Cytotoxicity of novel unsymmetrically substituted inhibitors of polyamine biosynthesis in human cancer cells.
The cytotoxicity of two novel polyamine analogues was compared with that of a known cytotoxic drug, etoposide, in a human promyelogenous leukemic cell line. CHEN-spm showed significant acute cytotoxicity in these cells and was comparable to etoposide in terms of IC(50) value. The cell death observed from both CHEN-spm and etoposide was typically apoptotic with increased DNA fragmentation, altered cell morphology, and cell cycle distribution. CPEN-spm, on the other hand, exhibited no toxic effects over the short-term (24 h) exposure period. Intracellular polyamine content decreased in the presence of all inhibitors but only CPEN-spm produced significant induction of spermidine/spermine N(1)-acetyltransferase in 24 h. Thus, increased polyamine catabolism appears not to be essential for the initiation of apoptotic cell death in these human leukemic cells.
Nairn
L M
LM
Department of Medicine and Therapeutics, University of Aberdeen, Foresterhill, Aberdeen, Scotland, United Kingdom.
Lindsay
G S
GS
Woster
P M
PM
Wallace
H M
HM
D000123:Acetyltransferases / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004273:DNA, Neoplasm / Q000037:antagonists & inhibitors; D004790:Enzyme Induction / Q000187:drug effects; D005047:Etoposide / Q000031:analogs & derivatives; D006801:Humans; D011073:Polyamines / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D000099228:Diamine N-Acetyltransferase
D000123:Acetyltransferases; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D004273:DNA, Neoplasm; D005047:Etoposide; D011073:Polyamines; D000099228:Diamine N-Acetyltransferase; C118771:N(1)-ethyl-N-(11)-((cycloheptyl)methyl)-4,8-diazaundecane; C083629:N(1)-ethyl-N-(11)-((cyclopropyl)methyl)-4,8-diazaundecane-1,11-diamine