title: BCL-2 antisense and cisplatin combination treatment of MCF-7 breast cancer cells with or without functional p53.
abstract: Chemotherapy has been used for treatment of breast cancer but with limited success. We characterized the effects of bcl-2 antisense and cisplatin combination therapy in two human isogenic breast carcinoma cells p53(+)MCF-7 and p53(-)MCF-7/E6. The transferrin-facilitated lipofection strategy we have developed yielded same transfection efficiency in both cells. Bcl-2 antisense delivered with this strategy significantly induced more cell death, apoptosis, and cytochrome c release in MCF-7/E6 than in MCF-7, but did not affect Fas level in both cells and activated caspase-8 equally. Cisplatin exerted same effects on cell viability and apoptosis in both cells, but released smaller amounts of cytochrome c while activated more caspase-8 in MCF-7/E6. The combination treatment yielded greater effects on cell viability, apoptosis, cytochrome c release, and caspase-8 activation than individual treatments in both cells although p53(-) cells were more sensitive. The potentiated activation of caspase-8 in the combination treatment suggested that caspase-8-mediated (but cytochrome c-independent) apoptotic pathway is the major contributor of the enhanced cell killing. Thus, bcl-2 antisense delivered with transferrin-facilitated lipofection can achieve the efficacy of killing breast cancer cells and sensitizing them to chemotherapy. Bcl-2 antisense and cisplatin combination treatment is a potentially useful therapeutic strategy for breast cancer irrespective of p53 status.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Omaha, NE 68198-5870, USA.
authors.forename: Hesham
authors.initials: H
authors.lastname: Basma
authors.forename: Hesham
authors.initials: H
authors.lastname: El-Refaey
authors.forename: Magdalene K
authors.initials: MK
authors.lastname: Sgagias
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Cowan
authors.forename: Xu
authors.initials: X
authors.lastname: Luo
authors.forename: Pi-Wan
authors.initials: PW
authors.lastname: Cheng
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry; D015153:Blotting, Western; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D002945:Cisplatin / Q000627:therapeutic use*; D045304:Cytochromes c / Q000378:metabolism; D018014:Gene Transfer Techniques; D016158:Genes, p53; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D020128:Inhibitory Concentration 50; D008081:Liposomes / Q000378:metabolism; D015233:Models, Statistical; D009336:Necrosis; D016376:Oligonucleotides, Antisense / Q000737:chemistry; D010714:Phosphatidylethanolamines; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D014162:Transfection; D014168:Transferrin / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D019014:fas Receptor / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D008081:Liposomes; D016376:Oligonucleotides, Antisense; D010714:Phosphatidylethanolamines; D019253:Proto-Oncogene Proteins c-bcl-2; D013778:Tetrazolium Salts; D013844:Thiazoles; D014168:Transferrin; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; C020888:1,2-dielaidoylphosphatidylethanolamine; D045304:Cytochromes c; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases; C022616:thiazolyl blue; D002945:Cisplatin