Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia.
King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia.
Biochim Biophys Acta Mol Basis Dis. 2021 Mar 1;1867(3):166040. doi: 10.1016/j.bbadis.2020.166040. Epub 2020 Dec 16.
Although vitamin D (VD) is chemoprotective and enhances 5-fluorouracil (5-FU) cytotoxicity against colorectal cancer (CRC), little is known about its potential calcium (Ca)-mediated anti-tumorigenic actions. Therefore, this study compared between VD and its non-calcaemic analogue, Paricalcitol (Pcal), ± 5-FU in relation to chemoprevention and Ca-mediated apoptosis in vivo and in vitro.
Seventy male mice were distributed to: negative controls, positive controls (PC), VD, Pcal, 5-FU, VD + 5-FU and Pcal+5-FU groups. All groups, except negative, received two consecutive azoxymethane (AOM)-injections (10 mg/Kg/week) for CRC induction. VD (1000 IU/kg; three times/week) and Pcal (1.25 μg/kg; three times/week) injections started week-16 post-AOM and for 10 weeks. Three successive 5-FU cycles began at week-21 (50 mg/Kg/week). Similar protocols with VD, Pcal and/or 5-FU were applied in the HT29 colon cancer cells.
The PC group had abundant malignant tumours, markedly elevated proliferation markers (survivin/CCND1) and declines in cyclin-dependent kinase-inhibitor-1A, pro-apoptotic molecules (p53/BAX/cytochrome_C/caspase-3), tissue Ca concentrations and Ca-dependent proteins (CaSR/CAM/CAMKIIA). All monotherapies equally reduced tumour numbers and proliferation markers whilst promoting the anti-tumorigenic molecules. VD and/or 5-FU, but not Pcal monotherapy, enhanced Ca levels and Ca-related molecules (CaSR/CAM/CAMKIIA/BAX/cytochrome_C) in vivo and in vitro. However, VD + 5-FU co-therapy showed the lowest tumour numbers, the highest cell numbers in sub-G1 phase of cell cycle, alongside the most effective modulations of oncogenes, tumour suppressors and Ca-related molecules at the gene and protein levels in vivo and in vitro.
VD was superior than Paricalcitol in potentiating 5-FU cytotoxicity, possibly by upregulating several Ca-related molecules involved in tumour suppression.
尽管维生素 D (VD) 具有化学预防作用，并增强了氟尿嘧啶 (5-FU) 对结直肠癌 (CRC) 的细胞毒性，但人们对其潜在的钙 (Ca) 介导的抗肿瘤作用知之甚少。因此，本研究比较了 VD 与其非钙类似物帕立骨化醇 (Pcal) 在体内和体外的化学预防和 Ca 介导的细胞凋亡方面的差异。
70 只雄性小鼠分为阴性对照组、阳性对照组 (PC)、VD、Pcal、5-FU、VD+5-FU 和 Pcal+5-FU 组。除阴性对照组外，所有组均接受两次连续的氧化偶氮甲烷 (AOM) 注射（10mg/kg/周）以诱导 CRC。VD（1000IU/kg；每周 3 次）和 Pcal（1.25μg/kg；每周 3 次）注射于 AOM 后 16 周开始，持续 10 周。5-FU 连续 3 个周期于第 21 周开始（50mg/kg/周）。HT29 结肠癌细胞中也应用了类似的 VD、Pcal 和/或 5-FU 方案。
PC 组有大量恶性肿瘤，增殖标志物（survivin/CCND1）显著升高，细胞周期蛋白依赖性激酶抑制剂-1A、促凋亡分子（p53/BAX/细胞色素 C/caspase-3）下降，组织 Ca 浓度和 Ca 依赖性蛋白（CaSR/CAM/CAMKIIA）减少。所有单药治疗均同等减少肿瘤数量和增殖标志物，同时促进抗肿瘤分子。VD 和/或 5-FU，但不是 Pcal 单药治疗，增加了体内和体外的 Ca 水平和 Ca 相关分子（CaSR/CAM/CAMKIIA/BAX/细胞色素 C）。然而，VD+5-FU 联合治疗在体内和体外显示出最低的肿瘤数量、细胞周期中 G1 期前细胞数量最多，以及基因和蛋白水平上对癌基因、肿瘤抑制基因和 Ca 相关分子的最有效调节。
VD 比帕立骨化醇更能增强 5-FU 的细胞毒性，可能是通过上调参与肿瘤抑制的几个 Ca 相关分子。
