Biochemical effects and growth inhibition in MCF-7 cells caused by novel sulphonamido oxa-polyamine derivatives.
The novel polyamine derivatives sulphonamido oxa-spermine (oxa-Spm) and sulphonamido oxa-spermidine (oxa-Spd) exhibited rapid cytotoxic action towards MCF-7 human breast cancer cells with IC50 values of 4.35 and 6.47 pM, respectively, after 24-h drug exposure. Neither compound is a substrate of serum amine oxidase. Both oxa-Spm and oxa-Spd caused cell shrinkage, as determined by phase-contrast microscopy. After incubation with 10 microM of either compound for 8 h, the cells underwent chromatin condensation and nuclear fragmentation. However, no clear DNA ladder was obtained by electrophoresis. The sulphonamido oxa-polyamine derivatives and especially oxa-Spd enhanced the activity of polyamine oxidase (PAO), an enzyme capable of oxidising N1-acetylated spermine and spermidine to spermidine and putrescine, respectively, generating cytotoxic H2O2 and 3-acetamidopropanal as by-products. The intracellular polyamine content was only marginally reduced in response to drug treatment. In conclusion, our data show that these novel sulphonamido oxa-polyamine derivatives possess high cytotoxic activity against MCF-7 cells and indicate that induction of PAO may mediate their cytotoxicity via apoptosis.
Pavlov
V
V
Department of Human and Animal Physiology, Faculty of Biology, University of Sofia St. Kliment Ohridski, Bulgaria.
Lin
P Kong Thoo
PK
Rodilla
V
V
D006631:Amine Oxidase (Copper-Containing) / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000633:toxicity*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002455:Cell Division; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008858:Microscopy, Phase-Contrast; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000378:metabolism; D011073:Polyamines / Q000378:metabolism; D013095:Spermidine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D013096:Spermine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D014407:Tumor Cells, Cultured; D000097667:Polyamine Oxidase
D006631:Amine Oxidase (Copper-Containing); D000970:Antineoplastic Agents; D000587:Oxidoreductases Acting on CH-NH Group Donors; D011073:Polyamines; D013095:Spermidine; D013096:Spermine; D013449:Sulfonamides; D000097667:Polyamine Oxidase; C455640:sulfonamido oxa-spermidine; C455639:sulfonamido oxa-spermine