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Telomeric DNA induces apoptosis and senescence of human breast carcinoma cells.

Yaar M, Eller MS, Panova I, Kubera J, Wee LH, Cowan KH, Gilchrest BA - Breast Cancer Res. (2007)

Bottom Line: We have identified an inducible cancer avoidance mechanism in cells that reduces mutation rate, reduces and delays carcinogenesis after carcinogen exposure, and induces apoptosis and/or senescence of already transformed cells by simultaneously activating multiple overlapping and redundant DNA damage response pathways.The human breast carcinoma cell line MCF-7, the adriamycin-resistant MCF-7 (Adr/MCF-7) cell line, as well as normal human mammary epithelial (NME) cells were treated with DNA oligonucleotides homologous to the telomere 3' overhang (T-oligos).Acting through ataxia telangiectasia mutated (ATM) and its downstream effectors, T-oligos induced apoptosis and senescence of MCF-7 cells but not NME cells, in which these signaling pathways were induced to a far lesser extent.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Dermatology, Boston University School of Medicine, Albany Street, Boston, MA 02118-2394, USA.

ABSTRACT

Introduction: Cancer is a leading cause of death in Americans. We have identified an inducible cancer avoidance mechanism in cells that reduces mutation rate, reduces and delays carcinogenesis after carcinogen exposure, and induces apoptosis and/or senescence of already transformed cells by simultaneously activating multiple overlapping and redundant DNA damage response pathways.

Methods: The human breast carcinoma cell line MCF-7, the adriamycin-resistant MCF-7 (Adr/MCF-7) cell line, as well as normal human mammary epithelial (NME) cells were treated with DNA oligonucleotides homologous to the telomere 3' overhang (T-oligos). SCID mice received intravenous injections of MCF-7 cells followed by intravenous administration of T-oligos.

Results: Acting through ataxia telangiectasia mutated (ATM) and its downstream effectors, T-oligos induced apoptosis and senescence of MCF-7 cells but not NME cells, in which these signaling pathways were induced to a far lesser extent. In MCF-7 cells, experimental telomere loop disruption caused identical responses, consistent with the hypothesis that T-oligos act by mimicking telomere overhang exposure. In vivo, T-oligos greatly prolonged survival of SCID mice following intravenous injection of human breast carcinoma cells.

Conclusion: By inducing DNA damage-like responses in MCF-7 cells, T-oligos provide insight into innate cancer avoidance mechanisms and may offer a novel approach to treatment of breast cancer and other malignancies.

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T-oligo effect on MCF-7 cells is comparable to that of cisplatin and ICI 182,780. MCF-7 cells were treated with cisplatin (10 μM), the anti-estrogen ICI 182,780 (100 nM) or T-oligo (40 μM) once and cell yields were determined at different intervals. (a) Within 5 days cisplatin decreased MCF-7 yield by 82 ± 0.1% and T-oligo did so by 79 ± 0.02% compared to diluent. The difference between the T-oligo and cisplatin effects was not significant (p = 1.0). (b) Compared to diluent, ICI 182,780 or T-oligo caused decreases in cell yield of MCF-7 cells of 72 ± 0.1% and 84 ± 0.02%, respectively. T-oligo was significantly more effective than ICI 182,780 (p < 0.005).
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Figure 6: T-oligo effect on MCF-7 cells is comparable to that of cisplatin and ICI 182,780. MCF-7 cells were treated with cisplatin (10 μM), the anti-estrogen ICI 182,780 (100 nM) or T-oligo (40 μM) once and cell yields were determined at different intervals. (a) Within 5 days cisplatin decreased MCF-7 yield by 82 ± 0.1% and T-oligo did so by 79 ± 0.02% compared to diluent. The difference between the T-oligo and cisplatin effects was not significant (p = 1.0). (b) Compared to diluent, ICI 182,780 or T-oligo caused decreases in cell yield of MCF-7 cells of 72 ± 0.1% and 84 ± 0.02%, respectively. T-oligo was significantly more effective than ICI 182,780 (p < 0.005).

Mentions: To compare the T-oligo effect to that of a recognized anti-breast cancer chemotherapeutic agent, cisplatin [44-48], and to an anti-estrogen frequently used to treat estrogen receptor positive breast cancers [49-51], MCF-7 cells were treated with customary doses of cisplatin (10 μM), the anti-estrogen ICI 182,780 (100 nM) or T-oligo (40 μM) as above (Figure 6). Within 5 days after a single treatment, compared to diluent, cisplatin decreased MCF-7 yield by 82 ± 0.1% and T-oligo did so by 79 ± 0.02%, an insignificant difference (p = 1.0; Figure 6a). Similarly, compared to diluent, within 5 days after a single treatment with ICI 182,780 or T-oligo, cell yield decreased by 72 ± 0.1% and 84 ± 0.02%, respectively (Figure 6b). Interestingly, in this comparison, T-oligo was significantly more effective than the anti-estrogen ICI 182,780 (p < 0.005).


