title: Targeting Cell Cycle Proteins in Breast Cancer Cells with siRNA by Using Lipid-Substituted Polyethylenimines.
abstract: The cell cycle proteins are key regulators of cell cycle progression whose deregulation is one of the causes of breast cancer. RNA interference (RNAi) is an endogenous mechanism to regulate gene expression and it could serve as the basis of regulating aberrant proteins including cell cycle proteins. Since the delivery of small interfering RNA (siRNA) is a main barrier for implementation of RNAi therapy, we explored the potential of a non-viral delivery system, 2.0 kDa polyethylenimines substituted with linoleic acid and caprylic acid, for this purpose. Using a library of siRNAs against cell cycle proteins, we identified cell division cycle protein 20 (CDC20), a recombinase RAD51, and serine-threonine protein kinase CHEK1 as effective targets for breast cancer therapy, and demonstrated their therapeutic potential in breast cancer MDA-MB-435, MDA-MB-231, and MCF7 cells with respect to another well-studied cell cycle protein, kinesin spindle protein. We also explored the efficacy of dicer-substrate siRNA (DsiRNA) against CDC20, RAD51, and CHEK1, where a particular DsiRNA against CDC20 showed an exceptionally high inhibition of cell growth in vitro. There was no apparent effect of silencing selected cell cycle proteins on the potency of the chemotherapy drug doxorubicin. The efficacy of DsiRNA against CDC20 was subsequently assessed in a xenograft model, which indicated a reduced tumor growth as a result of CDC20 DsiRNA therapy. The presented study highlighted specific cell cycle protein targets critical for breast cancer therapy, and provided a polymeric delivery system for their effective down-regulation.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta , Edmonton, AB , Canada.
authors.forename: Manoj B
authors.initials: MB
authors.lastname: Parmar
authors.affiliation: Department of Chemical and Materials Engineering, Faculty of Engineering, University of Alberta , Edmonton, AB , Canada ; School of Pharmacy, Chapman University , Irvine, CA , USA.
authors.forename: Hamidreza Montazeri
authors.initials: HM
authors.lastname: Aliabadi
authors.affiliation: Department of Chemical and Materials Engineering, Faculty of Engineering, University of Alberta , Edmonton, AB , Canada.
authors.forename: Parvin
authors.initials: P
authors.lastname: Mahdipoor
authors.affiliation: Department of Chemical and Materials Engineering, Faculty of Engineering, University of Alberta , Edmonton, AB , Canada.
authors.forename: Cezary
authors.initials: C
authors.lastname: Kucharski
authors.affiliation: Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta , Edmonton, AB , Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Maranchuk
authors.affiliation: Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, University of Alberta , Edmonton, AB , Canada.
authors.forename: Judith C
authors.initials: JC
authors.lastname: Hugh
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta , Edmonton, AB , Canada ; Department of Chemical and Materials Engineering, Faculty of Engineering, University of Alberta , Edmonton, AB , Canada ; Department of Biomedical Engineering, Faculty of Medicine and Dentistry, University of Alberta , Edmonton, AB , Canada.
authors.forename: Hasan
authors.initials: H
authors.lastname: Uludağ
keywords: CDC20; CHEK1; DsiRNA; RAD51; Xenograft; breast cancer therapy; cell cycle protein; lipid-substituted polymers; non-viral siRNA delivery; siRNA therapy