Protection against Adriamycin cytotoxicity and inhibition of DNA topoisomerase II activity by 3,4-dihydroxybenzoic acid.
The mechanism of Adriamycin (ADR) induced cytotoxicity is not completely understood. While a variety of mechanisms have been proposed, the production of free radicals by redox cycling of the semiquinone has been implicated in cytotoxicity, specifically for cardiotoxicity. To determine whether a scavenger of free radicals would modify the cytotoxicity of ADR, the benzoic acid derivative 3,4-dihydroxybenzoic acid (DHB) was investigated for its ability to protect against ADR-induced cytotoxicity and DNA double strand breaks in Chinese hamster V79 cells. V79 cells were treated with ADR, or its non-redox cycling analog iminodaunomycin, in the presence or absence of DHB. DHB provided significant protection (dose-modifying factor greater than 2.5 for ADR, and nearly 2 for iminodaunomycin) and also caused a dose-dependent decrease in DNA double strand breaks as measured by pulsed field gel electrophoresis. Assays of topoisomerase II activity showed that DHB inhibited topoisomerase II in a concentration-dependent manner, but did not inhibit topoisomerase I. Another non-toxic topoisomerase II inhibitor, the radioprotector WR-1065, also protected against ADR-induced cytotoxicity. These data identify DHB as a non-toxic inhibitor of DNA topoisomerase II and suggest that much of the cytotoxicity of ADR in actively growing V79 cells is due to mechanisms other than redox cycling by the semiquinone.
De Graff
William G
WG
Radiation Biology Branch, National Cancer Institute/NIH, Building 10, Room B3-B69, 10 Center Drive, Bethesda, MD 20892, USA. degraff@helix.nih.gov
Myers
L S
LS
Mitchell
James B
JB
Hahn
Stephen M
SM
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000633:toxicity; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival; D006224:Cricetinae; D004249:DNA Damage; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology / Q000633:toxicity*; D004587:Electrophoresis, Agar Gel; D005609:Free Radicals; D062385:Hydroxybenzoates / Q000494:pharmacology*; D010084:Oxidation-Reduction; D059005:Topoisomerase II Inhibitors
D000903:Antibiotics, Antineoplastic; D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D005609:Free Radicals; D062385:Hydroxybenzoates; D059005:Topoisomerase II Inhibitors; C009091:protocatechuic acid; D004317:Doxorubicin; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; C018979:5-iminodaunorubicin; D003630:Daunorubicin