Acridine-based agents with topoisomerase II activity inhibit pancreatic cancer cell proliferation and induce apoptosis.
A series of substituted 9-aminoacridines is evaluated for antiproliferative activity toward pancreatic cancer cells. The results indicate that the compounds inhibit cell proliferation by inducing a G1-S phase arrest. A model is also developed that explains the molecular basis to inhibition through a DNA "threading" mechanism. We conclude that the drug-DNA complex formed blocks topoisomerase II binding and activity leading to catalytic inhibition of the enzyme and the induction of apoptosis and programmed cell death.
Goodell
John R
JR
Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Ougolkov
Andrei V
AV
Hiasa
Hiroshi
H
Kaur
Harneet
H
Remmel
Rory
R
Billadeau
Daniel D
DD
Ferguson
David M
DM
D000609:Aminoacridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D010190:Pancreatic Neoplasms; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
D000609:Aminoacridines; D000970:Antineoplastic Agents; D059005:Topoisomerase II Inhibitors; D004247:DNA