-deficient mouse HSPCs and suppresses human leukemic colony formation and leukemia progression of primary human leukemia PDXs. Vitamin C also drives DNA hypomethylation and expression of a TET2-dependent gene signature in human leukemia cell lines. Furthermore, TET-mediated DNA oxidation induced by vitamin C treatment in leukemia cells enhances their sensitivity to PARP inhibition and could provide a safe and effective combination strategy to selectively target TET deficiency in cancer.

Silencing HIF-1α induces TET2 expression and augments ascorbic acid induced 5-hydroxymethylation of DNA in human metastatic melanoma cells. Biochem Biophys Res Commun. 2017 Aug 19;490(2):176-181. Expression and function of Ten-eleven translocation (TET) enzymes, which initiate DNA demethylation by catalyzing the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine (5 hmC) on methylated DNA, are frequently lost in malignant tissue. This ultimately results in lost expression of methylated tumor suppressor genes. Many malignancies, including melanoma, also aberrantly overexpress the oncogenic hypoxia inducible factor-1α (HIF-1α) transcription factor, however the association between HIF-1α and TET enzyme expression is largely uninvestigated. Interestingly, ascorbic acid, a critical cofactor for optimal TET enzyme function and normoxic regulation of HIF-1α protein stability, is frequently depleted in malignant tissue, and may further contribute to the malignant phenotype. In our studies, we found supplementation of WM9 human metastatic melanoma cells with ascorbic acid significantly increased 5 hmC content, which was abrogated by TET2 knockdown. Moreover, knockdown of HIF-1α increased TET2 gene and protein expression, and further augmented ascorbic acid-induced TET2 dependent 5-hydroxymethylation in both WM9 and T98G glioblastoma cells. Our data provides novel evidence that HIF-1α is involved in regulating TET expression and 5 hmC status of malignant cells. Furthermore, therapeutic intervention to inhibit HIF-1α in conjunction with adjuvant ascorbic acid may promote DNA demethylation and reexpression of critical tumor suppressor genes in malignant cells and warrants further investigation.