TY - JOUR
T1 - Effect of structural modification at the 4, 3′, and 2′ positions of doxorubicin on topoisomerase II poisoning, apoptosis, and cytotoxicity in human melanoma cells
AU - Gruber, Beata M.
AU - Anuszewska, Elzbieta L.
AU - Bubko, Irena
AU - Goździk, Aneta
AU - Fokt, Izabela
AU - Priebe, Waldemar
N1 - Funding Information:
Acknowledgment: This work was supported in part by a grant from The Welch Foundation (Houston, Texas, USA) to W. Priebe and research grant No. 3PO5FO1722 from the State Committee for Scientific Research (KBN, Poland).
PY - 2007/6
Y1 - 2007/6
N2 - Introduction: The mechanism of the cytotoxicity of anthracyclines is pleiotropic and its significance in cell growth inhibition seems to be highly specific and dependent on cell type and anthracycline drug. Resistance and the high cardiotoxicity of anthracyclines have stimulated many studies aimed at identifying critical substituents required for optimal activity. Many authors point to the fact that the double-strand breaks, the consequence of the activity of topoisomerase II poisons, and the inability of cells to repair the DNA lesions are the signal for apoptosis. The aim of this study was to define the influence of 4-demetoxy 2′-halogenated analogs with altered basicity at the 3′-position on topoisomerase II and the relationship of that interaction with apoptosis and the cytotoxicity of these novel anthracyclines. Parental human ME18 melanoma cells and the ME18/R subline, obtained experimentally, resistant to doxorubicin (DOX), exposed to 1.7 and 8.6 μM DOX or its analogs, annamycin and WP903 (both 0.3 and 3.0 μM) were studied. Materials and Methods: The MTT test was used to assay cytotoxicity. Interaction of the drugs with topoisomerase II and apoptosis were done by Western blot and fluorescence microscopy using Hoechst 33342. Results: The structural changes at positions 4, 2′, and 3′ can influence topoisomerase II interaction and apoptotic activity, although correlation between these events and cytotoxic consequences has not been proved. Conclusions: The biological response of the cells to the structurally similar anthracyclines may be variable and probably depends on the cell type which seems to be an additional problem in the multifactorial resistance of tumor cells to anthracyclines.
AB - Introduction: The mechanism of the cytotoxicity of anthracyclines is pleiotropic and its significance in cell growth inhibition seems to be highly specific and dependent on cell type and anthracycline drug. Resistance and the high cardiotoxicity of anthracyclines have stimulated many studies aimed at identifying critical substituents required for optimal activity. Many authors point to the fact that the double-strand breaks, the consequence of the activity of topoisomerase II poisons, and the inability of cells to repair the DNA lesions are the signal for apoptosis. The aim of this study was to define the influence of 4-demetoxy 2′-halogenated analogs with altered basicity at the 3′-position on topoisomerase II and the relationship of that interaction with apoptosis and the cytotoxicity of these novel anthracyclines. Parental human ME18 melanoma cells and the ME18/R subline, obtained experimentally, resistant to doxorubicin (DOX), exposed to 1.7 and 8.6 μM DOX or its analogs, annamycin and WP903 (both 0.3 and 3.0 μM) were studied. Materials and Methods: The MTT test was used to assay cytotoxicity. Interaction of the drugs with topoisomerase II and apoptosis were done by Western blot and fluorescence microscopy using Hoechst 33342. Results: The structural changes at positions 4, 2′, and 3′ can influence topoisomerase II interaction and apoptotic activity, although correlation between these events and cytotoxic consequences has not been proved. Conclusions: The biological response of the cells to the structurally similar anthracyclines may be variable and probably depends on the cell type which seems to be an additional problem in the multifactorial resistance of tumor cells to anthracyclines.
KW - Anthracyclines
KW - Apoptosis
KW - Cytotoxicity
KW - Topoisomerase II poisons
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U2 - 10.1007/s00005-007-0018-6
DO - 10.1007/s00005-007-0018-6
M3 - Article
C2 - 17557149
AN - SCOPUS:34250786135
SN - 0004-069X
VL - 55
SP - 193
EP - 198
JO - Archivum immunologiae et therapiae experimentalis
JF - Archivum immunologiae et therapiae experimentalis
IS - 3
ER -