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Preferential antitumor effect of the Src inhibitor dasatinib associated with a decreased proportion of aldehyde dehydrogenase 1-positive cells in breast cancer cells of the basal B subtype.

Kurebayashi J, Kanomata N, Moriya T, Kozuka Y, Watanabe M, Sonoo H - BMC Cancer (2010)

Bottom Line: Dasatinib decreased the expression levels of phosphorylated Src in all cell lines.Interestingly, dasatinib significantly decreased the proportion of ALDH1-positive cells in the basal B cell lines but not in the other cell lines.A combined use of dasatinib with etoposide additively inhibits their growth.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Breast and Thyroid Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan. kure@med.kawasaki-m.ac.jp

ABSTRACT

Background: Recent studies have suggested that the Src inhibitor dasatinib preferentially inhibits the growth of breast cancer cells of the basal-like subtype. To clarify this finding and further investigate combined antitumor effects of dasatinib with cytotoxic agents, a panel of breast cancer cell lines of various subtypes was treated with dasatinib and/or chemotherapeutic agents.

Methods: Seven human breast cancer cell lines were treated with dasatinib and/or seven chemotherapeutic agents. Effects of the treatments on c-Src activation, cell growth, cell cycle, apoptosis and the proportion of aldehyde dehydrogenase (ALDH) 1-positive cells were examined.

Results: The 50%-growth inhibitory concentrations (IC50s) of dasatinib were much lower in two basal B cell lines than those in the other cell lines. The IC50s of chemotherapeutic agents were not substantially different among the cell lines. Dasatinib enhanced antitumor activity of etoposide in the basal B cell lines. Dasatinib induced a G1-S blockade with a slight apoptosis, and a combined treatment of dasatinib with etoposide also induced a G1-S blockade in the basal B cell lines. Dasatinib decreased the expression levels of phosphorylated Src in all cell lines. Interestingly, dasatinib significantly decreased the proportion of ALDH1-positive cells in the basal B cell lines but not in the other cell lines.

Conclusions: The present study indicates that dasatinib preferentially inhibits the growth of breast cancer cells of the basal B subtype associated with a significant loss of putative cancer stem cell population. A combined use of dasatinib with etoposide additively inhibits their growth. Further studies targeting breast cancers of the basal B subtype using dasatinib with cytotoxic agents are warranted.

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Effects of dasatinib on c-Src phosphorylation in MDA-MB-157 cells. Dasatinib dose-dependently decreased the expression levels of p-Src (Y416 and Y-527) but not that of c-Src.
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Figure 2: Effects of dasatinib on c-Src phosphorylation in MDA-MB-157 cells. Dasatinib dose-dependently decreased the expression levels of p-Src (Y416 and Y-527) but not that of c-Src.

Mentions: To clarify anti-Src activity of dasatinib on breast cancer cells, changes in expression levels of c-Src and p-Src (Y416 and Y527) were examined before and after the treatment with dasatinib (0.1 or 1.0 μM) for 24 hours. Although dasatinib did not significantly change the expression levels of c-Src in any of the cell lines, dasatinib significantly suppressed the expression levels of either p-Src (Y416) or p-Src (Y527) in all cell lines in a dose-dependent manner (Figures 1, 2 and 3).


Preferential antitumor effect of the Src inhibitor dasatinib associated with a decreased proportion of aldehyde dehydrogenase 1-positive cells in breast cancer cells of the basal B subtype.

Kurebayashi J, Kanomata N, Moriya T, Kozuka Y, Watanabe M, Sonoo H - BMC Cancer (2010)

Effects of dasatinib on c-Src phosphorylation in MDA-MB-157 cells. Dasatinib dose-dependently decreased the expression levels of p-Src (Y416 and Y-527) but not that of c-Src.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2967550&req=5

Figure 2: Effects of dasatinib on c-Src phosphorylation in MDA-MB-157 cells. Dasatinib dose-dependently decreased the expression levels of p-Src (Y416 and Y-527) but not that of c-Src.
Mentions: To clarify anti-Src activity of dasatinib on breast cancer cells, changes in expression levels of c-Src and p-Src (Y416 and Y527) were examined before and after the treatment with dasatinib (0.1 or 1.0 μM) for 24 hours. Although dasatinib did not significantly change the expression levels of c-Src in any of the cell lines, dasatinib significantly suppressed the expression levels of either p-Src (Y416) or p-Src (Y527) in all cell lines in a dose-dependent manner (Figures 1, 2 and 3).

Bottom Line: Dasatinib decreased the expression levels of phosphorylated Src in all cell lines.Interestingly, dasatinib significantly decreased the proportion of ALDH1-positive cells in the basal B cell lines but not in the other cell lines.A combined use of dasatinib with etoposide additively inhibits their growth.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Breast and Thyroid Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan. kure@med.kawasaki-m.ac.jp

ABSTRACT

Background: Recent studies have suggested that the Src inhibitor dasatinib preferentially inhibits the growth of breast cancer cells of the basal-like subtype. To clarify this finding and further investigate combined antitumor effects of dasatinib with cytotoxic agents, a panel of breast cancer cell lines of various subtypes was treated with dasatinib and/or chemotherapeutic agents.

Methods: Seven human breast cancer cell lines were treated with dasatinib and/or seven chemotherapeutic agents. Effects of the treatments on c-Src activation, cell growth, cell cycle, apoptosis and the proportion of aldehyde dehydrogenase (ALDH) 1-positive cells were examined.

Results: The 50%-growth inhibitory concentrations (IC50s) of dasatinib were much lower in two basal B cell lines than those in the other cell lines. The IC50s of chemotherapeutic agents were not substantially different among the cell lines. Dasatinib enhanced antitumor activity of etoposide in the basal B cell lines. Dasatinib induced a G1-S blockade with a slight apoptosis, and a combined treatment of dasatinib with etoposide also induced a G1-S blockade in the basal B cell lines. Dasatinib decreased the expression levels of phosphorylated Src in all cell lines. Interestingly, dasatinib significantly decreased the proportion of ALDH1-positive cells in the basal B cell lines but not in the other cell lines.

Conclusions: The present study indicates that dasatinib preferentially inhibits the growth of breast cancer cells of the basal B subtype associated with a significant loss of putative cancer stem cell population. A combined use of dasatinib with etoposide additively inhibits their growth. Further studies targeting breast cancers of the basal B subtype using dasatinib with cytotoxic agents are warranted.

Show MeSH
Related in: MedlinePlus