The Bruton�s tyrosine kinase (BTK) inhibitor LFM-A13 has been widely employed as\nan antileukemic agent, but applications in solid cancer have been found recently. The compound promotes\napoptosis, has an antiproliferative effect, and increases cancer cell sensitivity to chemotherapy drugs.\nWe decided to assess the impact of the simultaneous use of erythropoietin (Epo) and LFM-A13 on signal\ntransduction in colon DLD-1 and HT-29 cells, as well as in tumor xenografts. The induction of apoptosis by\nEpo and LFM-A-13 in the cells was confirmed by phosphatidylserine externalization, loss of mitochondrial\nmembrane potential, and modulation of the expression of apoptotic protein BAX and antiapoptotic protein\nBCL-2 in colon adenocarcinoma cells. Nude mice were inoculated with adenocarcinoma cells and treated\nwith Epo and LFM-A13 in order to evaluate the degree of tumor regression. The simultaneous use of Epo\nand LFM-A13 severely inhibited cell growth, activated apoptosis, and also inhibited tumor growth in\nxenografts. The addition of Epo to LFM-A13 intensified the antiproliferative effect of LFM-A13, confirmed\nby the loss of mitochondrial membrane potential and the accumulation of apoptotic colon cancer cells\nwith externalized phosphatidylserine (PS). These preclinical results suggest that the combination of Epo\nand LFM-A13 has a high proapoptotic activity and should be tested in the clinic for the treatment of solid\ntumors such as colon cancer.
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