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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/or Eto on the proportion of ALDH1-positive cells in BT-474 cells. The cells were treated with 0.1 μM Eto and/or 0.1 μM dasatinib for two days, and ALDH1-positive cells were measured by the immunocytochemical analysis as described in the Materials and Methods. Dasatinib slightly increased the proportion of ALDH1-positive cells in BT-474 cells. *P < 0.05.
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Figure 12: Effects of dasatinib and/or Eto on the proportion of ALDH1-positive cells in BT-474 cells. The cells were treated with 0.1 μM Eto and/or 0.1 μM dasatinib for two days, and ALDH1-positive cells were measured by the immunocytochemical analysis as described in the Materials and Methods. Dasatinib slightly increased the proportion of ALDH1-positive cells in BT-474 cells. *P < 0.05.

Mentions: Dasatinib treatment (0.1 or 1.0 μM) significantly decreased the proportion of ALDH1-positive cells in the cell lines of the basal B subtype (Figures 10 and 11). In contrast, it increased the proportion in the BT-474 cell line (Figure 12). Eto treatment (0.1 or 1.0 μM) did not significantly decrease the proportion of ALDH1-positive cells in any of the cell lines tested. A combined treatment of dasatinib with Eto also significantly decreased the proportion of ALDH1-positive cells in the cell lines of the basal B subtype (Figures 10 and 11). The proportion of ALDH1-positive cells was 13.0 ± 1.4% for the control, 7.0 ± 1.6% for 0.1 μM dasatinib, 11.7 ± 0.1% for 0.1 μM Eto, and 5.2 ± 1.6% for combined treatment in MDA-MB-231 cells. The differences were significant among the control vs. dasatinib alone (P = 0.03) and Eto alone vs. combined treatment (P = 0.03). The proportion of ALDH1-positive cells was 14.1 ± 1.8% for the control, 7.3 ± 0.5% for 0.1 μM dasatinib, 15.6 ± 1.8% for 0.1 μM Eto, and 4.5 ± 1.9% for combined treatment in MDA-MB-157 cells. The differences were significant among the control vs. dasatinib alone (P = 0.01) and Eto alone vs. combined treatment (P < 0.01). No difference was observed between dasatinib alone and combined treatment in either cell line. These findings suggest that Eto did not enhance the decreased proportion of ALDH1-positive cells by dasatinib alone in these 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)

Effects of dasatinib and/or Eto on the proportion of ALDH1-positive cells in BT-474 cells. The cells were treated with 0.1 μM Eto and/or 0.1 μM dasatinib for two days, and ALDH1-positive cells were measured by the immunocytochemical analysis as described in the Materials and Methods. Dasatinib slightly increased the proportion of ALDH1-positive cells in BT-474 cells. *P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 12: Effects of dasatinib and/or Eto on the proportion of ALDH1-positive cells in BT-474 cells. The cells were treated with 0.1 μM Eto and/or 0.1 μM dasatinib for two days, and ALDH1-positive cells were measured by the immunocytochemical analysis as described in the Materials and Methods. Dasatinib slightly increased the proportion of ALDH1-positive cells in BT-474 cells. *P < 0.05.
Mentions: Dasatinib treatment (0.1 or 1.0 μM) significantly decreased the proportion of ALDH1-positive cells in the cell lines of the basal B subtype (Figures 10 and 11). In contrast, it increased the proportion in the BT-474 cell line (Figure 12). Eto treatment (0.1 or 1.0 μM) did not significantly decrease the proportion of ALDH1-positive cells in any of the cell lines tested. A combined treatment of dasatinib with Eto also significantly decreased the proportion of ALDH1-positive cells in the cell lines of the basal B subtype (Figures 10 and 11). The proportion of ALDH1-positive cells was 13.0 ± 1.4% for the control, 7.0 ± 1.6% for 0.1 μM dasatinib, 11.7 ± 0.1% for 0.1 μM Eto, and 5.2 ± 1.6% for combined treatment in MDA-MB-231 cells. The differences were significant among the control vs. dasatinib alone (P = 0.03) and Eto alone vs. combined treatment (P = 0.03). The proportion of ALDH1-positive cells was 14.1 ± 1.8% for the control, 7.3 ± 0.5% for 0.1 μM dasatinib, 15.6 ± 1.8% for 0.1 μM Eto, and 4.5 ± 1.9% for combined treatment in MDA-MB-157 cells. The differences were significant among the control vs. dasatinib alone (P = 0.01) and Eto alone vs. combined treatment (P < 0.01). No difference was observed between dasatinib alone and combined treatment in either cell line. These findings suggest that Eto did not enhance the decreased proportion of ALDH1-positive cells by dasatinib alone in these 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