The HSP90 inhibitor alvespimycin enhances the potency of telomerase inhibition by imetelstat in human osteosarcoma

被引:23
|
作者
Hu, Yafang [1 ,2 ,3 ]
Bobb, Daniel [4 ]
He, Jianping [5 ]
Hill, D. Ashley [6 ]
Dome, Jeffrey S. [1 ,2 ]
机构
[1] Childrens Natl Med Ctr, Ctr Canc & Immunol Res, Washington, DC 20010 USA
[2] Childrens Natl Med Ctr, Div Oncol, Washington, DC 20010 USA
[3] Southern Med Univ, Nanfang Hosp, Dept Neurol, Guangzhou, Guangdong, Peoples R China
[4] Childrens Natl Med Ctr, Res Anim Facil, Washington, DC 20010 USA
[5] Childrens Natl Med Ctr, Ctr Community & Clin Res, Washington, DC 20010 USA
[6] Childrens Natl Med Ctr, Div Pathol, Washington, DC 20010 USA
关键词
alvespimycin; HSP90; imetelstat; osteosarcoma; telomerase; TEMPLATE ANTAGONIST; IN-VITRO; CANCER; OLIGONUCLEOTIDE; CELLS; MECHANISM; GRN163L; SARCOMAS; COMPLEX; TARGETS;
D O I
10.1080/15384047.2015.1040964
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 H2AX 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.
引用
收藏
页码:949 / 957
页数:9
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