Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Umm Al-Qura University, Holy Makkah, Saudi Arabia. Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt.
Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Umm Al-Qura University, Holy Makkah, Saudi Arabia.
Cancer Prev Res (Phila). 2016 Jun;9(6):491-501. doi: 10.1158/1940-6207.CAPR-15-0439. Epub 2016 Mar 28.
Colorectal cancer is a common cancer with high mortality rate. Despite being the standard anti-colorectal cancer drug, 5-fluorouracil (5-FU) exhibits only limited therapeutic benefits. Herein, we investigated whether paricalcitol, a synthetic vitamin D analogue with potential antitumor properties, would enhance the chemopreventive efficacy of 5-FU on an intermediate-term (15 weeks) model of colorectal tumors induced by azoxymethane (AOM) in rats. After AOM injection, 5-FU was administered during the 9th and 10th weeks (12 mg/kg/day for 4 days, then 6 mg/kg every other day for another 4 doses), whereas paricalcitol (2.5 μg/kg/day; 3 days/week) was given from the 7th to the 15th week. At week 15, the animals were euthanized and their resected colons were examined macroscopically and microscopically. Quantitative RT-PCR was used to measure the transcription activities of Wnt, β-catenin, DKK-1, CDNK-1A, NF-κB, and COX-2 genes, and ELISA was used to quantify the protein levels of β-catenin, COX-2, HSP90, and VEGF. IHC was additionally used to measure β-catenin, HSP90, and inducible nitric oxide synthase (iNOS). Compared with their individual therapy, combination of 5-FU and paricalcitol showed more significant reducing effect on numbers of grown tumors and large aberrant crypts foci. Mechanistically, paricalcitol and 5-FU had cooperated together to repress the expression of procancerous Wnt, β-catenin, NF-κB, COX-2, iNOS, VEGF, and HSP-90 more, and to upregulate the expression of antitumorigenesis DKK-1 and CDNK-1A, compared with their monotherapies. Our findings suggest that combined use of paricalcitol with 5-FU exhibits an augmenting chemopreventive effect against colorectal tumors, and might potentially be useful for chemoprevention in colorectal cancer patients. Cancer Prev Res; 9(6); 491-501. ©2016 AACR.
结直肠癌是一种高死亡率的常见癌症。尽管氟尿嘧啶（5-FU）是标准的抗结直肠癌药物，但它的治疗效果有限。在这里，我们研究了合成维生素 D 类似物帕立骨化醇（具有潜在抗肿瘤特性）是否会增强 5-FU 在大鼠中由氧化偶氮甲烷（AOM）诱导的中期（15 周）结直肠肿瘤模型中的化学预防效果。在 AOM 注射后，在第 9 周和第 10 周（连续 4 天给予 12mg/kg/天，然后每 2 天给予 6mg/kg，再给予 4 个剂量）给予 5-FU，而帕立骨化醇（2.5μg/kg/天；每周 3 天）从第 7 周到第 15 周给予。在第 15 周，处死动物并检查其切除的结肠的宏观和微观。使用定量 RT-PCR 测量 Wnt、β-catenin、DKK-1、CDNK-1A、NF-κB 和 COX-2 基因的转录活性，使用 ELISA 定量测定β-catenin、COX-2、HSP90 和 VEGF 的蛋白水平。免疫组化还用于测量β-catenin、HSP90 和诱导型一氧化氮合酶（iNOS）。与单独治疗相比，5-FU 和帕立骨化醇联合使用对生长肿瘤和大异常隐窝灶的数量有更显著的减少作用。从机制上讲，与单独治疗相比，帕立骨化醇和 5-FU 联合使用可更有效地抑制致癌 Wnt、β-catenin、NF-κB、COX-2、iNOS、VEGF 和 HSP-90 的表达，并上调抗肿瘤 DKK-1 和 CDNK-1A 的表达。我们的研究结果表明，帕立骨化醇与 5-FU 联合使用可增强结直肠肿瘤的化学预防效果，可能对结直肠癌患者的化学预防有用。癌症预防研究; 9(6); 491-501. ©2016AACR.
