The HSP90 inhibitor alvespimycin enhances the potency of telomerase inhibition by imetelstat in human osteosarcoma.
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.
a Center for Cancer and Immunology Research and the Division of Oncology; Children's National Medical Center ; Washington, DC USA.
Yafang
Y
Hu
Daniel
D
Bobb
Jianping
J
He
D Ashley
DA
Hill
Jeffrey S
JS
Dome
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D016227:Benzoquinones / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D051379:Mice; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D009841:Oligonucleotides; D012516:Osteosarcoma / Q000378:metabolism*; D015398:Signal Transduction; D019098:Telomerase / Q000037:antagonists & inhibitors*; D059506:Telomere Shortening / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D016227:Benzoquinones; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D007211:Indoles; D047029:Lactams, Macrocyclic; D009841:Oligonucleotides; D016159:Tumor Suppressor Protein p53; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D009536:Niacinamide; D064007:Ataxia Telangiectasia Mutated Proteins; D019098:Telomerase; C519562:imetelstat
17-DMAG, 17-NN-Dimethyl Ethylene Diamine-Geldanamycin; 7-AAD, 7-Amino-Actinomycin D; ALT, alternative lengthening of telomeres; COG, the Children's Oncology Group; CTEP, the National Cancer Institute Cancer Therapy Evaluation Program; HSP90; TERT, the catalytic component of telomerase; TRAP, telomeric repeat amplification protocol.; alvespimycin; imetelstat; osteosarcoma; telomerase; γH2AX, phosphorylation of H2AX, TERC, the RNA component of telomerase