Cyclic induction of senescence with intermittent AZT treatment accelerates both apoptosis and telomere loss

Jung Ji Hyun, SunYoung Rha, Cheul Jeung Hei, Hwa Yang Sang, Whan An Sung, Hyuncheol Chung

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Background. 3′-azido-2′,3′-dideoxythymidine (AZT) is phosphorylated intracellularly to 3′-azido-3′-deoxythymidine- 5′-triphosphate (AZT-TP), which is incorporated into telomeric DNA, thereby blocking chain elongation. AZT is also known to inhibit reverse transcriptase, as well as other cellular enzymes including DNA polymerase γ, thymidine kinase, and telomerase. Methods. We induced cancer cell senescence by treating MCF-7 cells with AZT in dosages of IC10 and IC20 for an extended period (about 120 population doublings (PD)). We then investigated the sequential changes in cellular growth, expression of telomerase subunits and transcription factors (c-Myc, Mad1), telomerase activity and telomere length. Results. Senescence, apoptosis, growth delay, inhibition of telomerase activity and shortening of telomere length were all observed in a dose- and time-dependent manner. After the onset of senescence, the apoptosis rate increased slowly during early PDs. In contrast to senescence, the apoptotic rate showed little change after AZT removal, while it increased suddenly and significantly in a dose-dependent manner upon the second introduction of AZT. Continuous shortening of the telomeric length was observed with AZT, and, upon re-exposure to AZT, shortening of the telomere occurred more rapidly than with first exposure. Of the telomerase subunits, telomerase reverse transcriptase (hTERT) and c-Myc were the first to show a reduction in activity after AZT treatment, followed by changes in hTER , Mad1 and hTEP-1. Conclusion. Cyclic treatment with AZT initially suppressed hTERT and c-Myc, followed by suppression of hTER, Mad1 and hTEP-1. Furthermore, the treatment accelerated both telomere loss and apoptosis, even when administered at a senescence-inducing dosage level.

Original languageEnglish
Pages (from-to)227-236
Number of pages10
JournalBreast Cancer Research and Treatment
Volume93
Issue number3
DOIs
Publication statusPublished - 2005 Oct 1

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Telomerase
Telomere
Apoptosis
Telomere Shortening
Thymidine Kinase
Cell Aging
RNA-Directed DNA Polymerase
MCF-7 Cells
DNA-Directed DNA Polymerase
Growth
Transcription Factors
DNA
Enzymes
Population
Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

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title = "Cyclic induction of senescence with intermittent AZT treatment accelerates both apoptosis and telomere loss",
abstract = "Background. 3′-azido-2′,3′-dideoxythymidine (AZT) is phosphorylated intracellularly to 3′-azido-3′-deoxythymidine- 5′-triphosphate (AZT-TP), which is incorporated into telomeric DNA, thereby blocking chain elongation. AZT is also known to inhibit reverse transcriptase, as well as other cellular enzymes including DNA polymerase γ, thymidine kinase, and telomerase. Methods. We induced cancer cell senescence by treating MCF-7 cells with AZT in dosages of IC10 and IC20 for an extended period (about 120 population doublings (PD)). We then investigated the sequential changes in cellular growth, expression of telomerase subunits and transcription factors (c-Myc, Mad1), telomerase activity and telomere length. Results. Senescence, apoptosis, growth delay, inhibition of telomerase activity and shortening of telomere length were all observed in a dose- and time-dependent manner. After the onset of senescence, the apoptosis rate increased slowly during early PDs. In contrast to senescence, the apoptotic rate showed little change after AZT removal, while it increased suddenly and significantly in a dose-dependent manner upon the second introduction of AZT. Continuous shortening of the telomeric length was observed with AZT, and, upon re-exposure to AZT, shortening of the telomere occurred more rapidly than with first exposure. Of the telomerase subunits, telomerase reverse transcriptase (hTERT) and c-Myc were the first to show a reduction in activity after AZT treatment, followed by changes in hTER , Mad1 and hTEP-1. Conclusion. Cyclic treatment with AZT initially suppressed hTERT and c-Myc, followed by suppression of hTER, Mad1 and hTEP-1. Furthermore, the treatment accelerated both telomere loss and apoptosis, even when administered at a senescence-inducing dosage level.",
author = "Hyun, {Jung Ji} and SunYoung Rha and Hei, {Cheul Jeung} and Sang, {Hwa Yang} and Sung, {Whan An} and Hyuncheol Chung",
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Cyclic induction of senescence with intermittent AZT treatment accelerates both apoptosis and telomere loss. / Hyun, Jung Ji; Rha, SunYoung; Hei, Cheul Jeung; Sang, Hwa Yang; Sung, Whan An; Chung, Hyuncheol.

