title: Inhibition of the MUC1-C oncoprotein is synergistic with cytotoxic agents in the treatment of breast cancer cells.
abstract: Mucin 1 (MUC1) is a heterodimeric glycoprotein that is aberrantly overexpressed in most human breast cancers. The oncogenic MUC1-C subunit promotes survival and blocks the apoptotic response to genotoxic anticancer agents. In the present studies, human MCF-7 and ZR-75-1 breast cancer cells were treated with the MUC1-C inhibitor, GO-203, a cell-penetrating peptide that blocks MUC1-C homodimerization and thereby its oncogenic function. Treatment with GO-203 was found to promote the apoptotic response of MCF-7 and ZR-75-1 cells to the therapeutic drugs taxol and doxorubicin (DOX). This effect was (1) attenuated by a pan-caspase inhibitor, and (2) mediated, at least in part, by activation of the effector caspase-7 and cleavage of the downstream substrate PARP. Further analysis of the interaction between GO-203 and taxol using isobolograms, which evaluate the nature of the interaction of two drugs, demonstrated that the combination is highly synergistic. These results were supported by combination index (CI) analysis with values of less than 1. GO-203 was also highly synergistic with DOX in studies of both MCF-7 and ZR-75-1 breast cancer cells. These findings indicate that blocking MUC1-C function could be effective in combination with taxol and DOX for the treatment of breast cancer.
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Yasumitsu
authors.initials: Y
authors.lastname: Uchida
authors.forename: Deepak
authors.initials: D
authors.lastname: Raina
authors.forename: Surender
authors.initials: S
authors.lastname: Kharbanda
authors.forename: Donald
authors.initials: D
authors.lastname: Kufe
mesh_terms: D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells; D008969:Molecular Sequence Data; D018396:Mucin-1 / Q000737:chemistry / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*; D054730:Protein Interaction Domains and Motifs
chemical_list: C582521:(arginine)9-cysteinyl-glutaminyl-cysteinyl-arginyl-arginyl-lysyl-asparagine; D000970:Antineoplastic Agents; D003603:Cytotoxins; D018396:Mucin-1; D010455:Peptides; D004317:Doxorubicin; D017239:Paclitaxel
keywords: GO-203; MUC1; breast cancer; doxorubicin; synergy; taxol