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Zinc protoporphyrin binding to telomerase complexes and inhibition of telomerase activity

Zinc protoporphyrin (ZnPP), a naturally occurring metalloprotoporphyrin (MPP), is currently under development as a chemotherapeutic agent although its mechanism is unclear. When tested against other MPPs, ZnPP was the most effective DNA synthesis and cellular proliferation inhibitor while promoting...

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Autores principales: Zhu, Zhaowen, Tran, Huy, Mathahs, Meleah M., Fink, Brian D., Albert, John A., Moninger, Thomas O., Meier, Jeffery L., Li, Ming, Schmidt, Warren N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8573827/
https://www.ncbi.nlm.nih.gov/pubmed/34747573
http://dx.doi.org/10.1002/prp2.882
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author Zhu, Zhaowen
Tran, Huy
Mathahs, Meleah M.
Fink, Brian D.
Albert, John A.
Moninger, Thomas O.
Meier, Jeffery L.
Li, Ming
Schmidt, Warren N.
author_facet Zhu, Zhaowen
Tran, Huy
Mathahs, Meleah M.
Fink, Brian D.
Albert, John A.
Moninger, Thomas O.
Meier, Jeffery L.
Li, Ming
Schmidt, Warren N.
author_sort Zhu, Zhaowen
collection PubMed
description Zinc protoporphyrin (ZnPP), a naturally occurring metalloprotoporphyrin (MPP), is currently under development as a chemotherapeutic agent although its mechanism is unclear. When tested against other MPPs, ZnPP was the most effective DNA synthesis and cellular proliferation inhibitor while promoting apoptosis in telomerase positive but not telomerase negative cells. Concurrently, ZnPP down‐regulated telomerase expression and was the best overall inhibitor of telomerase activity in intact cells and cellular extracts with IC(50) and EC(50) values of ca 2.5 and 6 µM, respectively. The natural fluorescence properties of ZnPP enabled direct imaging in cellular fractions using non‐denaturing agarose gel electrophoresis, western blots, and confocal fluorescence microscopy. ZnPP localized to large cellular complexes (>600 kD) that contained telomerase and dysskerin as confirmed with immunocomplex mobility shift, immunoprecipitation, and immunoblot analyses. Confocal fluorescence studies showed that ZnPP co‐localized with telomerase reverse transcriptase (TERT) and telomeres in the nucleus of synchronized S‐phase cells. ZnPP also co‐localized with TERT in the perinuclear regions of log phase cells but did not co‐localize with telomeres on the ends of metaphase chromosomes, a site known to be devoid of telomerase complexes. Overall, these results suggest that ZnPP does not bind to telomeric sequences per se, but alternatively, interacts with other structural components of the telomerase complex to inhibit telomerase activity. In conclusion, ZnPP actively interferes with telomerase activity in neoplastic cells, thus promoting pro‐apoptotic and anti‐proliferative properties. These data support further development of natural or synthetic protoporphyrins for use as chemotherapeutic agents to augment current treatment protocols for neoplastic disease.
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spelling pubmed-85738272021-11-10 Zinc protoporphyrin binding to telomerase complexes and inhibition of telomerase activity Zhu, Zhaowen Tran, Huy Mathahs, Meleah M. Fink, Brian D. Albert, John A. Moninger, Thomas O. Meier, Jeffery L. Li, Ming Schmidt, Warren N. Pharmacol Res Perspect Original Articles Zinc protoporphyrin (ZnPP), a naturally occurring metalloprotoporphyrin (MPP), is currently under development as a chemotherapeutic agent although its mechanism is unclear. When tested against other MPPs, ZnPP was the most effective DNA synthesis and cellular proliferation inhibitor while promoting apoptosis in telomerase positive but not telomerase negative cells. Concurrently, ZnPP down‐regulated telomerase expression and was the best overall inhibitor of telomerase activity in intact cells and cellular extracts with IC(50) and EC(50) values of ca 2.5 and 6 µM, respectively. The natural fluorescence properties of ZnPP enabled direct imaging in cellular fractions using non‐denaturing agarose gel electrophoresis, western blots, and confocal fluorescence microscopy. ZnPP localized to large cellular complexes (>600 kD) that contained telomerase and dysskerin as confirmed with immunocomplex mobility shift, immunoprecipitation, and immunoblot analyses. Confocal fluorescence studies showed that ZnPP co‐localized with telomerase reverse transcriptase (TERT) and telomeres in the nucleus of synchronized S‐phase cells. ZnPP also co‐localized with TERT in the perinuclear regions of log phase cells but did not co‐localize with telomeres on the ends of metaphase chromosomes, a site known to be devoid of telomerase complexes. Overall, these results suggest that ZnPP does not bind to telomeric sequences per se, but alternatively, interacts with other structural components of the telomerase complex to inhibit telomerase activity. In conclusion, ZnPP actively interferes with telomerase activity in neoplastic cells, thus promoting pro‐apoptotic and anti‐proliferative properties. These data support further development of natural or synthetic protoporphyrins for use as chemotherapeutic agents to augment current treatment protocols for neoplastic disease. John Wiley and Sons Inc. 2021-11-08 /pmc/articles/PMC8573827/ /pubmed/34747573 http://dx.doi.org/10.1002/prp2.882 Text en © 2021 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Zhu, Zhaowen
Tran, Huy
Mathahs, Meleah M.
Fink, Brian D.
Albert, John A.
Moninger, Thomas O.
Meier, Jeffery L.
Li, Ming
Schmidt, Warren N.
Zinc protoporphyrin binding to telomerase complexes and inhibition of telomerase activity
title Zinc protoporphyrin binding to telomerase complexes and inhibition of telomerase activity
title_full Zinc protoporphyrin binding to telomerase complexes and inhibition of telomerase activity
title_fullStr Zinc protoporphyrin binding to telomerase complexes and inhibition of telomerase activity
title_full_unstemmed Zinc protoporphyrin binding to telomerase complexes and inhibition of telomerase activity
title_short Zinc protoporphyrin binding to telomerase complexes and inhibition of telomerase activity
title_sort zinc protoporphyrin binding to telomerase complexes and inhibition of telomerase activity
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8573827/
https://www.ncbi.nlm.nih.gov/pubmed/34747573
http://dx.doi.org/10.1002/prp2.882
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