The mechanisms of sensitization of gastrointestinal stromal tumor cells to DNA topoisomerase II inhibitors

Abstract

Aim. To examine the ability of receptor tyrosine kinase inhibitors to modulate gastrointestinal stromal tumor cells sensitivity to DNA topoisomerase II inhibitors.

Methods. The following receptor tyrosine kinase inhibitors were used in the present study - imatinib, crizotinib, cabozantinib and sunitinib. An ability of the named medications to sensitize gastrointestinal stromal tumor cells to DNA topoisomerase II inhibitor (doxorubicin) was examined by using an MTS-based colorimetric assay. The expression of apoptotic, DNA damage and repair markers was assessed with western blotting by using the corresponding monoclonal antibodies. Proliferative activity was examined in a real-time by utilizing an iCELLigence system (ACEA Biosciences Inc., USA).

Results. We found that all above-mentioned receptor tyrosine kinase inhibitors were able to sensitize gastrointestinal stromal tumor cells to topoisomerase II inhibitors. This leads to the decrease of proliferative activity of tumors cells and enhancement of apoptotic cell death. Importantly, this effect was observed in imatinib-resistant gastrointestinal stromal tumor cells. One of the possible molecular mechanisms responsible for sensitization of these cells to topoisomerase II inhibitors was the ability of the target medications to inhibit the homologous recombination. This is evidenced by substantial decrease of Rad51 recombinase expression as a result of receptor tyrosine kinase inhibitor effect on the cells with DNA damage caused by topoisomerase II inhibitors.

Conclusion. Receptor tyrosine kinase inhibitors are able to sensitize imatinib-resistant gastrointestinal stromal tumor cells to topoisomerase II inhibitors by inhibiting DNA homologous recombination.

Keywords

gastrointestinal stromal tumors / GIST / resistance / chemotherapeutic agents / receptor tyrosine kinase inhibitors / apoptosis / proliferation / DNA damage repair

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Dunaev P.D., Galembikova A.R., Boichuk S.V.