The synergistic interaction of mitoxantrone and herceptin

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Our laboratory has focused on elucidating the molecular and cellular responses to clinical and experimental DNA-acting anticancer agents, and to use this knowledge to enhance the anticancer activity of these drugs. Mitoxantrone, an anthracenedione, structurally similar to doxorubicin, is used for the treatment of leukaemia, breast and prostate cancers. Mitoxantrone is an intercalating agent that accumulates in the nucleus where it functions as a topoisomerase II poison and leads to the activation of NF-κB. Herceptin, a humanized antibody, is designed to target and block the function of HER-2 protein expression. Overexpression of the HER-2/neu (ErbB2) oncogene correlates with poor prognosis in breast and ovarian cancer cells and blocks TNF-induced apoptosis via the Akt/NF-κB pathway. Previous studies have shown that herceptin activity is synergistic with chemotherapeutic agents including cisplatin, docetaxel, and etoposide. Based on the synergy between herceptin and other chemotherapeutic drugs, the combination of mitoxantrone and herceptin was studied in BT 474 cells, a human breast cancer cell line overexpressing HER-2. Growth inhibition assays and growth curves showed that mitoxantrone and herceptin were synergistic in this cell line, with a significant reduction in cell number after 7 days. Based on these results, we present a model for the existence of pro-apoptotic cross-talk between NF-κB activation by mitoxantrone and the inhibition of the Akt/NF-κB pathway induced by herceptin. Our study suggests that the combined use of mitoxantrone and herceptin represents an effective therapeutic approach for the treatment of breast cancer and other tumours which overexpress the HER-2/neu gene.