title: Effective response of doxorubicin-sensitive and -resistant breast cancer cells to combinational siRNA therapy.
abstract: Chemotherapy is an effective approach to curb uncontrolled proliferation of malignant cells. However, most drugs rapidly lose their efficacy as a result of resistance development. We explored the potential of combinational siRNA silencing to prevent growth of drug-resistant breast cancer cells independent of chemotherapy. Resistance was induced in two breast cancer lines by chronic exposure to doxorubicin. Microarray analysis of apoptosis-related proteins showed Bcl2, survivin, NF B, and Mcl1 to be prominently up-regulated in drug-resistant cells. Human siRNA libraries against apoptosis-related proteins and kinases were screened using lipid-substituted polymers as non-viral carrier, and siRNAs were selected to diminish cell growth without affecting growth of skin fibroblasts. Surprisingly, the selected siRNAs led to similar responses in wild-type and drug-resistant cells, despite their phenotypic differences. Promising kinase siRNAs were co-delivered with anti-apoptotic Mcl-1 siRNA and Ribosomal Protein S6 Kinase (RPS6KA5) was found the most promising candidate for simultaneous silencing with Mcl-1. In both MDA435 wild type (WT) and MDA435 resistant (R) xenografts in nude mice, double silencing of Mcl-1/RPS6KA5 also led to improved inhibition of tumor growth in the absence of chemotherapy. We conclude that combinational silencing of well-selected targets could be a feasible therapeutic strategy in the absence of drug therapy and could provide a new avenue for therapy of drug-resistant breast cancers.
authors.affiliation: Department of Chemical & Material Engineering, Faculty of Engineering, University of Alberta, Edmonton, AB T6G 2G6, Canada. Electronic address: hm1@ualberta.ca.
authors.forename: Hamidreza Montazeri
authors.initials: HM
authors.lastname: Aliabadi
authors.affiliation: Department of Microbiology & Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Maranchuk
authors.affiliation: Department of Chemical & Material Engineering, Faculty of Engineering, University of Alberta, Edmonton, AB T6G 2G6, Canada.
authors.forename: Cezary
authors.initials: C
authors.lastname: Kucharski
authors.affiliation: Department of Chemical & Material Engineering, Faculty of Engineering, University of Alberta, Edmonton, AB T6G 2G6, Canada.
authors.forename: Parvin
authors.initials: P
authors.lastname: Mahdipoor
authors.affiliation: Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada.
authors.forename: Judith
authors.initials: J
authors.lastname: Hugh
authors.affiliation: Department of Chemical & Material Engineering, Faculty of Engineering, University of Alberta, Edmonton, AB T6G 2G6, Canada; Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1, Canada; Department of Biomedical Engineering, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada. Electronic address: huludag@ualberta.ca.
authors.forename: Hasan
authors.initials: H
authors.lastname: Uludağ
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000628:therapy*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics / Q000627:therapeutic use*; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics
chemical_list: D000903:Antibiotics, Antineoplastic; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D034741:RNA, Small Interfering; D004317:Doxorubicin; D019893:Ribosomal Protein S6 Kinases
keywords: Animal model; Breast cancer; Drug resistance; Mcl-1; Polycationic polymers; siRNA