Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin 300060, P, R, China.
Mol Cancer. 2013 Oct 7;12(1):116. doi: 10.1186/1476-4598-12-116.
Wnt/β-catenin signaling is a highly conserved pathway in organism evolution and is important in many biological processes. Overactivation of Wnt/β-catenin signaling is closely related to tumor development and progression. To identify potent small molecules that can fight aberrant Wnt/β-catenin-mediated cancer, we synthesized a novel pyrazoline derivative (N-(4-hydroxybenzyl)-1,3,4-triphenyl-4,5-dihydro-1H-pyrazole-5-carboxamide, BHX) to block Wnt signaling, and determined the absolute configuration of its precursor (ethyl 1,3,4-triphenyl-4,5-dihydro-1H-pyrazole-5-carboxylate). We then evaluated the inhibitory effect of BHX in vitro and in vivo.
Cell proliferation was assessed in three human cancer cell lines (A549, HT29, and MGC803) in the presence and absence of BHX using MTS assays. BHX effectively inhibited A549, HT29, and MGC803 cell proliferation with IC50 of 5.43 ± 1.99, 6.95 ± 0.24, and 7.62 ± 1.31 μM, respectively. BHX significantly induced apoptosis and G1 phase arrest in A549 and MGC803 cells. The β-catenin protein level was markedly reduced in A549 and MGC803 cells under BHX treatment. The inhibitory effect of BHX in vivo was investigated using a mouse xenograft model. A549 xenograft growth was suppressed by 50.96% in nude mice treated continuously with 100 mg/kg BHX for 21 d. Weight remained almost unchanged, which indicates the low toxicity of the compound.
Our data suggest that BHX is a new drug candidate for cancer treatment because of its potent effect on the Wnt/β-catenin pathway and low toxicity.
Wnt/β-连环蛋白信号通路在生物进化中高度保守，在许多生物学过程中都很重要。Wnt/β-连环蛋白信号通路的过度激活与肿瘤的发生和发展密切相关。为了鉴定能够对抗异常 Wnt/β-连环蛋白介导的癌症的有效小分子，我们合成了一种新型吡唑啉衍生物（N-（4-羟基苄基）-1,3,4-三苯基-4,5-二氢-1H-吡唑-5-甲酰胺，BHX）来阻断 Wnt 信号，并确定了其前体（乙酯 1,3,4-三苯基-4,5-二氢-1H-吡唑-5-羧酸）的绝对构型。然后，我们评估了 BHX 在体外和体内的抑制作用。
使用 MTS 测定法，在存在和不存在 BHX 的情况下，在三种人癌细胞系（A549、HT29 和 MGC803）中评估了细胞增殖。BHX 有效抑制 A549、HT29 和 MGC803 细胞增殖，IC50 分别为 5.43±1.99、6.95±0.24 和 7.62±1.31μM。BHX 显著诱导 A549 和 MGC803 细胞凋亡和 G1 期阻滞。在 BHX 处理下，A549 和 MGC803 细胞中的β-连环蛋白蛋白水平明显降低。在裸鼠异种移植模型中研究了 BHX 的体内抑制作用。在连续用 100mg/kg BHX 治疗 21 天的裸鼠中，A549 异种移植生长受到 50.96%的抑制。体重几乎不变，这表明该化合物的毒性较低。
我们的数据表明，BHX 是一种新的癌症治疗候选药物，因为它对 Wnt/β-连环蛋白通路具有强大的作用且毒性低。
