Futakuchi Mitsuru, Ogawa Kumiko, Tamano Seiko, Takahashi Seishiro, Shirai Tomoyuki
Department of Experimental Pathology and Tumor Biology, Graduate School of Medical Sciences, Nagoya City University, Mizuho-ku, Nagoya 467-8601, Japan.
Cancer Sci. 2004 Jan;95(1):18-24. doi: 10.1111/j.1349-7006.2004.tb03165.x.
To evaluate the suppressive effects of nuclear factor kappa B (NF-kappaB) inhibitors on metastasis, three agents, pentoxifylline (PTX, 0.5% in diet), N-acetyl-L-cysteine (NAC, 0.5% in diet), and aspirin (ASP, 0.5% in diet) were applied in an in vivo highly metastatic rat hepatocellular carcinoma (HCC) model in F344 male rats. Administration of NF-kappaB inhibitors for 8 weeks after induction of highly metastatic HCC by sequential treatment with diethylnitrosamine and N-nitrosomorpholine did not cause any significant change in survival rate or body weight. The incidence of HCC was 100% at week 23, regardless of treatment with NF-kappaB inhibitors. PTX, NAC, and ASP did not exert any significant effect on the development or differentiation of HCCs, although PTX tended to decrease the multiplicity of HCC. Although no lung metastasis was observed in the rats killed at the end of the period of carcinogen exposure, lung metastasis was found in 100% of animals in all the groups at the end of the experiment. Multiplicity of lung metastasis was significantly decreased by PTX and NAC, whereas ASP was without significant influence. The size of metastatic nodules was also significantly reduced in the PTX treatment group. Furthermore, the inhibitory kappa-B (IkappaB) protein level, considered to be a marker for the degree of NF-kappaB transcription, was significantly suppressed by PTX. mRNA expression in HCC for vascular cell adhesion molecule-1 (VCAM-1), which is considered to play a key role in attachment of cancer cells to the endothelium, was significantly suppressed by PTX. Among the splicing variants of VEGF, VEGF-A120, VEGF-A144, VEGF-A164, and VEGF-A188, suppressed mRNA expression of VEGF-A188 appeared to be correlated with suppression of lung metastasis formation. In conclusion, the present study demonstrated that NF-kappaB inhibitors have the potential to inhibit lung metastasis from rat HCCs in vivo, and PTX is especially promising. Its mechanism of action may involve suppression of VCAM-1 and VEGF-A188 production.
为评估核因子κB（NF-κB）抑制剂对转移的抑制作用，在F344雄性大鼠的体内高转移性大鼠肝细胞癌（HCC）模型中应用了三种药物，即己酮可可碱（PTX，饮食中含0.5%）、N-乙酰半胱氨酸（NAC，饮食中含0.5%）和阿司匹林（ASP，饮食中含0.5%）。在用二乙基亚硝胺和N-亚硝基吗啉序贯处理诱导高转移性HCC后，给予NF-κB抑制剂8周，生存率或体重未出现任何显著变化。在第23周时，无论是否用NF-κB抑制剂治疗，HCC的发生率均为100%。PTX、NAC和ASP对HCC的发生或分化均未产生任何显著影响，尽管PTX有降低HCC多发性的趋势。虽然在致癌物暴露期结束时处死的大鼠中未观察到肺转移，但在实验结束时所有组的动物中均发现100%出现肺转移。PTX和NAC显著降低了肺转移的多发性，而ASP无显著影响。PTX治疗组转移瘤的大小也显著减小。此外，被认为是NF-κB转录程度标志物的抑制性κB（IkappaB）蛋白水平被PTX显著抑制。血管细胞黏附分子-1（VCAM-1）在HCC中的mRNA表达被认为在癌细胞黏附于内皮细胞中起关键作用，其被PTX显著抑制。在血管内皮生长因子（VEGF）的剪接变体中，VEGF-A120、VEGF-A144、VEGF-A164和VEGF-A188中，VEGF-A188的mRNA表达受抑制似乎与肺转移形成的抑制相关。总之，本研究表明NF-κB抑制剂在体内有抑制大鼠HCC肺转移的潜力，PTX尤其有前景。其作用机制可能涉及抑制VCAM-1和VEGF-A188的产生。
