Simultaneous use of erythropoietin and LFM‐A13 as a new therapeutic approach for colorectal cancer

Background and Purpose Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase involved in the activation of signaling pathways responsible for cell maturation and viability. BTK has previously been reported to be overexpressed in colon cancers. This kind of cancer is often accompanied by anemia, which is treated with an erythropoietin supplement. The goal of the present study was to assess the effects of combination therapy with erythropoietin beta (Epo) and LFM-A13 (BTK inhibitor) on colon cancer in in vitro and in vivo models. Experimental Approach DLD-1 and HT-29 human colon adenocarcinoma cells were cultured with Epo and LFM-A13. Cell number, cell viability, expression of EpoR, BTK, Akt at mRNA, and protein levels were assessed. Nude mice were inoculated with adenocarcinoma cells and treated with Epo and LFM-A13. Key Results Simultaneous use of Epo and LFM-A13 exerts a mostly synergistic inhibitory effect on colon cancer cell growth. The featured therapeutic scheme resulted in effective cell killing, accompanied by attenuation of the BTK signaling pathways. Epo+LFM-A13 also prevented the normal process of microtubule assembly during mitosis via the down-regulation of PLK1 expression. The combined administration of Epo and LFM-A13 significantly reduced the growth rate of tumor cells, while it showed high-profile safety with no induced nephrotoxicity, hepatotoxicity, or changes in the hematological parameters. Conclusion and Implications Our findings demonstrate that Epo significantly enhances the antitumor activity of LFM-A13, indicating the potential use of a combination of Epo and LFM-A13 as an effective therapeutic approach for patients with colorectal cancer.