Antitumor activity of albendazole against the human colorectal cancer cell line HT-29: in vitro and in a xenograft model of peritoneal carcinomatosis
Antitumor activity of albendazole against the human colorectal cancer cell line HT-29: in vitro and in a xenograft model of peritoneal carcinomatosis
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DOI：
10.1007/s00280-004-0927-6
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发表时间：
2005-05-01
影响因子：
3
通讯作者：
Morris, DL
中科院分区：
文献类型：
--
作者：
Pourgholami, MH;Akhter, J;Morris, DL
腹膜表面仍然是结直肠癌患者的重要失败部位。我们最近发现，阿苯达唑(ABZ)是一种安全有效的驱虫药，在肝细胞癌中具有显著的抗肿瘤活性。此外，阿苯达唑还具有独特的理化和药代动力学性质，可能使其成为一种潜在的用于腹膜癌(PC)区域治疗的药物。因此，目前的研究旨在利用人结直肠癌细胞HT-29在体外和体内条件下研究这一概念。在细胞培养方面，研究了ABZ及其主要代谢产物阿苯达唑亚砜(ABZ-SO)和阿苯达唑砜(ABZ-SO2)对人结肠癌细胞株HT-29生长的影响。我们还研究了ABZ对细胞周期的影响以及可能诱导这些细胞凋亡的可能性。雄性裸鼠腹腔接种(Ip)用不同方案的ABZ处理HT-29细胞。或口服治疗6周。根据治疗结束时动物体内存在的腹膜肿瘤结节的数量来评估疗效。在体外，ABZ处理细胞5d后，细胞生长受到严重抑制。H-3-胸腺嘧啶核苷分析和台盼蓝活细胞计数证实了ABZ效应的剂量和时间依赖性，而恢复实验揭示了这种抑制的可逆性。ABZ-SO和ABZ-SO2也在细胞培养研究中进行了评估，并与母药进行了比较。在HT-29细胞中，ABZ和ABZ-SO的IC50值分别为0.12和2.35微米。另一种代谢物ABZ-SO2完全没有活性。对ABZ作用机制的研究表明，ABZ使HT-29细胞停滞在G(2)/M期，而TUNEL、DNA梯状条带和caspase-3活性均证实了ABZ诱导的细胞凋亡。在裸鼠的腹膜移植瘤中，ABZ能显著抑制腹膜肿瘤的生长。而候补IP。剂量(阿司匹林，150 mg/kg)对肿瘤生长的抑制程度最高(P<；0.001)，计划，如每周一次剂量，甚至整个疗程(6周)的一次剂量也有效地减少腹膜肿瘤的生长。然而，当口服ABZ时，没有观察到这种活性。这项研究首次显示了区域给药ABZ在抑制人结直肠癌腹膜肿瘤生长方面的强大作用。这种作用被认为是通过阻止肿瘤细胞处于周期的G(2)/M期和细胞凋亡来实现的。这些发现为ABZ在治疗结直肠癌细胞系产生的区域性前列腺癌方面的潜在价值提供了证据。
The peritoneal surface remains an important failure site for patients with colorectal cancer. We have recently shown that albendazole (ABZ), a safe and effective anthelmintic drug, has profound antitumor activity in hepatocellular cancer. Furthermore, albendazole also possesses unique physiochemical and pharmacokinetic properties probably making it a potential drug for use in the regional treatment of peritoneal carcinomatosis (PC). The current study was therefore designed to investigate this concept under both in vitro and in vivo conditions using human colorectal cancer cells HT-29. In cell culture, studies were conducted to investigate the effect of ABZ and its major metabolites, albendazole sulfoxide (ABZ-SO) and albendazole sulfone (ABZ-SO2) on the growth of human colorectal cell line HT-29. We also investigated the effects of ABZ on the cell cycle and the possible induction of apoptosis in these cells. Male nude mice inoculated intraperitoneally (i.p.) with HT-29 cells were treated with various schedules of ABZ given i.p. or orally for 6 weeks. Response was evaluated as the number of peritoneal tumor nodules present in animals at the end of the treatment period. In vitro, ABZ treatment of cells for 5 days led to profound inhibition of growth. H-3-Thymidine assay and trypan blue viable cell counts confirmed the dose- and time-dependency of the ABZ effect, while recovery experiments revealed the reversible nature of this inhibition. ABZ-SO and ABZ-SO2 were also evaluated in cell culture studies and compared with the parent drug. In HT-29 cells, the IC50 values were calculated to be 0.12 mu M for ABZ and 2.35 mu M for ABZ-SO. The other metabolite, ABZ-SO2, was completely inactive. Studies on the mechanism of ABZ action, revealed arrest of HT-29 cells at the G(2)/M phase of the cell cycle, while TUNEL, DNA laddering and caspase-3 activity all confirmed ABZ induced apoptosis. In nude mice with peritoneal HT-29 xenografts, ABZ profoundly inhibited peritoneal tumor growth. While alternate i.p. dosing (ABZ, 150 mg/kg) led to the highest degree of tumor growth suppression (P < 0.001), schedules such as once-weekly dosing and even a single dose for the entire course of treatment (6 weeks) were also effective in reducing peritoneal tumor growth. However, no such activity was observed when ABZ was administered orally. This study shows for the first time the potent effect of regionally administered ABZ in suppressing the growth of peritoneal tumors of human colorectal origin. The effect is thought to be brought about by arresting tumor cells at the G(2)/M phase of the cycle and apoptosis. These findings provide evidence for potential value of ABZ in the treatment of regional PC arising from colorectal cell lines.