Hu Yafang, Bobb Daniel, Lu Yunbiao, He Jianping, Dome Jeffrey S
Center for Cancer and Immunology Research, Children's National Medical Center, Washington, DC, USA; Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Research Animal Facility, Children's National Medical Center, Washington, DC, USA.
Cancer Genet. 2014 Sep;207(9):403-11. doi: 10.1016/j.cancergen.2014.09.002. Epub 2014 Sep 16.
Novel treatment approaches are desperately needed for malignant rhabdoid tumor (MRT). Telomerase is an attractive therapeutic target because it is specific to cancer and critical for cancer cell immortality. We evaluated the effect of the telomerase inhibitor imetelstat in preclinical models of MRT. Three MRT cell lines, BT-12, G401, and RT-peri, were treated with the telomerase inhibitor imetelstat. The effects of imetelstat on telomere length, DNA damage response, and cell proliferation were assessed. The efficacy of imetelstat in vivo was evaluated in subcutaneous xenografts derived from each of the cell lines. Treatment with imetelstat resulted in inhibition of telomerase activity, marked telomere shortening, and activation of the DNA damage response pathway, as measured by formation of γ-H2AX nuclear foci, phosphorylation of ATM, and phosphorylation of TP53. Imetelstat-treated G401 cells underwent complete growth arrest after 16 passages. The other two cell lines exhibited growth inhibition. Imetelstat resulted in 40-50% growth inhibition compared to placebo-treated controls in all three xenograft models. The activity of imetelstat as a single agent suggests that further studies of telomerase inhibitors in combination with other agents may be warranted.
恶性横纹肌样瘤（MRT）迫切需要新的治疗方法。端粒酶是一个有吸引力的治疗靶点，因为它对癌症具有特异性，并且对癌细胞的永生至关重要。我们在MRT的临床前模型中评估了端粒酶抑制剂艾美拉唑的效果。用端粒酶抑制剂艾美拉唑处理了三种MRT细胞系，BT-12、G401和RT-peri。评估了艾美拉唑对端粒长度、DNA损伤反应和细胞增殖的影响。在源自每种细胞系的皮下异种移植模型中评估了艾美拉唑在体内的疗效。用艾美拉唑处理导致端粒酶活性受到抑制、端粒显著缩短以及DNA损伤反应途径的激活，这通过γ-H2AX核灶的形成、ATM的磷酸化和TP53的磷酸化来衡量。用艾美拉唑处理的G401细胞在传代16次后完全停止生长。另外两种细胞系表现出生长抑制。与安慰剂处理的对照组相比，在所有三种异种移植模型中，艾美拉唑导致生长抑制40-50%。艾美拉唑作为单一药物的活性表明，可能有必要进一步研究端粒酶抑制剂与其他药物的联合使用。
