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.