Cytotoxic effect of depsipeptide against malignant rhabdoid tumor cells in vitro and in vivo

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Introduction: Malignant rhabdoid tumor (MRT) shows very poor prognosis because of its resistance to chemotherapeutic agents and new therapies are needed. We have recently shown that HDAC inhibitor depsipeptide induce apoptosis on osteosarcoma cells in vitro and in vivo through Fas/Fas ligand system (Oncogene 22; 9231, 2003). Here we show that depsipeptide also has an antitumor effect on MRT cells both in vitro and in vivo. Methods: We used five human MRT cell lines (TTC549, KP-MRT-NS, STM91-01, YAMRTK-1, TM87-16,). The cytotoxic effects of depsipeptide were determined in WST-1 assays. Sub-G1 populations were measured by flow cytometry. Acetylation of core histone in the cells was detected by immunoblotting. Antitumor activity in vivo was studied using human MRT xenografts in male nude mice. When implanted tumors became evident, we started to treat mice with 1.2, 2.5, 5.0mg/kg depsipeptide by i.v. on days 0, 4, and 8. Results: Depsipeptide inhibited proliferation of all MRT cells remarkably in a dose-dependent manner. IC50 of depsipeptide for 72 hours in culture were as follows; 0.7nM (TTC549), 2.3nM (KP-MRT-NS), 3.7nM (STM91-01), 5.8nM (YAMRTK-1), and 7.4nM (TM87-16). Apoptosis was induced in all tested cell lines. The amount in sub-G1 fractions was from 5.7% (KP-MRT-NS) to 10.3% (YAMRTK-1) for 24hr treatment, from 21.9% (KP-MRT-NS) to 55.5% (STM91-01) for 48hr, from 48.2% (KP-MRT-NS) to 69.9% (STM91-01) for 72hr, respectively. The combination of depsipeptide and PD98059 (MEK inhibitor) led synergistic effect on STM91-01 cells. Depsipeptide increases acetylation of histone H3 and H4 as early as 3hr after treatment. Administration of depsipeptide led to a significant suppression of growth in all treated mice. In vivo assay showed dose of 1.2, 2.5, and 5.0mg/kg caused a dose-dependent mean tumor size reduction of 59%, 73%, and 87%, compared to the mean tumor volume of control mice. Mice exhibited regression of tumor burden upon treatment with 5.0mg/kg (-13%). Conclusion: Depsipeptide is a promising antitumor agent against MRT.