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Inhibition of Src kinases by a selective tyrosine kinase inhibitor causes mitotic arrest
M M Moasser1, M Srethapakdi, K S Sachar
1Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. moasserm@mskcc.org
Abstract:
src kinase activity is elevated in some human tumors, including breast and colon cancers. The precise cellular function of the src family kinases is not clearly understood, but they appear to be involved in numerous signaling pathways. We studied the effects of PD173955, a novel src family-selective tyrosine kinase inhibitor, on cancer cell lines and found that it has significant antiproliferative activity due to a potent arrest of mitotic progression. The mitotic block occurs after chromosome condensation in prophase, before spindle assembly and without loss of cyclin A and B kinase activities. This effect is seen in cancer cell lines of all types with low or high activities of src kinases as well as in untransformed cell lines. In MDA-MB-468 breast cancer cells, this drug produces a rapid inhibition of cellular src and yes kinase activities as well as suppression of the mitotic hyperactivity of these kinases. This compound defines a novel class of antimitotic drugs that work through inhibition of src kinases and possibly other protein kinases that are required for progression through the initial phases of mitosis.
Insights
A novel src kinase inhibitor, PD173955, halts cancer cell division during mitosis. This drug shows significant antiproliferative effects by blocking mitotic progression in various cancer and normal cell lines.
Area of Science:
- Oncology
- Cell Biology
- Biochemistry
Background:
- Src family kinases are implicated in various signaling pathways and their activity is elevated in certain human cancers.
- The exact role of src family kinases in cellular functions remains incompletely understood.
Purpose of the Study:
- To investigate the effects of PD173955, a src family-selective tyrosine kinase inhibitor, on cancer cell lines.
- To determine the mechanism of action of PD173955 in inhibiting cancer cell proliferation.
Main Methods:
- Treatment of various cancer and untransformed cell lines with PD173955.
- Analysis of mitotic progression, chromosome condensation, spindle assembly, and kinase activities (src, yes, cyclin A, cyclin B).
- Assessment of cellular src and yes kinase activities in MDA-MB-468 breast cancer cells.
Main Results:
- PD173955 demonstrated significant antiproliferative activity across diverse cancer cell lines and untransformed cells.
- The drug induced a potent mitotic block after chromosome condensation but before spindle assembly.
- PD173955 rapidly inhibited cellular src and yes kinase activities and suppressed their mitotic hyperactivity in breast cancer cells.
Conclusions:
- PD173955 defines a novel class of antimitotic drugs targeting src kinases.
- Inhibition of src kinases by PD173955 is crucial for progression through early mitotic phases.
- This compound holds potential for cancer therapy by disrupting mitotic progression via src kinase inhibition.