Antitumor activity of albendazole against the human colorectal cancer cell line HT-29: in vitro and in a xenograft model of peritoneal carcinomatosis.
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. (3)H-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 IC(50) values were calculated to be 0.12 microM for ABZ and 2.35 microM 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.
Pourgholami
Mohammad H
MH
Cancer Research Laboratories, Department of Surgery, St George Hospital, University of New South Wales, Kogarah, Sydney, NSW 2217, Australia.
Akhter
Javed
J
Wang
Lisa
L
Lu
Ying
Y
Morris
David L
DL
D015766:Albendazole / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma / Q000188:drug therapy*; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D006801:Humans; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010534:Peritoneal Neoplasms / Q000188:drug therapy*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
D000871:Anthelmintics; D015766:Albendazole