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Can cytotoxic activity of anthracyclines be related to DNA damage?
M Nishiyama1, N Horichi, Z Mazouzi
1Laboratoire de Pharmacologie Cellulaire et Molèculaire, ICIG, Hôpital Paul Brousse, Villejuif, France.
Abstract:
Accumulation, cytotoxicity, and DNA damages produced by doxorubicin (DOX), pirarubicin (THP-DOX), fluoro-doxorubicin (ME2303) or its isolated metabolite M1 have been investigated in human myelogenous leukemia cells, sensitive (K562) and resistant to DOX (K562/DOX). These compounds differed by lipophilicity and/or sugar moiety either with (DOX, THP-DOX) or without (ME2303, M1) amino group. In K562 cells, the cytotoxicity was correlated to DNA single-stranded breaks and the intracellular drug amount of DOX or M1. This was not true when the cells were treated with THP-DOX or ME2303. In addition, THP-DOX produced total DNA protein cross-linking. In K562 cells DNA damage was not repaired, while in K562/DOX repair of DNA damage produced by all drugs could be observed. Although in K562/DOX cells drug accumulation was much reduced, higher intracellular drug concentration was required to induce similar level of cytotoxicity and DNA damage. Thus, cytotoxicity produced by anthracycline is not always associated with DNA damage. Different level of resistance to DOX, THP-DOX, ME2303 or M1 is associated with reduced drug accumulation which varies with the structure.
Insights
Doxorubicin analogs
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Anthracyclines like doxorubicin (DOX) are crucial in cancer therapy.
- Understanding their mechanisms in sensitive and resistant leukemia cells is vital.
Purpose of the Study:
- To investigate the accumulation, cytotoxicity, and DNA damage of DOX and its analogs (THP-DOX, ME2303, M1) in human myelogenous leukemia cells.
- To compare these effects in DOX-sensitive (K562) and DOX-resistant (K562/DOX) cell lines.
Main Methods:
- Cell culture of K562 and K562/DOX human myelogenous leukemia cells.
- Treatment with doxorubicin (DOX), pirarubicin (THP-DOX), fluoro-doxorubicin (ME2303), and its metabolite M1.
- Assessment of intracellular drug accumulation, cytotoxicity, DNA single-stranded breaks, and DNA-protein cross-linking.
Main Results:
- Cytotoxicity correlated with DNA damage and intracellular drug levels for DOX and M1 in K562 cells, but not for THP-DOX or ME2303.
- THP-DOX induced DNA-protein cross-linking.
- DNA damage repair was observed in K562/DOX cells but not in K562 cells.
- Drug resistance in K562/DOX cells involved reduced accumulation and higher required drug concentrations for effects.
Conclusions:
- Anthracycline-induced cytotoxicity is not always directly linked to DNA damage.
- Drug resistance mechanisms involve reduced intracellular accumulation, varying with drug structure.
- Structural differences in anthracyclines influence their interaction with leukemia cells and resistance pathways.