title: Enhanced efficacy of chemotherapy for breast cancer stem cells by simultaneous suppression of multidrug resistance and antiapoptotic cellular defense.
abstract: While chemotherapy is universally recognized as a frontline treatment strategy for breast cancer, it is not always successful; among the leading causes of treatment failure is existing and/or acquired multidrug resistance. Cancer stem cells (CSCs), which constitute a minority of the cells of a tumor, are acknowledged to be responsible for increased resistance to chemo-drugs through a combination of increased expression of ATP-binding cassette transporters (ABC transporters), an increased anti-apoptotic defense, and/or the ability for extensive DNA repair like normal stem cells. Consequently, more effective therapy, especially targeted to CSCs, is urgently required. We studied the characteristics of 231-CSCs (CD44+/CD24-) sorted from human MDA-MB-231 breast cancer cells and demonstrated that 231-CSCs exhibited enhanced capacities for proliferation, migration, tumorigenesis and chemotherapy resistance. To address these multifunctional facets of CSCs, we devised a non-ionic surfactant-based vesicle (niosome) co-delivery system to simultaneously deliver siRNAs, targeted to both the ABC transporter (ABCG2) and the anti-apoptosis defense gene (BCL2), and doxorubicin (DOX) to CSCs. The rationale is to sensitize CSCs to DOX by down regulating the drug-resistance gene ABCG2 and simultaneously induce apoptosis by lowering BCL2 expression. The co-delivery system (CDS) successfully delivered siRNAs and DOX to the cytoplasm and nuclei, respectively, and resulted in a down-regulation of ABCG2- and BCL2 mRNAs in CSCs by 60% and 65%, respectively, compared to the control. A corresponding decrease in protein expression was observed using Western blotting. The IC50 of DOX in CSCs concurrently decreased significantly. Our result established CDS as a promising multi-drug delivery platform for cancer treatment.
  
  
  CONCLUSIONS
  Cancer stem cells (CSCs) are acknowledged to be responsible for increased resistance to chemo-drugs through a combination of increased expression of ABC transporters, an increased anti-apoptotic defense, and/or the ability for extensive DNA repair like normal stem cells. Consequently, effective therapy, especially to CSCs, is urgently required. In current study, we studied the characteristics of 231-CSCs sorted from human MDA-MB-231 breast cancer cells and found that 231-CSCs possessed enhanced proliferation, migration, tumorigenesis, and DOX resistance. We employed a non-ionic surfactant-based vesicle (niosome) delivery system to simultaneously deliver siRNAs targeted to multi-drug resistance genes, and DOX to kill 231-CSCs. The CDS showed an enhanced therapeutic effect by resensitizing 231-CSCs to DOX and may constitute a promising candidate for cancer chemotherapy.
authors.affiliation: Orthopaedic Research Laboratory, Aarhus University Hospital, Denmark. Electronic address: mingsun.health@gmail.com.
authors.forename: Ming
authors.initials: M
authors.lastname: Sun
authors.affiliation: Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Denmark. Electronic address: chuanxuyang@inano.au.dk.
authors.forename: Chuanxu
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Biomedicine, Aarhus University, Denmark.
authors.forename: Jin
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Orthopaedic Research Laboratory, Aarhus University Hospital, Denmark.
authors.forename: Miao
authors.initials: M
authors.lastname: Wang
authors.affiliation: Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Denmark.
authors.forename: Muwan
authors.initials: M
authors.lastname: Chen
authors.affiliation: Orthopaedic Research Laboratory, Aarhus University Hospital, Denmark.
authors.forename: Dang Quang Svend
authors.initials: DQS
authors.lastname: Le
authors.affiliation: Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Denmark. Electronic address: jk@mb.au.dk.
authors.forename: Jørgen
authors.initials: J
authors.lastname: Kjems
authors.affiliation: Orthopaedic Research Laboratory, Aarhus University Hospital, Denmark.
authors.forename: Cody Eric
authors.initials: CE
authors.lastname: Bünger
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents
keywords: Breast cancer stem cells; Co-delivery; Doxorubicin; Drug resistance; Non-ionic surfactant; siRNA