Enhanced efficacy of 5-fluorouracil in combination with a dual histone deacetylase and phosphatidylinositide 3-kinase inhibitor (CUDC-907) in colorectal cancer cells.
Enhanced efficacy of 5-fluorouracil in combination with a dual histone deacetylase and phosphatidylinositide 3-kinase inhibitor (CUDC-907) in colorectal cancer cells.
复制标题
5-氟尿嘧啶与双重组蛋白脱乙酰酶和磷脂酰肌醇 3-激酶抑制剂 (CUDC-907) 联合使用可增强结直肠癌细胞中的功效。
DOI：
10.4103/1319-3767.199136
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发表时间：
2017-01
期刊：
影响因子：
--
通讯作者：
Alajez NM
中科院分区：
文献类型：
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作者：
Hamam R;Ali D;Vishnubalaji R;Alsaaran ZF;Chalisserry EP;Alfayez M;Aldahmash A;Alajez NM
5-氟尿嘧啶(5-FU)被广泛应用于结直肠癌的治疗。然而，5-FU作为单一药物的疗效是有限的，存在多种不良反应。因此，本研究的目的是评价组蛋白脱乙酰酶和磷脂酰肌醇3-激酶的双重抑制剂CUDC-907联合5-FU对结直肠癌细胞的抑制作用。用AlamarBlue和集落形成实验检测细胞存活率。用吖啶橙/溴化乙锭染色和流式细胞术检测细胞的凋亡和坏死事件，以及细胞周期进程。免疫印迹法检测组蛋白H3的乙酰化和AKT的磷酸化。我们的数据显示，CUDC-907与5-FU联合使用时，对HCT116、RKO、Colo-205和HT-29结直肠癌细胞的毒性增强。同样，HCT116细胞的克隆形成能力也受到抑制。经CUDC-907和5-FU处理的细胞出现凋亡和坏死，并表现为多倍体增加。此外，经CUDC-907处理的CRC细胞显示出更高程度的组蛋白H3赖氨酸9乙酰化(H3K9ac)和降低的AKT磷酸化(Ser473)。我们的数据首次揭示了CUDC-907与5-FU联合应用时对结直肠癌细胞的抑制作用增强，支持将其作为一种潜在的治疗策略应用于结直肠癌治疗。
5-Fluorouracil (5-FU) is widely used in the treatment of patients with colorectal cancer (CRC). However, the efficacy of 5-FU as a single agent is limited, with multiple undesired side effects. Therefore, the aim of the current study was to assess the efficacy of CUDC-907 (a dual inhibitor of histone deacetylase and phosphatidylinositide 3-kinase) in combination with 5-FU against CRC cells. Cell viability was determined using AlamarBlue and colony formation assays. Acridine orange/ethidium bromide staining and flow cytometry were used to measure apoptotic and necrotic events, as well as cell cycle progression. Immunoblotting was used to assess acetylation of histone H3 and phosphorylation of AKT. Our data revealed enhanced toxicity of CUDC-907 against HCT116, RKO, COLO-205, and HT-29 CRC cells when combined with 5-FU. Similarly, the colony formation capability of HCT116 cells was suppressed by the combination treatment. Cells treated with CUDC-907 and 5-FU underwent apoptosis and necrosis, and exhibited increased polyploidy. Furthermore, CRC cells treated with CUDC-907 exhibited a higher degree of histone H3 lysine 9 acetylation (H3K9ac) and reduced AKT phosphorylation (Ser473). Our data revealed, for the first time, the enhanced inhibitory effect of CUDC-907 against CRC cells when combined with 5-FU, supporting the application of this combination as a potential therapeutic strategy in CRC treatment.