Makaluvamines vary in ability to induce dose-dependent DNA cleavage via topoisomerase II interaction.
The makaluvamines are marine natural products that were originally isolated because of their cytotoxicity in a cell-based mechanism screen. They have significant anti-cancer activity in animal models. There is, however, disagreement in the literature as to whether these compounds target topoisomerase II via a clinically relevant mechanism. This work shows that the makaluvamines can induce dose-dependent DNA cleavage via topoisomerase II. For most of the makaluvamines the levels of cleavage are significantly below those achieved by equimolar concentrations of etoposide. To some extent these results might explain the discrepancies present in the literature.
Matsumoto
S S
SS
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City 84112, USA.
Haughey
H M
HM
Schmehl
D M
DM
Venables
D A
DA
Ireland
C M
CM
Holden
J A
JA
Barrows
L R
LR
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy; D011758:Pyrroles / Q000378:metabolism / Q000494:pharmacology*; D015363:Quinolones / Q000378:metabolism / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011758:Pyrroles; D015363:Quinolones; D059005:Topoisomerase II Inhibitors; C119051:makaluvamine H; C119050:makaluvamine I; C106021:makaluvamine N; D005047:Etoposide; D004247:DNA; D004250:DNA Topoisomerases, Type II