Hu Yafang, Bobb Daniel, He Jianping, Hill D Ashley, Dome Jeffrey S
a Center for Cancer and Immunology Research and the Division of Oncology; Children's National Medical Center ; Washington, DC USA.
Cancer Biol Ther. 2015;16(6):949-57. doi: 10.1080/15384047.2015.1040964. Epub 2015 Apr 28.
The unsatisfactory outcomes for osteosarcoma necessitate novel therapeutic strategies. This study evaluated the effect of the telomerase inhibitor imetelstat in pre-clinical models of human osteosarcoma. Because the chaperone molecule HSP90 facilitates the assembly of telomerase protein, the ability of the HSP90 inhibitor alvespimycin to potentiate the effect of the telomerase inhibitor was assessed. The effect of single or combined treatment with imetelstat and alvespimycin on long-term growth was assessed in osteosarcoma cell lines (143B, HOS and MG-63) and xenografts derived from 143B cells. Results indicated that imetelstat as a single agent inhibited telomerase activity, induced telomere shortening, and inhibited growth in all 3 osteosarcoma cell lines, though the bulk cell cultures did not undergo growth arrest. Combined treatment with imetelstat and alvespimycin resulted in diminished telomerase activity and shorter telomeres compared to either agent alone as well as higher levels of γH2AX and cleaved caspase-3, indicative of increased DNA damage and apoptosis. With dual telomerase and HSP90 inhibition, complete growth arrest of bulk cell cultures was achieved. In xenograft models, all 3 treatment groups significantly inhibited tumor growth compared with the placebo-treated control group, with the greatest effect seen in the combined treatment group (imetelstat, p = 0.045, alvespimycin, p = 0.034; combined treatment, p = 0.004). In conclusion, HSP90 inhibition enhanced the effect of telomerase inhibition in pre-clinical models of osteosarcoma. Dual targeting of telomerase and HSP90 warrants further investigation as a therapeutic strategy.
骨肉瘤的治疗效果不尽人意，因此需要新的治疗策略。本研究评估了端粒酶抑制剂艾美司他在人骨肉瘤临床前模型中的作用。由于伴侣分子热休克蛋白90（HSP90）促进端粒酶蛋白的组装，因此评估了HSP90抑制剂阿维司比霉素增强端粒酶抑制剂作用的能力。在骨肉瘤细胞系（143B、HOS和MG-63）以及源自143B细胞的异种移植模型中，评估了艾美司他与阿维司比霉素单药或联合治疗对长期生长的影响。结果表明，艾美司他作为单一药物可抑制端粒酶活性，诱导端粒缩短，并抑制所有3种骨肉瘤细胞系的生长，尽管大量细胞培养物未发生生长停滞。与单独使用任何一种药物相比，艾美司他与阿维司比霉素联合治疗导致端粒酶活性降低、端粒缩短，同时γH2AX和裂解的半胱天冬酶-3水平升高，表明DNA损伤和细胞凋亡增加。通过双重抑制端粒酶和HSP90，实现了大量细胞培养物的完全生长停滞。在异种移植模型中，与安慰剂治疗的对照组相比，所有3个治疗组均显著抑制肿瘤生长，联合治疗组的效果最为显著（艾美司他，p = 0.045；阿维司比霉素，p = 0.034；联合治疗，p = 0.004）。总之，在骨肉瘤临床前模型中，抑制HSP90可增强端粒酶抑制的效果。作为一种治疗策略，双重靶向端粒酶和HSP90值得进一步研究。
