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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

Cell cycle analysis of midostaurin treated cells. TNBC and non-TNBC cells indicated were cultured in the presence and absence of either 1 μM midostaurin or 1 μM VX-680 for indicated periods and subjected to cell cycle analysis. The positions of sub G1, 2N, 4N, and 8N DNA are indicated at the bottom
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Fig8: Cell cycle analysis of midostaurin treated cells. TNBC and non-TNBC cells indicated were cultured in the presence and absence of either 1 μM midostaurin or 1 μM VX-680 for indicated periods and subjected to cell cycle analysis. The positions of sub G1, 2N, 4N, and 8N DNA are indicated at the bottom

Mentions: It has been reported that Aurora kinases are expressed in M phase and the activity is required for the proper mitotic progression [33]. Previous studies have reported that the inhibition of Aurora kinase A suppresses spindle organization [15], and that the inhibition of both Aurora kinases A and B by VX-680 results in the accumulation of 4N DNA cells followed by the induction of 8N DNA cells and apoptosis [32]. To evaluate the effect of midostaurin on mitotic progression, the structure of cell nuclei of the TNBC cell line, MDA-MB-468 was observed after the midostaurin treatment (Fig. 7). Midostaurin, as well as VX-680, suppressed the phosphorylation of Histone H3 Ser10 in M phase cells, and induced defect of spindle organization as judged by immunostaining [34]. Flow cytometric analysis indicated that midostaurin accumulates 4N DNA cells regardless of the breast cancer subtypes suggesting the induction of G2/M arrest (Fig. 8). Furthermore, even 8N DNA cells were found in the TNBC cell lines, BT-20 and MDA-MB-468, and less significantly or not in non-TNBC cell lines. Sub-G1 fraction was observed in the TNBC cell lines but not in non-TNBC cell lines in consistent with the result of the cleavage of PARP (Fig. 2). VX-680, in agreement with the previous study, showed the results almost identical to those of midostaurin [30]. Namely, midostaurin showed the inhibitory effect on cell cycle progression of the cancer cell lines employed as in the case of VX-680, and induced apoptosis restrictively in the TNBC cells.Fig. 7


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)

Cell cycle analysis of midostaurin treated cells. TNBC and non-TNBC cells indicated were cultured in the presence and absence of either 1 μM midostaurin or 1 μM VX-680 for indicated periods and subjected to cell cycle analysis. The positions of sub G1, 2N, 4N, and 8N DNA are indicated at the bottom
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig8: Cell cycle analysis of midostaurin treated cells. TNBC and non-TNBC cells indicated were cultured in the presence and absence of either 1 μM midostaurin or 1 μM VX-680 for indicated periods and subjected to cell cycle analysis. The positions of sub G1, 2N, 4N, and 8N DNA are indicated at the bottom
Mentions: It has been reported that Aurora kinases are expressed in M phase and the activity is required for the proper mitotic progression [33]. Previous studies have reported that the inhibition of Aurora kinase A suppresses spindle organization [15], and that the inhibition of both Aurora kinases A and B by VX-680 results in the accumulation of 4N DNA cells followed by the induction of 8N DNA cells and apoptosis [32]. To evaluate the effect of midostaurin on mitotic progression, the structure of cell nuclei of the TNBC cell line, MDA-MB-468 was observed after the midostaurin treatment (Fig. 7). Midostaurin, as well as VX-680, suppressed the phosphorylation of Histone H3 Ser10 in M phase cells, and induced defect of spindle organization as judged by immunostaining [34]. Flow cytometric analysis indicated that midostaurin accumulates 4N DNA cells regardless of the breast cancer subtypes suggesting the induction of G2/M arrest (Fig. 8). Furthermore, even 8N DNA cells were found in the TNBC cell lines, BT-20 and MDA-MB-468, and less significantly or not in non-TNBC cell lines. Sub-G1 fraction was observed in the TNBC cell lines but not in non-TNBC cell lines in consistent with the result of the cleavage of PARP (Fig. 2). VX-680, in agreement with the previous study, showed the results almost identical to those of midostaurin [30]. Namely, midostaurin showed the inhibitory effect on cell cycle progression of the cancer cell lines employed as in the case of VX-680, and induced apoptosis restrictively in the TNBC cells.Fig. 7

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