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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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Additive antitumor activity of dasatinib and Eto in MDA-MB-231 cells. The cells were treated with indicated concentrations of Eto and/or 0.1 μM dasatinib for three days, and the cell count was measured by a Coulter counter as described in the Materials and Methods. Dasatinib additively inhibited the growth of MDA-MB-231 cells. Open circles represent values treated with Eto alone. Closed circles represent values treated with Eto plus dasatinib. The values are expressed as mean ± S.E. of at least two separate experiments.
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Figure 4: Additive antitumor activity of dasatinib and Eto in MDA-MB-231 cells. The cells were treated with indicated concentrations of Eto and/or 0.1 μM dasatinib for three days, and the cell count was measured by a Coulter counter as described in the Materials and Methods. Dasatinib additively inhibited the growth of MDA-MB-231 cells. Open circles represent values treated with Eto alone. Closed circles represent values treated with Eto plus dasatinib. The values are expressed as mean ± S.E. of at least two separate experiments.

Mentions: To explore combined antitumor effects of dasatinib with cytotoxic agents, combined treatments of dasatinib (0.1 μM) with the indicated concentrations of Eto were examined in the basal B cell lines. The combination index of the IC50 was 0.2 in either cell line, that is, dasatinib additively enhanced the antitumor effect of Eto in these cell lines (Figures 4 and 5). Similar additive interactions were also observed in the combination of dasatinib with Pac or SN38 in these cell lines (Supplementary Figure 2). These additive interactions were not observed in the other cell lines.


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)

Additive antitumor activity of dasatinib and Eto in MDA-MB-231 cells. The cells were treated with indicated concentrations of Eto and/or 0.1 μM dasatinib for three days, and the cell count was measured by a Coulter counter as described in the Materials and Methods. Dasatinib additively inhibited the growth of MDA-MB-231 cells. Open circles represent values treated with Eto alone. Closed circles represent values treated with Eto plus dasatinib. The values are expressed as mean ± S.E. of at least two separate experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Additive antitumor activity of dasatinib and Eto in MDA-MB-231 cells. The cells were treated with indicated concentrations of Eto and/or 0.1 μM dasatinib for three days, and the cell count was measured by a Coulter counter as described in the Materials and Methods. Dasatinib additively inhibited the growth of MDA-MB-231 cells. Open circles represent values treated with Eto alone. Closed circles represent values treated with Eto plus dasatinib. The values are expressed as mean ± S.E. of at least two separate experiments.
Mentions: To explore combined antitumor effects of dasatinib with cytotoxic agents, combined treatments of dasatinib (0.1 μM) with the indicated concentrations of Eto were examined in the basal B cell lines. The combination index of the IC50 was 0.2 in either cell line, that is, dasatinib additively enhanced the antitumor effect of Eto in these cell lines (Figures 4 and 5). Similar additive interactions were also observed in the combination of dasatinib with Pac or SN38 in these cell lines (Supplementary Figure 2). These additive interactions were not observed in the other cell lines.

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