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Midostaurin preferentially attenuates proliferation of triple-negative breast cancer cell lines through inhibition of Aurora kinase family.

Kawai M, Nakashima A, Kamada S, Kikkawa U - J. Biomed. Sci. (2015)

Bottom Line: It is, thus, required to develop an effective therapeutic reagent to treat TNBC.Following studies indicated that midostaurin attenuates the phosphorylation reaction mediated by Aurora kinase in the cells and directly inhibits this protein kinase in vitro, and that this reagent induces apoptosis accompanying accumulation of 4N and 8N DNA cells in TNBC cells.The precise study of midostaurin on cell growth will contribute to the development of the drug for the treatment of TNBC.

View Article: PubMed Central - PubMed

Affiliation: Biosignal Research Center, Kobe University, Kobe, 657-8501, Japan. 090s381s@stu.kobe-u.ac.jp.

ABSTRACT

Background: Breast cancer is classified into three subtypes by the expression of biomarker receptors such as hormone receptors and human epidermal growth factor receptor 2. Triple-negative breast cancer (TNBC) expresses none of these receptors and has an aggressive phenotype with a poor prognosis, which is insensitive to the drugs that target the hormone receptors and human epidermal growth factor receptor 2. It is, thus, required to develop an effective therapeutic reagent to treat TNBC.

Results: The study using a panel of 19 breast cancer cell lines revealed that midostaurin, a multi-target protein kinase inhibitor, suppresses preferentially the growth of TNBC cells comparing with non-TNBC cells. Clustering analysis of the drug activity data for the panel of cancer cell lines predicted that midostaurin shares the target with Aurora kinase inhibitors. Following studies indicated that midostaurin attenuates the phosphorylation reaction mediated by Aurora kinase in the cells and directly inhibits this protein kinase in vitro, and that this reagent induces apoptosis accompanying accumulation of 4N and 8N DNA cells in TNBC cells.

Conclusion: Midostaurin suppresses the proliferation of TNBC cells among the breast cancer cell lines presumably through the inhibition of the Aurora kinase family. The precise study of midostaurin on cell growth will contribute to the development of the drug for the treatment of TNBC.

No MeSH data available.


Related in: MedlinePlus

Hierarchical clustering of drugs based on similarity of anti-proliferation effect profiles on breast cancer cell lines. Two-dimensional hierarchical clustering was applied to growth inhibitory activity data of 76 anticancer drugs, including midostaurin, of a panel of breast cancer cell lines. The sensitivity level against each drug in a single cell line relative to its mean value across all cell lines was depicted according to the color scale shown at the upper left corner in the figure, and gray indicates missing values. Drugs with similar mechanisms of action tended to cluster together
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Fig3: Hierarchical clustering of drugs based on similarity of anti-proliferation effect profiles on breast cancer cell lines. Two-dimensional hierarchical clustering was applied to growth inhibitory activity data of 76 anticancer drugs, including midostaurin, of a panel of breast cancer cell lines. The sensitivity level against each drug in a single cell line relative to its mean value across all cell lines was depicted according to the color scale shown at the upper left corner in the figure, and gray indicates missing values. Drugs with similar mechanisms of action tended to cluster together

Mentions: To find the target molecule(s) of midostaurin responsible for its anti-proliferative effect, the drug efficacy pattern of midostaurin against the panel of cancer cell lines was compared with that of the drugs having known targets by clustering analysis. The dataset of drug sensitivity of 45 breast cancer cell lines against various known target [14] were utilized as the reference data. The reference data lack HS578T and MDA-MB-435S and contain 17 of the 19 cell lines employed in this study, and were merged with the drug sensitivity data of midostaurin of 17 cell lines, while ZR-75-30 in Fig. 1a and other three cell lines in the reference data were excluded because of excess missing values. The resulting data of 75 drugs, 74 drugs in the reference data and midostaurin, and 41 cell lines were then applied for clustering analysis as shown in Fig. 3. Gefitinib and AG1478, for example, which are potent inhibitors of the EGF receptor kinase [30], were classified into the same cluster (Lines No. 46 and 47 from the top of the panel, respectively). Doxorubicin, CPT-11, and topotecan, which are potent inhibitors of the topoisomerases [14] were classified into the same cluster (Lines No. 64 to 66 from the top of the panel, respectively). These data are similar to the previous report [14] confirming the validity of the clustering analysis. Under these conditions, midostaurin was found in the cluster with VX-680 and GSK1070916, Aurora kinase inhibitors [14, 31]. These results suggest that Aurora kinase is a candidate for the target, which is responsible for the anti-proliferative effect of midostaurin in the TNBC cell lines.Fig. 3


Midostaurin preferentially attenuates proliferation of triple-negative breast cancer cell lines through inhibition of Aurora kinase family.

