Cancer Letters

Cancer Letters

Volume 165, Issue 1, 10 April 2001, Pages 43-49
Cancer Letters

In vitro and in vivo suppression of growth of hepatocellular carcinoma cells by albendazole

https://doi.org/10.1016/S0304-3835(01)00382-2Get rights and content

Abstract

Tubulin protein is a major target of drug molecules, and consequently, tubulin inhibitors have attracted great attention as antimitotic antitumor agents for chemotherapeutic use. It has been shown that, the benzimidazole carbamate group of antiparasitics including albendazole act by inhibiting tubulin polymerization. In this study, albendazole was tested in culture against a range of human, rat and mice hepatocellular carcinoma (HCC) cells and in vivo against human SKHEP-1 tumor growth in nude mice. Albendazole induced a dose-dependent inhibition of [3H]thymidine incorporation in all cell lines examined and a dramatic decline in cell numbers in SKHEP-1 cells. The inhibitory effect of albendazole was evident at the 100 nM concentration and at 1000 nM, proliferation in all cell lines examined was inhibited by more than 80%, while, proliferation of HepG2, Hep3B and SKHEP-1 were suppressed by more than 90%, compared to control. Cell cycle analysis revealed that, depending on the dose employed, albendazole can arrest SKHEP-1 cells at both G0–G1 (250 nM) and G2-M (1000 nM) phases of the cycle. Albendazole treatment (300 mg/kg per day oral for 20 days) of nude mice inoculated subcutaneously with SKHEP-1, led to profound suppression of tumor growth. Immunohistochemical analysis of these tumors revealed that compared to control, those treated with albendazole have lower growth fractions. These findings demonstrate that albendazole strongly suppresses both in vitro and in vivo proliferation of HCC cells.

Introduction

Albendazole a benzimidazole carbamate (methyl 5-propylthio-1H-benzimidazole-2-yl carbamate) is a broad spectrum antiparasitic which is used worldwide against a variety of parasites [1], [2]. Studies conducted on the mechanism of action of BZs have demonstrated that, by binding to tubulin, these drugs inhibit microtubule polymerization [3], [4], [5], [6]. Inhibitors of microtubule polymerization have been shown to exhibit experimentally and clinically, useful antitumor activity [7]. Consequently, the reported activity of BZs against human mammalian tubulin raises the question of whether these agents also possess anticancer properties. In 1985 Lacey and Watson reported the activity of BZs against mouse L1210 leukemia cells [8]. However, except for this and a report investigating the suitability of HCC cells as an in vitro model for the study of albendazole metabolism [9], no other report concerning the possible antitumor effect of BZs has appeared in literature. This coupled with our experience with these drugs [1], [10] and the fact that to date, there are very limited chemotherapeutic options available for the treatment of HCC [11], [12], led to the design of the current study. The study was undertaken to test the effect of albendazole, the most commonly used of the BZs, on cell proliferation rates, cell viability, cell cycle kinetics and the in vivo effects of the drug on xenografts in nude mice.

Section snippets

Cell culture

HepG2, Hep3-B, Hep1-6, SKHEP-1, PLC/PRF/5, and HTC cells were obtained from European Collection of Cell Cultures (ECACC; U.K.). Novikoff was obtained from Cancer Research Centre (DKFZ) Heidelberg, Germany. Cells were cultured in MEM or DMEM supplemented with 10% FBS, 50 units/ml penicillin, 50 units/ml streptomycin, 25 μg/ml amphotericin B (Gibco, Grand Island, NY) and maintained subconfluent at 37°C in humidified incubators containing 5% CO2. Albendazole (Sigma, Australian subsidiary) was

Inhibition of [3H]thymidine incorporation by albendazole

[3H]Thymidine incorporation assay was used to determine the effect of albendazole on cell proliferation in a number of human (HepG2, Hep3-B, PLC/PRF/5, SKHEP-1), rat (HTC and Novikoff) and mice (Hep1-6) HCC cell lines. Results obtained show that, in all cell lines examined, albendazole effectively reduces thymidine incorporation (Table 1). When treated with the 100 nM concentration of albendazole, compared to other cell lines, SKHEP-1 demonstrated the highest level of sensitivity to albendazole

Discussion

Albendazole is a drug that has been in use in the clinic for nearly two decades as the treatment of choice in a number of parasitic diseases. However, the mechanisms of action described for the drug suggest that, it may hold greater potential than it is currently employed for. To explore this possibility, we set out testing the drug against a range of HCC cell lines under both in vitro and in vivo conditions.

Results from the cell proliferation studies clearly demonstrated that all human, rat

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