Zinc protoporphyrin binding to telomerase complexes and inhibition of telomerase activity

Zhaowen Zhu; Huy Tran; Meleah M Mathahs; Brian D Fink; John A Albert; Thomas O Moninger; Jeffery L Meier; Ming Li; Warren N Schmidt

doi:10.1002/prp2.882

Back

Zinc protoporphyrin binding to telomerase complexes and inhibition of telomerase activity

Journal article

Open access

Peer reviewed

Zinc protoporphyrin binding to telomerase complexes and inhibition of telomerase activity

Zhaowen Zhu, Huy Tran, Meleah M Mathahs, Brian D Fink, John A Albert, Thomas O Moninger, Jeffery L Meier, Ming Li and Warren N Schmidt

Pharmacology research & perspectives, Vol.9(6), pp.e00882-n/a

12/2021

DOI: 10.1002/prp2.882

PMCID: PMC8573827

PMID: 34747573

Files and links (1)

url

https://doi.org/10.1002/prp2.882View

Published (Version of record) Open Access

Abstract

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 and EC 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.

Antineoplastic Agents - administration & dosage

Antineoplastic Agents - pharmacology

Apoptosis - drug effects

Cell Line, Tumor

Cell Proliferation - drug effects

Enzyme Inhibitors - administration & dosage

Enzyme Inhibitors - pharmacology

HEK293 Cells

Humans

Inhibitory Concentration 50

Microscopy, Confocal

Protoporphyrins - administration & dosage

Protoporphyrins - pharmacology

Telomerase - antagonists & inhibitors

Telomerase - metabolism

Telomere - metabolism

Details

Title: Subtitle: Zinc protoporphyrin binding to telomerase complexes and inhibition of telomerase activity
Creators: Zhaowen Zhu - Veterans Health Administration
Huy Tran - University of Iowa
Meleah M Mathahs - Veterans Health Administration
Brian D Fink - Veterans Health Administration
John A Albert - Veterans Health Administration
Thomas O Moninger - Roy J. and Lucille A. Carver College of Medicine
Jeffery L Meier - Veterans Health Administration
Ming Li - Veterans Health Administration
Warren N Schmidt - Veterans Health Administration
Resource Type: Journal article
Publication Details: Pharmacology research & perspectives, Vol.9(6), pp.e00882-n/a
DOI: 10.1002/prp2.882
PMID: 34747573
PMCID: PMC8573827
NLM abbreviation: Pharmacol Res Perspect
ISSN: 2052-1707
eISSN: 2052-1707
Grant note: I01 BX000159 / BLRD VA
Language: English
Date published: 12/2021
Academic Unit: Dermatology; Infectious Diseases; Epidemiology; Gastroenterology and Hepatology; Internal Medicine
Record Identifier: 9984359801502771

Metrics

15 Record Views

5 Times Cited - Web of Science