T-oligo as an anticancer agent in colorectal cancer.
T-oligo as an anticancer agent in colorectal cancer.
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T-oligo 作为结直肠癌的抗癌剂。
DOI：
10.1016/j.bbrc.2014.03.013
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发表时间：
2014
影响因子：
3.1
通讯作者：
Puri,Neelu
中科院分区：
文献类型：
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作者：
Wojdyla,Luke;Stone,AmandaL;Sethakorn,Nan;Uppada,SrijayaprakashB;Devito,JosephT;Bissonnette,Marc;Puri,Neelu
在美国，2014年估计将有96，830例结直肠癌（CRC）新发病例和50，310例死亡。CRC通常在疾病的晚期被发现，此时没有有效的化疗。因此，迫切需要对正常细胞具有最小影响的有效新疗法。T-oligo是一种与3′-端粒突出端同源的寡核苷酸，在多种恶性肿瘤细胞中诱导有效的DNA损伤反应，但其在CRC中的疗效尚未研究。这是第一次研究证明T-寡核苷酸在两种CRC细胞系HT-29和LoVo中诱导的抗癌作用，这两种细胞系对常规化疗具有高度抗性。在这项研究中，我们发现T-oligo可能通过p53/p73途径介导其DNA损伤反应，从而抑制细胞增殖并诱导凋亡或衰老。此外，还观察到下游DNA损伤反应蛋白（包括E2 F1、p53或p73）的上调。在LoVo细胞中，T-oligo诱导衰老，降低克隆形成，并增加衰老相关蛋白p21，p27和p53的表达。此外，观察到保护端粒末端的shelterin蛋白复合物的两种组分POT 1和TRF 2的下调。此外，我们研究了T-oligo与EGFR酪氨酸激酶抑制剂吉非替尼（Gefitinib）组合的抗增殖作用，这导致了对细胞增殖的附加抑制作用。总的来说，这些数据提供了证据，表明T-oligo单独或与其他分子靶向治疗联合使用，具有作为CRC抗癌药物的潜力。
In the United States, there will be an estimated 96,830 new cases of colorectal cancer (CRC) and 50,310 deaths in 2014. CRC is often detected at late stages of the disease, at which point there is no effective chemotherapy. Thus, there is an urgent need for effective novel therapies that have minimal effects on normal cells. T-oligo, an oligonucleotide homologous to the 3′-telomere overhang, induces potent DNA damage responses in multiple malignant cell types, however, its efficacy in CRC has not been studied. This is the first investigation demonstrating T-oligo-induced anticancer effects in two CRC cell lines, HT-29 and LoVo, which are highly resistant to conventional chemotherapies. In this investigation, we show that T-oligo may mediate its DNA damage responses through the p53/p73 pathway, thereby inhibiting cellular proliferation and inducing apoptosis or senescence. Additionally, upregulation of downstream DNA damage response proteins, including E2F1, p53 or p73, was observed. In LoVo cells, T-oligo induced senescence, decreased clonogenicity, and increased expression of senescence associated proteins p21, p27, and p53. In addition, downregulation of POT1 and TRF2, two components of the shelterin protein complex which protects telomeric ends, was observed. Moreover, we studied the antiproliferative effects of T-oligo in combination with an EGFR tyrosine kinase inhibitor, Gefitinib, which resulted in an additive inhibitory effect on cellular proliferation. Collectively, these data provide evidence that T-oligo alone, or in combination with other molecularly targeted therapies, has potential as an anti-cancer agent in CRC.