Enhancing the efficacy of chemotherapeutic drugs by the suppression of antiapoptotic cellular defense.

T Minko, PhD, SS Dharap, BS

Department of Pharmaceutics, Rutgers, The State University of New Jersey, Edison, NJ United States

AIM. To verify that concurrent induction of apoptosis by an anticancer drug with the inhibition of cellular defensive mechanisms may significantly increase the efficacy of cancer chemotherapy. METHODS. The experiments were carried out on sensitive and multidrug resistant human ovarian carcinoma cell lines. A traditional anticancer drug – doxorubicin (DOX) was used as an inductor of apoptosis. A synthetic BCL-2 homology 3 domain peptide (BH3) was used to suppress cellular antiapoptotic defense. BH3 was delivered by the fusion with the antennapedia internalization sequence. Cytotoxicity, apoptosis induction, caspases 1-10, caspase activators, antiapoptotic and proapoptotic members of BCL-2 family proteins were studied. RESULTS. Incubation of cells with DOX alone led to simultaneous overexpression of both proapoptotic and antiapoptotic members of BCL-2 family. As a result, apoptosis induction was accompanied by the activation of antiapoptotic cellular defense that finally induced multidrug resistance. BH3 alone inhibited most antiapoptotic members of BCL-2 family proteins. However, its ability to induce apoptosis was limited. DOX in combination with BH3 was able to induce apoptosis more at a higher level when compared with DOX and BH3 separately. Simultaneously cellular antiapoptotic defense was suppressed. As a result, the cytotoxicity of the DOX in the presence of BH3 was much higher. CONCLUSIONS. The combination of apoptosis inductor (DOX) and a suppressor of antiapoptotic cellular defense (BH3) provided in one drug delivery system led to the significant increase in the efficacy of chemotherapy and might be used both for cancer treatment and prevention of multidrug resistance during chemotherapy.

KEY WORDS: BH3 peptide, apoptosis, multidrug resistance, BCL-2 protein family, drug delivery.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Apoptosis - Molecular Mechanisms.