Amplification of pepleomycin-mediated DNA cleavage and apoptosis by unfused aromatic cations.
An important approach to improve chemotherapy of members of the bleomycin (BLM) family of antibiotics is to find compounds (amplifiers) that enhance the activity of BLM-mediated DNA cleavage and apoptosis. Using a DNA-sequencing technique and pulsed field gel electrophoresis, we have investigated whether BLM-mediated cleavage of isolated and cellular DNA is amplifed by three compounds (RW-12, LS-20, 1S-5Me) which have a conformationally flexible, unfused polyaromatic system and cationic side chain in the molecules. RW-12 enhanced most effectively both pepleomycin (PEM)-induced cytotoxicity and apoptosis. The order of the maximum enhancing effect of amplifiers on PEM-mediated DNA damage is RW-12 > LS-20 > 1S-5Me. RW-12 amplified PEM-mediated DNA cleavage most effectively not only in vitro but also in cultured cells. We have reported that the order of the DNA binding constants of these compounds is RW-12 > LS-20 > 1S-5Me. In this study, we found a good correlation between PEM-mediated cleavage of isolated DNA and cellular DNA. These results suggest that BLM amplifiers bind to DNA and by doing so enhance drug-mediated DNA degradation, ultimately leading to apoptosis. The present study on amplifiers of anticancer agents shows a novel approach to the potentially effective anticancer therapy.
Kawanishi
S
S
Department of Hygiene, Mie University School of Medicine, Tsu, Mie 514-8507, Japan. kawanisi@doc.medic.mie-u.ac.jp
Oikawa
S
S
Kawanishi
M
M
Sugiyama
H
H
Saito
I
I
Strekowski
L
L
Wilson
W D
WD
D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D002412:Cations; D004249:DNA Damage / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D019951:DNA Polymerase beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D018922:HL-60 Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007364:Intercalating Agents / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009707:Nucleosomes / Q000187:drug effects / Q000378:metabolism; D017663:Peplomycin / Q000633:toxicity*
D002412:Cations; D007364:Intercalating Agents; D009707:Nucleosomes; D017663:Peplomycin; D019951:DNA Polymerase beta