Table 1.
Antisense Oligonucleotide Effects in Telomerase Inhibition
| Target | Cells Tested* | Effect of treatment | Efficiency of inhibiton | Ref. |
|---|---|---|---|---|
| hTR | HeLa (cervical) | Loss of telomeric DNA; crisis after 23-26 PD | Reduction of activity | [29] |
| hTR | SGC7901 (gastric) | Telomere length shortening; increased apoptosis | Significant reduction of activity |
[30] |
| hTR | U251-MG (malignant glioma) |
Apoptosis only in some populations after 30 PD; differentiation of some populations |
Complete ablation of activity |
[31] |
| hTR | HeLa (cervical) A498 (kidney) |
Reduction in cell viability; appearance of giant, senescent-like cells; reduction in growth rate |
≥75% inhibition of telomerase activity | [32] |
| hTR | MCF-7 (breast) | Progressive telomere shortening for 30 PD; induction of apoptosis; reduction of proliferation and colony formation |
significant suppression of telomerase activity |
[33] |
| hTERT | EJ28, 5637, J28, HT1197 (bladder) |
Reduction of hTERT mRNA (≤88%); impairment of cell viability; G1 arrest |
≤60% inhibition of activity | [34] |
| hTERT | PMC42 (breast) | Decreased telomerase activity; significant apoptosis; Rapid effect: 24 hours post-transfection No significant telomere shortening |
Up to 50% reduction of activity |
[35] |
| hTR and hTERT simultaneously |
SW480 (colon) |
Significant inhibition of proliferation by 24 hours Decrease in telomerase activity by 48 hours continuing to decrease through 72 hours Significant increase in apoptosis |
combination treatment 0.2 mmol/L for 72 hours; 80% inhibition of activity |
[38] |
| hTR (2-5A) |
U251-MG (malignant glioma) |
Significant decrease in cell viability after 5 days Significant impairment of tumor growth in nude mice |
hTR undetectable after treatment |
[39] |
| hTR (2-5A) |
PC3, DU145 (prostate) |
Significant decrease in cell viability within 6 days Significant suppression of tumor growth in nude mice |
Cell viability reduced to 9-18% within 6 days of treatment |
[40] |
| hTR (2′-O-Me) |
DU145, LNCaP (prostate) |
Telomere shortening; halt of cell proliferation after delay (in relation to telomere shortening); 90% reduction in colony forming ability in LNCaP cells |
>75% inhibition of activity up to >85% inhibition in DU145 |
[91] |
| hTERT (PS) |
EJ28 (bladder) |
Maximum decrease in hTERT mRNA 12 hours after treatment; immediate and continued reduction of cell viability with successive transfections of constructs |
>60% inhibition of activity; up to 88% reduction in hTERT mRNA |
[34] |
| hTR (PS) |
HL-60 (leukemia) |
Efficient but not selective; non-complementary constructs had nearly same effect as complementary; more efficient than PNA |
IC50 of 0.5 and 0.6 nM | [42] |
| hTR (PS) |
MKN-28, SGC7901, MKN-45 (gastric) |
After 96 hours, significant growth inhibition in poor and moderately differentiated cell lines but not in well-differentiated Apoptosis in poor and moderately differentiated lines |
Inhibition of activity at 5 mmol/L; complete inhibition at 10 mmol/L |
[43] |
| hTERT (PNA) |
DU145 (prostate) U2OS (osteogenic sarcoma) |
Efficient introduction of naked PNA against hTERT using photochemical internalization approach; effect most prominent 6 hours after treatment becoming less pronounced 24-48 hours after treatment |
Telomerase activity reduced to 8.4 ± 0.79% of control |
[46] |
| single stranded G-rich overhang (PNA) |
AT-SV1 †(Ataxia telangiectasia) |
No inhibition of telomerase activity; decrease in colony sizes; slight decrease in median telomere length Synergistic effect with PNA blocking telomerase activity |
Virtual elimination of colony formation when combined with telomerase inhibitor |
[44] |
| hTR (PNA) |
AT-SV1 †(Ataxia telangiectasia) |
Inhibition of telomerase activity; proliferation arrest after 5 to 30 generations; median telomere length shortened by 377 bp; reduction in colony size |
62% reduction of telomerase activity with 10 mM treatment |
[45] |
| hTR (LNA) |
DU145 (prostate) |
Inhibition of activity up to 40 hours post-transfection High-affinity binding and selectivity |
Some LNAs resulted in >80% inhibition of telomerase activity |
[47] |
| hTR (NP and NPS) |
various | Telomerase inhibition by both NP and NPS resulting in reduction of telomere length NP: most effective targets within template region NPS: may use PS group interacting with hTERT to stabilize secondary structure |
NP: sub-nM IC50 NPS: ∼50 pM IC50 |
[48] |
| hTR (NP and NPS) |
HME50-5E †(spontaneously immortalized breast epithelial cells) |
NP inefficient without lipid carrier; NPS efficient with or without carrier; 0.5 mM NPS caused telomere shortening, senescence by day 100, massive apoptosis by day 115 Addition of -thio group significantly increased potency |
NP: IC50 ∼0.5-1 mM with lipid NPS: IC50 0.5-5 nM with lipid |
[49] |
| hTR (GRN163) |
various | Inhibition of telomerase activity within 24-72 hours after treatment WI-38 and BJ fibroblast survival not affected by up to 100 mM treatment for 72 hours Induction of telomere shortening, growth arrest, cell death, and tumor growth suppression in nude mice |
IC50 of 26-44 pM | [51- 54] |
| (GRN163L) | various | Sevenfold lower IC50 in tested cell lines; more rapid telomeric attrition and growth inhibition; lipid modification eliminates need for carrier In early clinical trials |
[55] |
Antisense modifications: 2-5A = 2′-5′-oligoadenylate; 2′-O-Me = 2′-O-methyl-RNA; PS = phosphorothioate; PNA = peptide nucleic acid; LNA = locked nucleic acid; NP = oligonucleotide N3′-P5′ phosphoramidates; NPS = N3′-P5′ thio-phosphoramidates.
*
All listed are cancer cell lines unless otherwise specified (†)