4-氨基苯酚维甲酰胺对肝癌和恶性黑色素瘤细胞的抑制作用

INHIBITORY EFFECTS ON HEPATOCARCINOMA AND B16 MELANOMA CELLS BY N-(4-HYDROPHENYL) RETINAMIDE

高度恶性肿瘤如肝癌或恶性黑色素瘤病人即使手术治疗,仍然有相当多的病人预后不好,或发生转移。本文研究了自行合成的4-氨基苯酚维甲酰胺(4-HPR),一种维甲酸的衍生物,通过观察对肝癌细胞和恶性黑色素瘤细胞的作用,发现该衍生物具有较强的抑制肝癌细胞迁移能力,7721-k3肝癌细胞的迁移细胞数从对照组的201(27.2,经过6h的作用后即下降到58±5.03(p<0.05,n=4);黑色素瘤细胞则从302±30.1下降到254±25.04(p<0.05,n=4);侵润能力也显著下降,7721-k3细胞穿过人工模拟基底膜的细胞数从对照组的27±13.1下降到11.2±3.3,黑色素瘤细胞则从67.5±10.1下降到24.3±3.2(p<0.05,n=3)。而且发现3μmol/L 4-HPR作用B16黑色素瘤细胞48h可诱导37.11±0.94%细胞的调亡,与相同微克分子浓度的维甲酸相比,具有显著性差别(p<0.05)。但是不能显著诱导7721-k3细胞凋亡。4-HPR诱导B16黑色素瘤细胞凋亡的作用机制尚不清楚,我们利用与肿瘤恶性程度密切有关的乳糖基神经酰胺磺酰基转移酶(CST)基因,转染B16细胞使之高表达以后,可以部分抑制这些细胞对4-HPR诱导凋亡的敏感性,但是不能完全抑制。4-HPR是目前已知毒副作用最小的维生素A类化合物,有可能成为恶性黑色素瘤或肝癌治疗的一个有效的药物。

In this paper, a significantly effect of N-(4-hydrophenyl) retinamide (4-HPR) ,a derivative of retinoic acid, was observed on inhibition of migration,invasion,cell growth,and induction of apoptosis in hepatoma cells and B16 melanoma cells. The number of migratory hepatoma cells reduced significantly from the control 201 ± 27.2 to 58 ± 5.03 after 6-hour incubation with 4-HPR (p< 0.01, n = 4). The number of migratory B16 melanoma cells reduced from the control 302 ± 30.1 to 254±25.04 (p<0.05,n=4). The invasive ability of these cells was also suppressed by 4-HPR treatment. Cells that penetrated the artificial membrane matrigel decreased from 27 ±13.1 to 11.2 ± 3.3 in hepatoma cells,from 67.5 ± 10.1 to 24. 3 ± 3.2 in B16 melanoma cells (p<0.05,n = 3). Furthermore, cell growth was significantly inhibited especially in B16 melanoma cells and 37. 11 ± 0. 94 % cells were induced to apoptosis after 48-hour induction by 4-HPR, which was significantly higher than those by retinoic acid treatment (p<0.05). Although the mechanism of 4-HPR effects was not very clear,over expression of CST,which was inhibited by 4-HPR in our previous study,could diminish the apoptosis-inducing effect by 4-HPR. We believe that 4-HPR has a strong inhibitory effect on melanoma and hepatocarcinoma cells and might become a potent therapeutic agent.