Back to Search
Start Over
The HSP90 inhibitor alvespimycin enhances the potency of telomerase inhibition by imetelstat in human osteosarcoma.
- Source :
-
Cancer biology & therapy [Cancer Biol Ther] 2015; Vol. 16 (6), pp. 949-57. Date of Electronic Publication: 2015 Apr 28. - Publication Year :
- 2015
-
Abstract
- 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.
- Subjects :
- Animals
Apoptosis drug effects
Ataxia Telangiectasia Mutated Proteins metabolism
Cell Line, Tumor
Cell Proliferation drug effects
Cell Survival drug effects
DNA Damage
Disease Models, Animal
Enzyme Activation drug effects
Enzyme Inhibitors pharmacology
Humans
Mice
Niacinamide pharmacology
Oligonucleotides
Signal Transduction
Telomere Shortening drug effects
Tumor Suppressor Protein p53 metabolism
Xenograft Model Antitumor Assays
Benzoquinones pharmacology
HSP90 Heat-Shock Proteins antagonists & inhibitors
Indoles pharmacology
Lactams, Macrocyclic pharmacology
Niacinamide analogs & derivatives
Osteosarcoma metabolism
Telomerase antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1555-8576
- Volume :
- 16
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Cancer biology & therapy
- Publication Type :
- Academic Journal
- Accession number :
- 25920748
- Full Text :
- https://doi.org/10.1080/15384047.2015.1040964