Idarubicin and Idarubicinol Effects on Breast Cancer Multicellular Spheroids

Abstract

Despite extensive preclinical evaluation in several experimental models, no studies have determined the effect of idarubicin and its metabolite idarubicinol on multicellular spheroids, a model which mimics the microregions of solid tumors. The principal aim of the present study was to investigate the in vitro cytotoxicity of idarubicin and its metabolite idarubicinol on MCF-7 breast cancer cells growing as monolayers or multicellular spheroids and to evaluate the influence of the length of exposure on the cytotoxic effect of both drugs. Cytoxicity was evaluated on monolayer and spheroid cultures exposed to idarubicin and idarubicinol 0.01-1000 ng/ml for 24 h or treated for 6, 12, 24 and 48 h to 100 ng/ml of both drugs. The IC50 of idarubicin and idarubicinol were 3.3+/-0.4 and 3.6+/-0.7 ng/ml, respectively, on MCF-7 monolayers and 7.9+/-1.1 and 5.3+/-0.7 ng/ml in multicellular spheroids, respectively. The antiproliferative effects of 100 ng/ml idarubicin and idarubicinol on MCF-7 spheroids was characterized by a marked time-dependence, which was less evident on MCF-7 growing as monolayer. In conclusion, the present experimental data demonstrate, for the first time, that idarubicin and idarubicinol have significant cytotoxic activity against multicellular spheroids, comparable to the antiproliferative effects on monolayer cells. In contrast, spheroids displayed substantial resistance after short exposure times that was not present in the two dimensional cultures.

Multicellular tumor spheroids: An underestimated tool is catching up again

“…According to the wide range of commercially available cytotoxicity/viability assays based on absorption, luminescence or fluorescence that are routinely applied to monitor membrane integrity, intracellular activity or energetic status in monolayer cultures, numerous approaches are expected to be compatible with spheroid cultures. Indeed, some of them have already been used for small spheroids with a size of <200 m (Kosaka et al, 1996;Mellor et al, 2005;Orlandi et al, 2005). Disappointingly, we found numerous approaches to be inappropriate since the assay signals did not correlate linearly with the number of cells per spheroid when using larger cultures.…”

Idarubicin Stimulates Cell Cycle- and TET2-Dependent Oxidation of DNA 5-Methylcytosine in Cancer Cells

“…Ida is a commonly used anticancer drug . First, we investigated the cytotoxicity of Ida using T47D cells.…”

Cyclooxygenase-2 inhibitor is a robust enhancer of anticancer agents against hepatocellular carcinoma multicellular spheroids

“…The results obtained in this study were consistent with those in the studies by Ponce de León and Barrera-Rodríguez,33 and Sutherland et al34 Cells isolated from MCSs generally exhibit higher resistance to cytotoxic drugs than the same cells grown as monolayers 33,34. The higher chemoresistance observed in MCSs may be associated with increased deoxyribonucleic acid repair in spheroids, limited uptake and diffusion of drugs, and a specific microenvironment, which can directly or indirectly affect the activity of cytotoxic compounds by reducing the proliferation rate of the tumor cells 35,36…”