Abstract
Cancer stem cells (CSCs) exhibit self-renewal activity and give rise to other cell types in tumors. Due to the infinite proliferative potential of CSCs, drugs targeting these cells are necessary to completely inhibit cancer development. The β-lapachone (bL) compound is widely used to treat cancer development; however, its effect on cancer stem cells remain elusive. Thus, we investigated the effect of bL on mammosphere formation using breast-cancer stem-cell (BCSC) marker-positive cells, MDA-MB-231. MDA-MB-231 cells, which are negative for reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H):quinone oxidoreductase (NQO1) expression, were constructed to stably express NQO1 (NQO1 stable cells). The effect of bL on these cells was evaluated by wound healing and Transwell cell-culture chambers, ALDEFLUOR assay, and mammosphere formation assay. Here, we show that bL inhibited the proliferative ability of mammospheres derived from BCSC marker-positive cells, MDA-MB-231, in an NQO1-dependent manner. The bL treatment efficiently downregulated the expression level of BCSC markers cluster of differentiation 44 (CD44), aldehyde dehydrogenase 1 family member A1 (ALDH1A1), and discs large (DLG)-associated protein 5 (DLGAP5) that was recently identified as a stem-cell proliferation marker in both cultured cells and mammosphered cells. Moreover, bL efficiently downregulated cell proliferation and migration activities. These results strongly suggest that bL could be a therapeutic agent for targeting breast-cancer stem-cells with proper NQO1 expression.
Highlights
Cancer stem cells (CSCs) have self-renewal activity; their population in tumors is very low, ranging from 0.1 to only a few percent
A characteristic of breast-cancer stem-cell (BCSC) is an enhanced resistance to drugs, radiation, and cell stress that is strongly associated with metastasis and relapse
We found that bL induces cell death and disruption of mammospheres derived from MDA-MB-231 cells (BCSC-positive marker cells) in an NQO1-dependent manner
Summary
Cancer stem cells (CSCs) have self-renewal activity; their population in tumors is very low, ranging from 0.1 to only a few percent. Stem cells (SCs) in breast tissue exhibit self-renewal activity and divide into transient amplifying progenitor cells, which become differentiated cells. BCSCs may originate from stem cells, transient amplifying progenitor cells, or differentiated cells through genetic alteration by environmental stimuli, indicating that the development of BCSCs is a very dynamic process [2]. Well-defined BCSC markers for the identification of BCSCs in tumor tissue and cell lines are cluster of differentiation 44 positive (CD44+)/CD24−/aldehyde dehydrogenase positive (ALDH+) phenotypes, other possible human BCSC markers, such as CD49f+, were proposed [2,3,4,5,6,7].
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