Department of Food Science and Biotechnology, National Chung Hsing University, Taichung, Taiwan.
Department of Anesthesiology, Chi Mei Medical Center, Tainan, Taiwan; Department of the Senior Citizen Service Management, Chia Nan University of Pharmacy and Science, Tainan, Taiwan.
J Nutr Biochem. 2015 Jun;26(6):607-15. doi: 10.1016/j.jnutbio.2014.12.012. Epub 2015 Feb 14.
This study aimed to investigate the anti-metastatic activity of α-carotene (AC) in Lewis lung carcinoma (LLC) and in combination with taxol in LLC-xenografted C57BL/6 mice. Cell culture studies reveal that AC significantly inhibited invasion, migration and activities of matrix metalloproteinase (MMP)-2, -9 and urokinase plasminogen activator but increased protein expression of tissue inhibitor of MMP (TIMP)-1, -2 and plasminogen activator inhibitor (PAI)-1. These effects of AC are similar to those of β-carotene at the same concentration (2.5 μM). AC (2.5 μM) also significantly inhibited integrin β1-mediated phosphorylation of focal adhesion kinase (FAK) which then decreased the phosphorylation of MAPK family. Findings from the animal model reveal that AC treatment (5m g/kg) alone significantly decreased lung metastasis without affecting primary tumor growth, whereas taxol treatment (6 mg/kg) alone exhibited significant inhibition on both actions, as compared to tumor control group. AC treatment alone significantly decreased protein expression of integrin β1 but increased protein expression of TIMP-1 and PAI-1 without affecting protein expression of TIMP-2 and phosphorylation of FAK in lung tissues, whereas taxol treatment alone significantly increased protein expression of TIMP-1, PAI-1 and TIMP-2 but decreased protein expression of integrin β1 and phosphorylation of FAK. The combined treatment produced stronger actions on lung metastasis and lung tissues protein expression of TIMP-1, TIMP-2 and PAI-1. Overall, we demonstrate that AC effectively inhibits LLC metastasis and suppresses lung metastasis in combination with taxol in LLC-bearing mice, suggesting that AC could be used as an anti-metastatic agent or as an adjuvant for anti-cancer drugs.
本研究旨在探讨α-胡萝卜素（AC）在Lewis 肺癌（LLC）中的抗转移活性，以及与紫杉醇联合应用于 LLC 异种移植 C57BL/6 小鼠中的效果。细胞培养研究表明，AC 可显著抑制侵袭、迁移和基质金属蛋白酶（MMP）-2、-9 和尿激酶纤溶酶原激活物的活性，但增加组织金属蛋白酶抑制剂（TIMP）-1、-2 和纤溶酶原激活物抑制剂（PAI）-1 的蛋白表达。AC 的这些作用与相同浓度（2.5 μM）的β-胡萝卜素相似。AC（2.5 μM）还可显著抑制整合素β1 介导的黏着斑激酶（FAK）磷酸化，进而减少 MAPK 家族的磷酸化。动物模型研究结果表明，AC 处理（5m g/kg）单独应用可显著降低肺转移，而不影响原发肿瘤生长，而紫杉醇处理（6 mg/kg）单独应用对两种作用均有显著抑制作用，与肿瘤对照组相比。AC 处理单独应用可显著降低肺组织中整合素β1 的蛋白表达，但增加 TIMP-1 和 PAI-1 的蛋白表达，而不影响 FAK 的磷酸化和 TIMP-2 的蛋白表达，而紫杉醇处理单独应用可显著增加 TIMP-1、PAI-1 和 TIMP-2 的蛋白表达，但降低整合素β1 和 FAK 的磷酸化。联合治疗在肺转移和肺组织 TIMP-1、TIMP-2 和 PAI-1 的蛋白表达方面产生了更强的作用。总之，我们证明 AC 可有效抑制 LLC 转移，并与紫杉醇联合应用抑制 LLC 荷瘤小鼠的肺转移，表明 AC 可作为抗转移剂或抗癌药物的辅助剂。
