Enhancing the efficacy of chemotherapeutic drugs by the suppression of antiapoptotic cellular defense.
The study was aimed at evaluating the combination of a traditional anticancer drug doxorubicin (DOX) with a suppressor of antiapoptotic cellular defense--synthetic peptide corresponding to the minimal sequence of BCL-2 homology 3 (BH3) domain. BH3 peptide was delivered into cells by fusion with a peptide corresponding to the Antennapedia (Ant) internalization sequence. The cytotoxicity of DOX, Ant-BH3 and Ant-BH3 mixed in with DOX, mitochondrial transmembrane potential, expression of genes encoding pro- and antiapoptotic members of BCL-2 protein family and caspases, caspases activity, apoptosis induction were assessed in human ovarian carcinoma cells. It was found that the combination in one drug formulation of DOX and Ant-BH3 produced two main effects: (1) enhancing the apoptosis induction by an anticancer drug, and (2) preventing the development of antiapoptotic cellular drug resistance. The results confirmed that anticancer drug-BH3 combination might form the basis for a new advanced anticancer proapoptotic drug delivery systems.
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Department of Pharmaceutics, Ernest Mario School of Pharmacy Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854-8020, USA. minko@cop.rutgers.edu
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D000595:Amino Acid Sequence; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000235:genetics; D004317:Doxorubicin / Q000627:therapeutic use*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007425:Intracellular Membranes / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D008969:Molecular Sequence Data; D010051:Ovarian Neoplasms; D010446:Peptide Fragments / Q000096:biosynthesis / Q000627:therapeutic use*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000627:therapeutic use*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D014407:Tumor Cells, Cultured
C474007:Bax protein (53-86); D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D004317:Doxorubicin; D020169:Caspases