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.

Statement of significance: 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.

Keywords: Breast cancer stem cells; Co-delivery; Doxorubicin; Drug resistance; Non-ionic surfactant; siRNA.