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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 and Eto on cell cycle progression and induction of apoptosis in MDA-MB-157 cells. Dasatinib induced a G1-S blockade with a slight apoptosis, Eto induced a slight G1-S blockade, and the combined treatment induced a G1-S blockade with a slight apoptosis in MDA-MB-157 cells.
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Figure 9: Effects of dasatinib and Eto on cell cycle progression and induction of apoptosis in MDA-MB-157 cells. Dasatinib induced a G1-S blockade with a slight apoptosis, Eto induced a slight G1-S blockade, and the combined treatment induced a G1-S blockade with a slight apoptosis in MDA-MB-157 cells.

Mentions: To elucidate the mechanism of action of dasatinib and/or Eto in the cell lines of the basal B subtype, effects of single or combined treatments on cell cycle progression and induction of apoptosis were examined. Dasatinib (0.1 μM) induced a significant G1-S cell cycle blockade associated with a slight apoptosis in both cell lines (Figures 8 and 9). Percentages of cells in the G0/G1 phase were 54.3 ± 0.2 for the control and 70.3 ± 0.9 for dasatinib (P < 0.01) in MDA-MB-231 cells. Those were 60.5 ± 0.3 for the control and 70.8 ± 1.4 for dasatinib (P < 0.01) in MDA-MB-157 cells. Percentages of apoptotic cells were 3.2 ± 0.2 for the control and 8.0 ± 0.1 for dasatinib (P < 0.01) in MDA-MB-231 cells. These were 3.0 ± 0.5 for the control and 6.3 ± 0.5 for dasatinib (P < 0.01) in MDA-MB-157 cells. Eto (0.1 μM) induced a significant G2 accumulation in the MDA-MB-231 cell line (Figure 8). Percentages of cells in the G2/M phase were 18.8 ± 0.4 for the control and 25.4 ± 2.2 for Eto (P = 0.01) in MDA-MB-231 cells. Eto induced slight apoptosis in MDA-MB-157 cell lines (Figure 9). Percentages of apoptotic cells were 3.0 ± 0.5 for the control and 6.0 ± 0.6 for Eto (P = 0.01) in MDA-MB-157 cells.


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 and Eto on cell cycle progression and induction of apoptosis in MDA-MB-157 cells. Dasatinib induced a G1-S blockade with a slight apoptosis, Eto induced a slight G1-S blockade, and the combined treatment induced a G1-S blockade with a slight apoptosis in MDA-MB-157 cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 9: Effects of dasatinib and Eto on cell cycle progression and induction of apoptosis in MDA-MB-157 cells. Dasatinib induced a G1-S blockade with a slight apoptosis, Eto induced a slight G1-S blockade, and the combined treatment induced a G1-S blockade with a slight apoptosis in MDA-MB-157 cells.
Mentions: To elucidate the mechanism of action of dasatinib and/or Eto in the cell lines of the basal B subtype, effects of single or combined treatments on cell cycle progression and induction of apoptosis were examined. Dasatinib (0.1 μM) induced a significant G1-S cell cycle blockade associated with a slight apoptosis in both cell lines (Figures 8 and 9). Percentages of cells in the G0/G1 phase were 54.3 ± 0.2 for the control and 70.3 ± 0.9 for dasatinib (P < 0.01) in MDA-MB-231 cells. Those were 60.5 ± 0.3 for the control and 70.8 ± 1.4 for dasatinib (P < 0.01) in MDA-MB-157 cells. Percentages of apoptotic cells were 3.2 ± 0.2 for the control and 8.0 ± 0.1 for dasatinib (P < 0.01) in MDA-MB-231 cells. These were 3.0 ± 0.5 for the control and 6.3 ± 0.5 for dasatinib (P < 0.01) in MDA-MB-157 cells. Eto (0.1 μM) induced a significant G2 accumulation in the MDA-MB-231 cell line (Figure 8). Percentages of cells in the G2/M phase were 18.8 ± 0.4 for the control and 25.4 ± 2.2 for Eto (P = 0.01) in MDA-MB-231 cells. Eto induced slight apoptosis in MDA-MB-157 cell lines (Figure 9). Percentages of apoptotic cells were 3.0 ± 0.5 for the control and 6.0 ± 0.6 for Eto (P = 0.01) in MDA-MB-157 cells.

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