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Published on: August 12, 2015
The G-quadruplex-interactive molecule BRACO-19 inhibits tumor growth, consistent with telomere targeting and
Angelika M Burger1, Fangping Dai, Christoph M Schultes
1Institute for Experimental Oncology, Freiburg, Germany.
Abstract:
Interference with telomerase and telomere maintenance is emerging as an attractive target for anticancer therapies. Ligand-induced stabilization of G-quadruplex formation by the telomeric DNA single-stranded 3' overhang inhibits telomerase from catalyzing telomeric DNA synthesis and from capping telomeric ends. We report here the effects of a 3,6,9-trisubstituted acridine compound, BRACO-19, on telomerase function in vitro and in vivo. The biological activity of BRACO-19 was evaluated in the human uterus carcinoma cell line UXF1138L, which has very short telomeres (2.7 kb). In vitro, nuclear human telomerase reverse transcriptase (hTERT) expression was drastically decreased after 24 hours, induction of cellular senescence and complete cessation of growth was seen after 15 days, paralleled by telomere shortening of ca. 0.4 kb. In vivo, BRACO-19 was highly active as a single agent against early-stage (68 mm(3)) tumors in a s.c. growing xenograft model established from UXF1138L cells, if given chronically at 2 mg per kg per day i.p. BRACO-19 produced growth inhibition of 96% compared with controls accompanied by partial regressions (P < 0.018). Immunostaining of xenograft tissues showed that this response was paralleled by loss of nuclear hTERT protein expression and an increase in atypical mitoses indicative of telomere dysfunction. Cytoplasmic hTERT expression and its colocalization with ubiquitin was observed suggesting that hTERT is bound to ubiquitin and targeted for enhanced degradation upon BRACO-19 treatment. This is in accord with a model of induced displacement of telomerase from the telomere. The in vitro and in vivo data presented here is consistent with the G-quadruplex binding ligand BRACO-19 producing an anticancer effect by inhibiting the capping and catalytic functions of telomerase.
Insights
BRACO-19, a G-quadruplex ligand, effectively inhibits telomerase function by targeting human telomerase reverse transcriptase (hTERT). This anticancer agent halts tumor growth and induces senescence by disrupting telomere maintenance.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Telomere maintenance and telomerase activity are critical for cancer cell proliferation.
- Targeting telomerase offers a promising strategy for anticancer therapies.
- G-quadruplex (G4) structures in telomeres can be targeted by small molecules to inhibit telomerase.
Purpose of the Study:
- To investigate the anticancer effects of BRACO-19, a G4-binding ligand, on telomerase function in vitro and in vivo.
- To evaluate BRACO-19's efficacy in a human uterus carcinoma cell line (UXF1138L) with short telomeres.
- To elucidate the mechanism of action of BRACO-19 in inhibiting telomerase.
Main Methods:
- In vitro studies using UXF1138L cells to assess effects on human telomerase reverse transcriptase (hTERT) expression, cellular senescence, growth, and telomere length.
- In vivo xenograft studies in mice bearing UXF1138L tumors to evaluate BRACO-19's anti-tumor activity.
- Immunostaining of xenograft tissues to analyze hTERT protein expression, telomere dysfunction, and hTERT degradation.
Main Results:
- BRACO-19 significantly decreased nuclear hTERT expression, induced cellular senescence, and inhibited growth in vitro.
- In vivo, BRACO-19 demonstrated high anti-tumor activity, causing 96% growth inhibition and partial tumor regressions.
- BRACO-19 treatment led to loss of nuclear hTERT, increased atypical mitoses, and suggested enhanced hTERT degradation via ubiquitination.
Conclusions:
- BRACO-19 effectively inhibits both in vitro and in vivo telomerase function.
- The compound acts by inhibiting telomerase's catalytic and capping functions, leading to telomere dysfunction and cancer cell death.
- BRACO-19 represents a potent G-quadruplex-binding ligand with significant anticancer potential by targeting telomerase.
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