On the role of topoisomerase I in mediating the cytotoxicity of 9-aminoacridine-based anticancer agents.
The cytotoxicity and mechanism of action of a series of substituted 9-aminoacridines is evaluated using topoisomerase I and cancer cell growth inhibition assays. In previous work, compounds of this type were shown to catalytically inhibit topoisomerase II, leading to a G1-S phase arrest of the cell cycle and apoptosis in pancreatic cancer cells in vitro and in vivo. The present study expands the potential utility of these compounds in the development of cancer therapeutics by showing that these compounds inhibit proliferation of cell lines derived from the nine most common human cancers. Further results show that at least one of the compounds effectively stabilizes topoisomerase I-DNA adduct formation in intact cells. RNA interference experiments, however, indicate that this interaction does not contribute to the drug-induced killing of cancer cells indicating the compounds may be non-lethal poisons of topoisomerase I.
Gálvez-Peralta
Marina
M
Division of Oncology Research, Mayo Clinic, 200 First St., S.W., Rochester, MN 55905, United States.
Hackbarth
Jennifer S
JS
Flatten
Karen S
KS
Kaufmann
Scott H
SH
Hiasa
Hiroshi
H
Xing
Chenguo
C
Ferguson
David M
DM
D000166:Acridines / Q000494:pharmacology; D000585:Aminacrine / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004264:DNA Topoisomerases, Type I / Q000378:metabolism / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D008956:Models, Chemical; D009369:Neoplasms / Q000188:drug therapy*; D034741:RNA, Small Interfering / Q000378:metabolism
D000166:Acridines; D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D005047:Etoposide; D000585:Aminacrine; D004317:Doxorubicin; D004264:DNA Topoisomerases, Type I