Leucovorin Enhances the Anti-cancer Effect of Bortezomib in Colorectal Cancer Cells.
Leucovorin Enhances the Anti-cancer Effect of Bortezomib in Colorectal Cancer Cells.
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DOI：
10.1038/s41598-017-00839-9
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发表时间：
2017-04-06
影响因子：
4.6
通讯作者：
Li Y
中科院分区：
文献类型：
--
作者：
Wang S;Wang L;Zhou Z;Deng Q;Li L;Zhang M;Liu L;Li Y
结直肠癌是世界范围内的主要癌症类型。 5-氟尿嘧啶通常与亚叶酸联合使用，是结直肠癌化疗中最常用的药物，但结直肠癌细胞对5-氟尿嘧啶产生耐药性是化疗失败的主要原因。大多数接受静脉注射 5-氟尿嘧啶的患者会出现副作用。亚叶酸由于其类似维生素的特性，几乎没有副作用。药物再利用是指将已批准的药物用于治疗新的适应症。在这项研究中，我们进行了一项新的药物再利用筛选，以确定美国食品和药物管理局批准的化疗化合物与亚叶酸具有对抗结直肠癌细胞的协同活性。我们发现，硼替佐米和亚叶酸的组合比单独使用任何一种药物都能更好地增强半胱天冬酶的激活并增加结直肠癌细胞的凋亡。此外，在小鼠结直肠癌异种移植物中也观察到协同诱导细胞凋亡和抑制肿瘤生长。这些数据支持亚叶酸增强硼替佐米的抗癌作用，并提出了这种针对结直肠癌的新型组合治疗方法。
Colorectal cancer is a major cancer type worldwide. 5-fluorouracil, often given with leucovorin, is the most commonly used drug in colorectal cancer chemotherapy, yet development of drug resistance to 5-fluorouracil in colorectal cancer cells is the primary cause of chemotherapy failure. Most patients receiving intravenous 5-fluorouracil develop side effects. Leucovorin, due to its vitamin-like profile, has few side-effects. Drug repurposing is the application of approved drugs to treat new indications. In this study, we performed a novel drug-repurposing screening to identify Food and Drug Administration-approved chemotherapeutic compounds possessing synergistic activity with leucovorin against colorectal cancer cells. We found that the combination of bortezomib and leucovorin enhanced caspase activation and increased apoptosis in colorectal cancer cells better than either agent alone. Further, the synergistic induction of apoptosis and inhibition of tumor growth were also observed in mouse colorectal cancer xenografts. These data support leucovorin enhances the anti-cancer effect of bortezomib and present this novel combinatorial treatment against colorectal cancer.