Cytotoxic efficacy of a novel dinuclear platinum(II) complex in human breast cancer cells.
Evaluation of the cytotoxicity of a novel dinuclear platinum(II) complex of formula Pt(2)(2-picoline)(4)(berenil)(2) employing a MTT assay and inhibition of [(3)H]thymidine incorporation into DNA in both MDA-MB-231 and MCF-7 breast cancer cells demonstrated that the complex was more of a potent antiproliferative agent than cisplatin. The DNA-binding ability of Pt(2)(2-picoline)(4)(berenil)(2) estimated by an ethidium displacement assay indicated that the complex showed strong specificity for AT base pairs in the minor groove of DNA. Our study showed that Pt(2)(2-picoline)(4)(berenil)(2) was a potent catalytic inhibitor of topoisomerase II in opposition to cisplatin. Pt(2)(2-picoline)(4)(berenil)(2) was found to be a more active inhibitor of collagen biosynthesis than cisplatin. The up regulation of beta(1)-integrin and insulin-like growth factor I (IGF-I) receptor expression by the complex was shown to be accompanied by an increase in the expression of mitogen activated protein kinases in breast cell lines. The phenomenon was related to the increased expression of nuclear factor-kappaB (NuF-kappaBeta) by Pt(2)(2-picoline)(4)(berenil)(2) as shown by the Western immunoblot analysis. Flow cytometric analysis and a fluorescent microscopy assay demonstrated that cell death appeared to result from apoptosis, with the possibility of secondary necrosis. The data presented suggested that Pt(2)(2-picoline)(4)(berenil)(2) impaired growth and metabolism of breast cancer cells more efficiently than cisplatin. These results indicated also the different properties of Pt(2)(2-picoline)(4)(berenil)(2) and cisplatin.
Bielawska
Anna
A
Department of Medicinal Chemistry, Medical University of Białystok, Kilińskiego 1, 15-089 Białystok, Poland.
Popławska
Bozena
B
Surazyński
Arkadiusz
A
Czarnomysy
Robert
R
Bielawski
Krzysztof
K
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003094:Collagen / Q000096:biosynthesis; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D047468:Immunoprecipitation; D008856:Microscopy, Fluorescence; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000494:pharmacology*
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D003094:Collagen; D004247:DNA; C427203:calf thymus DNA