Department of Monitored Pharmacotherapy, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland.
Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland.
Int J Mol Sci. 2018 Apr 23;19(4):1262. doi: 10.3390/ijms19041262.
The Bruton’s tyrosine kinase (BTK) inhibitor LFM-A13 has been widely employed as an antileukemic agent, but applications in solid cancer have been found recently. The compound promotes apoptosis, has an antiproliferative effect, and increases cancer cell sensitivity to chemotherapy drugs. We decided to assess the impact of the simultaneous use of erythropoietin (Epo) and LFM-A13 on signal transduction in colon DLD-1 and HT-29 cells, as well as in tumor xenografts. The induction of apoptosis by Epo and LFM-A-13 in the cells was confirmed by phosphatidylserine externalization, loss of mitochondrial membrane potential, and modulation of the expression of apoptotic protein BAX and antiapoptotic protein BCL-2 in colon adenocarcinoma cells. Nude mice were inoculated with adenocarcinoma cells and treated with Epo and LFM-A13 in order to evaluate the degree of tumor regression. The simultaneous use of Epo and LFM-A13 severely inhibited cell growth, activated apoptosis, and also inhibited tumor growth in xenografts. The addition of Epo to LFM-A13 intensified the antiproliferative effect of LFM-A13, confirmed by the loss of mitochondrial membrane potential and the accumulation of apoptotic colon cancer cells with externalized phosphatidylserine (PS). These preclinical results suggest that the combination of Epo and LFM-A13 has a high proapoptotic activity and should be tested in the clinic for the treatment of solid tumors such as colon cancer.
布鲁顿酪氨酸激酶（BTK）抑制剂 LFM-A13 已被广泛用作抗白血病药物，但最近发现其在实体瘤中的应用。该化合物可促进细胞凋亡、具有抗增殖作用，并增加癌细胞对化疗药物的敏感性。我们决定评估同时使用促红细胞生成素（Epo）和 LFM-A13 对结肠 DLD-1 和 HT-29 细胞以及肿瘤异种移植物中信号转导的影响。通过磷脂酰丝氨酸外翻、线粒体膜电位丧失以及细胞凋亡蛋白 BAX 和抗细胞凋亡蛋白 BCL-2 的表达调节，证实了 Epo 和 LFM-A-13 在结肠腺癌细胞中诱导细胞凋亡。将结肠癌细胞接种于裸鼠，并用 Epo 和 LFM-A13 进行治疗，以评估肿瘤消退的程度。同时使用 Epo 和 LFM-A13 可严重抑制细胞生长，激活细胞凋亡，并抑制异种移植物中的肿瘤生长。Epo 可增强 LFM-A13 的抗增殖作用，通过线粒体膜电位丧失和细胞凋亡的结肠癌细胞中磷脂酰丝氨酸（PS）的积累得到证实。这些临床前结果表明，Epo 和 LFM-A13 的联合使用具有很高的促凋亡活性，应该在临床上用于治疗结肠癌等实体瘤。
Zotero 插件
