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Inhibitory effects of telomere-mimic phosphorothioate oligonucleotides on various human tumor cells in vitro
T Ohnuma1, F L Li, J F Holland
1Department of Medicine, Mount Sinai Medical Center, New York, NY 10029, USA.
Abstract:
We tested the cell growth inhibitory effects of telomere-mimic oligomers, 5'-d(TTAGGG)n-3' where n = 1, 2, 3 or 4 in the following 8 human tumor cell lines: 2780 ovarian carcinoma, HEp-2 squamous cell carcinoma, VAMT-1 mesothelioma, DND-1A melanoma, MOLT-3 ALL, Jurkat lymphoma, Daudi Burkitt lymphoma, and JAR choriocarcinoma. As controls, 1 scrambled 6-mer and 2 scrambled 24-mers were tested. Among the compounds tested, the 6-mer and 12-mer were not active in any of the cell lines studied. Increases in the length of oligonucleotides from 18- to 24-mer resulted in increased cell growth inhibitory activity in sensitive cell lines. Cells in suspension cultures, MOLT-3 ALL and Daudi Burkitt lymphoma were generally more sensitive than the monolayers (24-mer ID90 = -3 microM). While the inhibitory effects of authentic 24-mer oligomer were more pronounced than the scrambled oligomers, both of the scrambled 24-mers also showed some degree of inhibitory activity. Except for modest activity of the 24-mer in 2 cell lines, DND-1A and 2780, none of the compounds tested were active against solid tumor cell lines. These data indicate that further study of the telomere-mimic 24-mer is warranted as candidate compound for the treatment of leukemia/lymphoma.
Insights
Telomere-mimic oligomers show potential for treating leukemia and lymphoma. The 24-mer showed significant cell growth inhibition in these cancer types, warranting further investigation.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Telomeres are protective caps at the ends of chromosomes, crucial for maintaining genomic stability.
- Telomere-mimic oligomers are synthetic DNA sequences designed to interact with telomere-related cellular processes.
- Dysregulation of telomere length is a hallmark of many cancers, making telomere-targeting agents a therapeutic interest.
Purpose of the Study:
- To evaluate the cell growth inhibitory effects of telomere-mimic oligomers with varying lengths (n=1-4, corresponding to 6-mer to 24-mer) in human tumor cell lines.
- To compare the activity of authentic telomere-mimic oligomers against scrambled control sequences.
- To identify specific cancer types that are sensitive to telomere-mimic oligomer treatment.
Main Methods:
- Synthesis and testing of telomere-mimic oligomers 5'-d(TTAGGG)n-3' (n=1, 2, 3, 4).
- In vitro cell growth inhibition assays were performed on 8 human tumor cell lines (ovarian carcinoma, squamous cell carcinoma, mesothelioma, melanoma, acute lymphoblastic leukemia, lymphoma, Burkitt lymphoma, choriocarcinoma).
- Control experiments included scrambled 6-mer and 24-mer oligonucleotides.
Main Results:
- Oligomers of 6-mer and 12-mer showed no significant activity across tested cell lines.
- Increased oligonucleotide length from 18-mer to 24-mer correlated with enhanced cell growth inhibitory activity in sensitive cell lines.
- Suspension culture cell lines (MOLT-3 ALL, Daudi Burkitt lymphoma) were more sensitive to the 24-mer than monolayer cell lines.
- The authentic 24-mer exhibited more pronounced inhibitory effects than scrambled controls, though scrambled 24-mers also showed some activity.
- Solid tumor cell lines (except for modest activity in DND-1A melanoma and 2780 ovarian carcinoma) were largely unresponsive to the tested compounds.
Conclusions:
- The telomere-mimic 24-mer demonstrates significant potential as an anti-cancer therapeutic candidate, particularly for leukemia and lymphoma.
- Further research into the 24-mer is warranted due to its selective activity against hematological malignancies.
- The findings suggest that telomere-targeting strategies may be effective for specific cancer types, especially those with high proliferation rates in suspension.