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

Kazimierz Studzian,Malgorzata Lukawska,Irena Oszczapowicz,Krzysztof Kik,Leszek Szmigiero,Malgorzata Strek

doi:10.1007/s10637-015-0276-9

Kazimierz Studzian, Malgorzata Lukawska + Show 4 more

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https://doi.org/10.1007/s10637-015-0276-9

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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.

Highlights

Anthracyclines have received significant attention due to their effectiveness and extensive use as anticancer agents
The IC50 values for daunorubicin derivatives were in the range of 75–626 nM. In this series of anthracyclines, the parent daunorubicin was the most cytotoxic drug, exhibiting 8 and 2 times higher activity compared to its analogs DRBM and DRBH, respectively
Our experiments provided conclusive evidence that the hexamethyleneimine moiety enhances the uptake of anthracycline derivatives (DOXH and DRBH) by H9c2(2-1) cells

Summary

Introduction

Anthracyclines have received significant attention due to their effectiveness and extensive use as anticancer agents. One of the many possible strategies for improving the therapeutic effectiveness of anthracyclines is the synthesis of new analogs with modified structures. Structural modifications of the anthracycline molecule may change many biological properties of these drugs, such as cellular uptake, subcellular localization, and cellular target affinity, which may affect the drugs’ selectivity toward cancer cells [3]. Modifications at the C-3′ position of the daunosamine moiety of anthracycline may result in Invest New Drugs (2015) 33:1032–1039 improvement of some biological properties that are important for the anticancer action of these compounds [4,5,6,7]. The low cardiotoxicity of these compounds seems to be a very promising feature, how modification of the daunosamine group of anthracycline at the C-3′ position produces this effect remains unclear. One possible method to reduce the cardiotoxicity of anthracyclines may be to reduce their accumulation in cardiac cells

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