Telomeric DNA induces apoptosis and senescence of human breast carcinoma cells.

Yaar M, Eller MS, Panova I, Kubera J, Wee LH, Cowan KH, Gilchrest BA - Breast Cancer Res. (2007)

T-oligo effect on MCF-7 cells is comparable to that of cisplatin and ICI 182,780. MCF-7 cells were treated with cisplatin (10 μM), the anti-estrogen ICI 182,780 (100 nM) or T-oligo (40 μM) once and cell yields were determined at different intervals. (a) Within 5 days cisplatin decreased MCF-7 yield by 82 ± 0.1% and T-oligo did so by 79 ± 0.02% compared to diluent. The difference between the T-oligo and cisplatin effects was not significant (p = 1.0). (b) Compared to diluent, ICI 182,780 or T-oligo caused decreases in cell yield of MCF-7 cells of 72 ± 0.1% and 84 ± 0.02%, respectively. T-oligo was significantly more effective than ICI 182,780 (p < 0.005).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC1851376&req=5

Figure 6: T-oligo effect on MCF-7 cells is comparable to that of cisplatin and ICI 182,780. MCF-7 cells were treated with cisplatin (10 μM), the anti-estrogen ICI 182,780 (100 nM) or T-oligo (40 μM) once and cell yields were determined at different intervals. (a) Within 5 days cisplatin decreased MCF-7 yield by 82 ± 0.1% and T-oligo did so by 79 ± 0.02% compared to diluent. The difference between the T-oligo and cisplatin effects was not significant (p = 1.0). (b) Compared to diluent, ICI 182,780 or T-oligo caused decreases in cell yield of MCF-7 cells of 72 ± 0.1% and 84 ± 0.02%, respectively. T-oligo was significantly more effective than ICI 182,780 (p < 0.005).
Mentions: To compare the T-oligo effect to that of a recognized anti-breast cancer chemotherapeutic agent, cisplatin [44-48], and to an anti-estrogen frequently used to treat estrogen receptor positive breast cancers [49-51], MCF-7 cells were treated with customary doses of cisplatin (10 μM), the anti-estrogen ICI 182,780 (100 nM) or T-oligo (40 μM) as above (Figure 6). Within 5 days after a single treatment, compared to diluent, cisplatin decreased MCF-7 yield by 82 ± 0.1% and T-oligo did so by 79 ± 0.02%, an insignificant difference (p = 1.0; Figure 6a). Similarly, compared to diluent, within 5 days after a single treatment with ICI 182,780 or T-oligo, cell yield decreased by 72 ± 0.1% and 84 ± 0.02%, respectively (Figure 6b). Interestingly, in this comparison, T-oligo was significantly more effective than the anti-estrogen ICI 182,780 (p < 0.005).

Bottom Line: We have identified an inducible cancer avoidance mechanism in cells that reduces mutation rate, reduces and delays carcinogenesis after carcinogen exposure, and induces apoptosis and/or senescence of already transformed cells by simultaneously activating multiple overlapping and redundant DNA damage response pathways.The human breast carcinoma cell line MCF-7, the adriamycin-resistant MCF-7 (Adr/MCF-7) cell line, as well as normal human mammary epithelial (NME) cells were treated with DNA oligonucleotides homologous to the telomere 3' overhang (T-oligos).Acting through ataxia telangiectasia mutated (ATM) and its downstream effectors, T-oligos induced apoptosis and senescence of MCF-7 cells but not NME cells, in which these signaling pathways were induced to a far lesser extent.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Dermatology, Boston University School of Medicine, Albany Street, Boston, MA 02118-2394, USA.

ABSTRACT

Introduction: Cancer is a leading cause of death in Americans. We have identified an inducible cancer avoidance mechanism in cells that reduces mutation rate, reduces and delays carcinogenesis after carcinogen exposure, and induces apoptosis and/or senescence of already transformed cells by simultaneously activating multiple overlapping and redundant DNA damage response pathways.

Methods: The human breast carcinoma cell line MCF-7, the adriamycin-resistant MCF-7 (Adr/MCF-7) cell line, as well as normal human mammary epithelial (NME) cells were treated with DNA oligonucleotides homologous to the telomere 3' overhang (T-oligos). SCID mice received intravenous injections of MCF-7 cells followed by intravenous administration of T-oligos.

Results: Acting through ataxia telangiectasia mutated (ATM) and its downstream effectors, T-oligos induced apoptosis and senescence of MCF-7 cells but not NME cells, in which these signaling pathways were induced to a far lesser extent. In MCF-7 cells, experimental telomere loop disruption caused identical responses, consistent with the hypothesis that T-oligos act by mimicking telomere overhang exposure. In vivo, T-oligos greatly prolonged survival of SCID mice following intravenous injection of human breast carcinoma cells.

Conclusion: By inducing DNA damage-like responses in MCF-7 cells, T-oligos provide insight into innate cancer avoidance mechanisms and may offer a novel approach to treatment of breast cancer and other malignancies.

Show MeSH
Related in: MedlinePlus