Cytotoxicity of Vitex agnus-castus fruit extract and its major component, casticin, correlates with differentiation status in leukemia cell lines.

We have demonstrated that an extract from the ripe fruit of Vitex agnus-castus (Vitex) exhibits cytotoxic activities against various types of solid tumor cells, whereas its effects on leukemia cells has not been evaluated to date. In this study, the effects of Vitex and its major component, casticin, on leukemia cell lines, HL-60 and U-937, were investigated by focusing on proliferation, induction of apoptosis and differentiation. Identification and quantitation by NMR spectroscopy showed that casticin accounted for approximate 1% weight of Vitex. Dose-dependent cytotoxicity of Vitex and casticin was observed in both cell lines, and HL-60 cells were more sensitive to the cytotoxicity of Vitex/casticin compared to U-937 cells. Furthermore, compared to unstimulated HL-60 cells, phorbol 12-myristate 13-acetate (PMA)- and 1,25-dihydroxyvitamin D3 (VD3)-differentiated HL-60 cells acquired resistance to Vitex/casticin based on the results from cell viability and apoptosis induction analysis. Since the HL-60 cell line is more immature than the U-937 cell line, these results suggested that the levels of cytotoxicity of Vitex/casticin were largely attributed to the degree of differentiation of leukemia cells; that is, cell lines with less differentiated phenotype were more susceptible than the differentiated ones. RT-PCR analysis demonstrated that PMA upregulated the expression of intercellular adhesion molecule-1 (ICAM-1) in HL-60 cells, and that anti-ICAM-1 monoclonal antibody not only abrogated PMA-induced aggregation and adhesion of the cells but also restored its sensitivity to Vitex. These results suggested that ICAM-1 plays a crucial role in the acquired resistance in PMA-differentiated HL-60 cells by contributing to cell adhesion. These findings provide fundamental insights into the clinical application of Vitex/casticin for hematopoietic malignancy.

gem-Diamine 1-N-iminosugars and related iminosugars, candidate of therapeutic agents for tumor metastasis.

Cancer metastasis is one of the major challenges in cancer research. Inhibitors of tumor metastasis are rapidly emerging as important new drug candidates for cancer therapy. Tumor metastasis formation occurs via a complex multistage process which involves a crucial step of tumor invasion through the basement membrane. Tumor cell invasion involves attachment of tumor cell to the basement membrane through laminin, degradation of the matrix by proteolytic enzymes from the tumor cell and cell migration through the basement membrane. New drugs aimed at the metabolism of tumor cell surface oligosaccharides and/or catabolism of glycoconjugates of extracellular matrix and basement membrane could inhibit tumor metastasis. In this article, current progress in the control of tumor metastasis by gem-diamine 1-N-iminosugars and related iminosugars (nojirimycin and d-glucaro-delta-lactam), which are potent and specific inhibitors of carbohydrate metabolism and catabolism, has been reviewed. gem-Diamine 1-N-iminosugars related to d-glucuronic acid and l-iduronic acid, nojirimycin and d-glucaro-delta-lactam suppress invasion of B16 melanoma variants and 3LL (lung carcinoma) cells through reconstituted basement membrane, and inhibit pulmonary metastasis of these tumor cells in mice and/or cKDH-8/11 (liver carcinoma) cells in rats. These results suggest that the metabolism of beta-d-glucuronide and alpha-l-iduronide of glycoconjugates and/or the processing of carbohydrates of tumor cell surface may participate in tumor metastasis. That these gem-diamine 1-N-iminosugars and related iminosugars are potent inhibitors of tumor metastasis holds promise of new drug candidates for cancer chemotherapy.