In: Breast Cancer Research and Treatment, Vol. 93, No. 3, 01.10.2005, p. 227-236.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Cyclic induction of senescence with intermittent AZT treatment accelerates both apoptosis and telomere loss

AU - Hyun, Jung Ji

AU - Rha, SunYoung

AU - Hei, Cheul Jeung

AU - Sang, Hwa Yang

AU - Sung, Whan An

AU - Chung, Hyuncheol

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N2 - Background. 3′-azido-2′,3′-dideoxythymidine (AZT) is phosphorylated intracellularly to 3′-azido-3′-deoxythymidine- 5′-triphosphate (AZT-TP), which is incorporated into telomeric DNA, thereby blocking chain elongation. AZT is also known to inhibit reverse transcriptase, as well as other cellular enzymes including DNA polymerase γ, thymidine kinase, and telomerase. Methods. We induced cancer cell senescence by treating MCF-7 cells with AZT in dosages of IC10 and IC20 for an extended period (about 120 population doublings (PD)). We then investigated the sequential changes in cellular growth, expression of telomerase subunits and transcription factors (c-Myc, Mad1), telomerase activity and telomere length. Results. Senescence, apoptosis, growth delay, inhibition of telomerase activity and shortening of telomere length were all observed in a dose- and time-dependent manner. After the onset of senescence, the apoptosis rate increased slowly during early PDs. In contrast to senescence, the apoptotic rate showed little change after AZT removal, while it increased suddenly and significantly in a dose-dependent manner upon the second introduction of AZT. Continuous shortening of the telomeric length was observed with AZT, and, upon re-exposure to AZT, shortening of the telomere occurred more rapidly than with first exposure. Of the telomerase subunits, telomerase reverse transcriptase (hTERT) and c-Myc were the first to show a reduction in activity after AZT treatment, followed by changes in hTER , Mad1 and hTEP-1. Conclusion. Cyclic treatment with AZT initially suppressed hTERT and c-Myc, followed by suppression of hTER, Mad1 and hTEP-1. Furthermore, the treatment accelerated both telomere loss and apoptosis, even when administered at a senescence-inducing dosage level.

AB - Background. 3′-azido-2′,3′-dideoxythymidine (AZT) is phosphorylated intracellularly to 3′-azido-3′-deoxythymidine- 5′-triphosphate (AZT-TP), which is incorporated into telomeric DNA, thereby blocking chain elongation. AZT is also known to inhibit reverse transcriptase, as well as other cellular enzymes including DNA polymerase γ, thymidine kinase, and telomerase. Methods. We induced cancer cell senescence by treating MCF-7 cells with AZT in dosages of IC10 and IC20 for an extended period (about 120 population doublings (PD)). We then investigated the sequential changes in cellular growth, expression of telomerase subunits and transcription factors (c-Myc, Mad1), telomerase activity and telomere length. Results. Senescence, apoptosis, growth delay, inhibition of telomerase activity and shortening of telomere length were all observed in a dose- and time-dependent manner. After the onset of senescence, the apoptosis rate increased slowly during early PDs. In contrast to senescence, the apoptotic rate showed little change after AZT removal, while it increased suddenly and significantly in a dose-dependent manner upon the second introduction of AZT. Continuous shortening of the telomeric length was observed with AZT, and, upon re-exposure to AZT, shortening of the telomere occurred more rapidly than with first exposure. Of the telomerase subunits, telomerase reverse transcriptase (hTERT) and c-Myc were the first to show a reduction in activity after AZT treatment, followed by changes in hTER , Mad1 and hTEP-1. Conclusion. Cyclic treatment with AZT initially suppressed hTERT and c-Myc, followed by suppression of hTER, Mad1 and hTEP-1. Furthermore, the treatment accelerated both telomere loss and apoptosis, even when administered at a senescence-inducing dosage level.

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