Kawai M, Nakashima A, Kamada S, Kikkawa U - J. Biomed. Sci. (2015)

Hierarchical clustering of drugs based on similarity of anti-proliferation effect profiles on breast cancer cell lines. Two-dimensional hierarchical clustering was applied to growth inhibitory activity data of 76 anticancer drugs, including midostaurin, of a panel of breast cancer cell lines. The sensitivity level against each drug in a single cell line relative to its mean value across all cell lines was depicted according to the color scale shown at the upper left corner in the figure, and gray indicates missing values. Drugs with similar mechanisms of action tended to cluster together
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4491224&req=5

Fig3: Hierarchical clustering of drugs based on similarity of anti-proliferation effect profiles on breast cancer cell lines. Two-dimensional hierarchical clustering was applied to growth inhibitory activity data of 76 anticancer drugs, including midostaurin, of a panel of breast cancer cell lines. The sensitivity level against each drug in a single cell line relative to its mean value across all cell lines was depicted according to the color scale shown at the upper left corner in the figure, and gray indicates missing values. Drugs with similar mechanisms of action tended to cluster together
Mentions: To find the target molecule(s) of midostaurin responsible for its anti-proliferative effect, the drug efficacy pattern of midostaurin against the panel of cancer cell lines was compared with that of the drugs having known targets by clustering analysis. The dataset of drug sensitivity of 45 breast cancer cell lines against various known target [14] were utilized as the reference data. The reference data lack HS578T and MDA-MB-435S and contain 17 of the 19 cell lines employed in this study, and were merged with the drug sensitivity data of midostaurin of 17 cell lines, while ZR-75-30 in Fig. 1a and other three cell lines in the reference data were excluded because of excess missing values. The resulting data of 75 drugs, 74 drugs in the reference data and midostaurin, and 41 cell lines were then applied for clustering analysis as shown in Fig. 3. Gefitinib and AG1478, for example, which are potent inhibitors of the EGF receptor kinase [30], were classified into the same cluster (Lines No. 46 and 47 from the top of the panel, respectively). Doxorubicin, CPT-11, and topotecan, which are potent inhibitors of the topoisomerases [14] were classified into the same cluster (Lines No. 64 to 66 from the top of the panel, respectively). These data are similar to the previous report [14] confirming the validity of the clustering analysis. Under these conditions, midostaurin was found in the cluster with VX-680 and GSK1070916, Aurora kinase inhibitors [14, 31]. These results suggest that Aurora kinase is a candidate for the target, which is responsible for the anti-proliferative effect of midostaurin in the TNBC cell lines.Fig. 3

Bottom Line: It is, thus, required to develop an effective therapeutic reagent to treat TNBC.Following studies indicated that midostaurin attenuates the phosphorylation reaction mediated by Aurora kinase in the cells and directly inhibits this protein kinase in vitro, and that this reagent induces apoptosis accompanying accumulation of 4N and 8N DNA cells in TNBC cells.The precise study of midostaurin on cell growth will contribute to the development of the drug for the treatment of TNBC.

View Article: PubMed Central - PubMed

Affiliation: Biosignal Research Center, Kobe University, Kobe, 657-8501, Japan. 090s381s@stu.kobe-u.ac.jp.

ABSTRACT

Background: Breast cancer is classified into three subtypes by the expression of biomarker receptors such as hormone receptors and human epidermal growth factor receptor 2. Triple-negative breast cancer (TNBC) expresses none of these receptors and has an aggressive phenotype with a poor prognosis, which is insensitive to the drugs that target the hormone receptors and human epidermal growth factor receptor 2. It is, thus, required to develop an effective therapeutic reagent to treat TNBC.

Results: The study using a panel of 19 breast cancer cell lines revealed that midostaurin, a multi-target protein kinase inhibitor, suppresses preferentially the growth of TNBC cells comparing with non-TNBC cells. Clustering analysis of the drug activity data for the panel of cancer cell lines predicted that midostaurin shares the target with Aurora kinase inhibitors. Following studies indicated that midostaurin attenuates the phosphorylation reaction mediated by Aurora kinase in the cells and directly inhibits this protein kinase in vitro, and that this reagent induces apoptosis accompanying accumulation of 4N and 8N DNA cells in TNBC cells.

Conclusion: Midostaurin suppresses the proliferation of TNBC cells among the breast cancer cell lines presumably through the inhibition of the Aurora kinase family. The precise study of midostaurin on cell growth will contribute to the development of the drug for the treatment of TNBC.

No MeSH data available.


Related in: MedlinePlus