Imatinib enchances the sensitivity of gastrointestinal stromal tumors to topoisomerase II inhibitors

Objective: to study the sensitivity of gastrointestinal stromal tumors (GISTs) to the topoisomerases type II inhibitors and ability of imatinib to enhance GISTs sensitivity to the chemotherapeutic drugs indicated above.

Subjects and Methods. We studied the sensitivity of gastrointestinal stromal tumors (GISTs) to the topoisomerases II inhibitors and ability of imatinib to enhance GISTs sensitivity to these chemotherapeutic agents. The expression of DNA damage and repair (DDR) markers was examined by western-blotting. Cleaved forms of poly (ADP-rybose) polymerase and caspase-3 were served as an apoptotic markers measured by western blotting. Amount of apoptotic cells was counted by flow cytometry analysis by using a propidium iodide DNA staining procedure and counting the numbers of hypodiploid cells.

Results. We observed the sensitivity of GISTs to topoisomerase II inhibitors – doxorubicine and etoposide inducing DNA double-strand breaks and apoptotic cell death. Imatinib enhances GISTs sensitivity to topoisomerase II inhibitors. This might be due to reduced ability of GISTs to repair DNA damage by homologous recombination. Imatinib-induced reduction of Rad51 recombinase might be due to increased proteasome-dependent degradation.

Conclusion. GIST cells are sensitive to topoisomerase II inhibitors (etoposide and doxorubicin) in vitro. Imatinib enhances GISTs sensitivity to the chemotherapeutic agents indicated above.

1. Gramza A.W., Corless C.L., Heinrich M.C. Resistance to tyrosine kinase inhibitors in gastrointestinal stromal tumors. Clin Cancer Res 2009;15(24):7510–8.

2. Verweij J., Casali P.G., Zalcberg J. et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet 2004;364(9440):1127–34.

3. Hopkins T.G., Marples M., Stark D. Sunitinib in the management of gastrointestinal stromal tumours (GISTs). Eur J Surg Oncol 2008;34(8):844–50.

4. Boichuk S., Rausch J., Duensing A. New developments in management of gastrointestinal stromal tumors: regorafenib, the new player in the team. Gastrointestinal Cancer: Targets and Therapy 2014;4:1–10.

5. Demetri G.D., Reichardt P., Kang Y.K. et al. GRID study investigators. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013;381(9863):295–302.

6. Dematteo R.P., Heinrich M.C., El-Rifai W.M., Demetri G. Clinical management of gastrointestinal stromal tumors: before and after STI-571. Hum Pathol 2002;33(5):466–77.

7. Blay J.Y., Reichardt P. Advanced gastrointestinal stromal tumor in Europe: a review of updated treatment recommendations. Expert Rev Anticancer Ther 2009;9(6):831–8.

8. Casper E.S. Gastrointestinal stromal tumors. Curr Treat Options Oncol 2000; l(3):267–73.

9. Boichuk S., Lee D. J., Mehalek K.R. et аl. Unbiased compound screening identifies unexpected drug sensitivities and novel treatment options for gastrointestinal stromal tumors. Cancer Res 2014;74(4):1200–13.

10. Бойчук С.В., Рамазанов Б.Р., Галембикова А.Р. и др. Состояние системы репарации повреждений ДНК в гастроинтестинальных опухолях и перспективы их терапии. Казанский медицинский журнал 2014;(6):888–91. [Boichuk S.V., Ramazanov B.R., Galembikova A.R. et al. Condition of repair system of DNA damage in gastrointestinal tumors and prospects of their therapy. Kazanskiy meditsinskiy zhurnal = Kazan Medical Journal 2014;(6):888–91. (In Russ.)].

11. Bauer S., Parry J.A., Mühlenberg T. et al. Proapoptotic activity of bortezomib in gastrointestinal stromal tumor cells. Cancer Res 2010;70(1):150–9.

12. Liu Y., Tseng M., Perdreau S.A. et al. Histone H2AX is a mediator of gastrointestinal stromal tumor cell apoptosis following treatment with imatinib mesylate. Cancer Res 2007;67(6):2685–92.

13. Wu D., Ingram A., Lahti J.H. et al. Apoptotic release of histones from nucleosomes. J Biol Chem 2002;277(14):12001–8.