Subcellular localization of anthracyclines in cultured rat cardiomyoblasts as possible predictors of cardiotoxicity

Abstract

SummaryIn this study, we compared the cellular uptake, intracellular localization and cytotoxicity of two groups of anthracycline derivatives in cultured H9c2(2-1) rat cardiomyoblasts. The first group consisted of doxorubicin (DOX) and two of its derivatives containing a formamidino group (–N = CH–N<) at the C-3′ position with a morpholine (DOXM) or a hexamethyleneimine (DOXH) ring. The second group consisted of daunorubicin (DRB) and its derivatives containing a morpholine (DRBM) or a hexamethyleneimine (DRBH) ring. DOXH and DRBH were taken up by cardiomyoblasts more efficiently than estimated for other tested anthracyclines. The cellular uptakes of DOXM and DRBM were reduced compared to those of the parent compounds. Applied structural modifications of DOX and DRB influenced the subcellular localization of the tested derivatives. DOX and DOXH were localized primarily in nuclei, whereas the other anthracyclines were found in the nuclei and cytoplasm. The percentages of the compounds that accumulated in the nuclei were 80.2 and 54.2 % for DOX and DOXH, respectively. The lowest nuclear accumulation values were observed for DRBM (19.9 %), DRBH (21.9 %) and DOXM (23.7 %). The ability of anthracyclines to accumulate in the nuclei correlated with their DNA binding constants (r = 0.858, P = 0.029). A correlation was found between the accumulation of the tested anthracyclines in the nuclei of cardiomyoblasts and their cardiotoxicity in vivo, which was observed in our previous study. We suggest that cytotoxicity and the anthracycline accumulation level in the nuclei of cultured cardiomyoblasts could be used for early prediction of their cardiotoxicity.

Intracellular PK/PD Relationships of Free and Liposomal Doxorubicin: Quantitative Analyses and PK/PD Modeling

“…One possible explanation for this could be the genomic ploidy observed in renal cell carcinomas and Caki-2 cells (ATCC HTB-47, ) allowing a large number of high affinity binding sites for doxorubicin in nuclei. Similar relationship of DNA content and nuclear uptake of anthracyclines, such as doxorubicin, has also been hypothesized earlier . Interestingly, the high nuclear concentrations of doxorubicin did not induce high cytotoxicity in Caki-2 cells.…”

Anthracyclines Suppress Both NADPH Oxidase- Dependent and -Independent NETosis in Human Neutrophils

“…To begin the screening, we want to make sure to use a dosage that would be enough to inhibit NETosis by all the drugs. The IC50 values of the different drugs comprise a wide range based on the different cell type and duration (for example, anthracycline; 0.35–6.5 µM, alkylating agents; ~10 µM, protein kinase inhibitors; ~8–10 µM) [65,66]. Previous reports related to drug screening strategies, made some consideration for the selection of compound/drug screening dosages [67,68].…”

Lipophilicity profiling of anthracycline antibiotics by microemulsion electrokinetic chromatography–effects on cardiotoxicity and endotheliotoxicity

“…The lipophilicity of the studied anthracyclines has not yet been experimentally determined, all the available data originates from in silico studies . A particular attention should be paid to the lack of the data on the influence of lipophilicity on the anthracyclines toxicity towards endothelium, previous study suggesting that their cardiotoxicity may be connected to the injurious effects on the coronary endothelial cells .…”