Antisense inhibition of methylenetetrahydrofolate reductase reduces cancer cell survival in vitro and tumor growth in vivo
Antisense inhibition of methylenetetrahydrofolate reductase reduces cancer cell survival in vitro and tumor growth in vivo
复制标题
DOI：
10.1158/1078-0432.ccr-04-2047
复制
发表时间：
2005-03-01
影响因子：
11.5
通讯作者：
Rozen, R
中科院分区：
文献类型：
--
作者：
Stankova, A;Shang, JJ;Rozen, R
目的：许多癌细胞系依赖于蛋氨酸，当蛋氨酸供应有限时，它们的增殖会减少。亚甲基四氢叶酸还原酶 (MTHFR) 产生叶酸衍生物，用于将同型半胱氨酸重新甲基化为蛋氨酸。我们研究了反义介导的 MTHFR 抑制对人类癌细胞存活的影响。 实验设计：我们检测了 MTHFR 反义与标准细胞毒性药物组合的体外和体内抗癌作用。结果：与对照寡核苷酸相比，针对 MTHFR (EX5) 的特异性反义在体外对人结肠、肺、乳腺癌、前列腺和神经母细胞瘤肿瘤细胞的生长显示出显着的抑制作用。细胞毒性药物（5-氟尿嘧啶、顺铂或紫杉醇）增强了 EX5 的作用。在体内，反义分子单独或与细胞毒性药物组合可抑制人结肠癌和肺癌异种移植物的生长。与对照寡核苷酸相比，用EX5治疗分别抑制结肠肿瘤和肺肿瘤的生长60%和45%。与单独的 EX5 相比，EX5 与 5-氟尿嘧啶的组合使结肠肿瘤的生长额外减少了 30%，与单独的顺铂相比，EX5 与顺铂的组合使肺部肿瘤的生长额外减少了 40%。 EX5 的生长抑制与 MTHFR 蛋白量的减少和细胞凋亡标记物的量增加有关。结论：我们的结果证实，MTHFR 抑制可减少肿瘤生长，并表明通过反义或小分子抑制 MTHFR 可能是一种新型抗癌方法。
Purpose: Many cancer lines are methionine dependent and decrease proliferation when methionine supply is limited. Methylenetetrahydrofolate reductase (MTHFR) generates the folate derivative for homocysteine remethylation to methionine. We investigated the effect of antisense-mediated inhibition of MTHFR on survival of human cancer cells.Experimental Design: We examined the in vitro and in vivo anticancer effects of a combination of MTHFR antisense and standard cytotoxic drugs.Results: Specific antisense against MTHFR (EX5) showed significant inhibitory effects on growth of human colon, lung, breast, prostate, and neuroblastoma tumor cells in vitro compared with that of the control oligonucleotide. Cytotoxic drugs (5-fluorouracil, cisplatin, or paclitaxel) potentiated the effect of EX5. In vivo, antisense alone or in combination with cytotoxic drugs inhibited the growth of human colon and lung carcinoma xenografts. In comparison with control oligonucleotide, treatment with EX5 inhibited growth of colon tumors and lung tumors by 60% and 45%, respectively. EX5 with 5-fluorouracil decreased growth of colon tumors by an additional 30% compared with EX5 alone, and EX5 with cisplatin decreased growth of lung tumors by an additional 40% compared with cisplatin alone. Growth inhibition by EX5 was associated with decreased amounts of MTHFR protein and with increased amounts of an apoptosis marker.Conclusions: Our results confirm that MTHFR inhibition decreases tumor growth and suggest that inhibition of MTHFR by antisense or small molecules may be a novel anticancer approach.