Zinc protoporphyrin binding to telomerase complexes and inhibition of telomerase activity*

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

doi:10.1002/prp2.882

Cited by 3 publications

(1 citation statement)

References 60 publications

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“…Both ZnPP and SnPP have been demonstrated to induce G1/S phase cell cycle arrest. However, this does not necessarily result in growth arrest, as cells may still proliferate at a slower rate ( 18 ). Conversely, cobalt protoporphyrin (CoPP) acts as an HO-1 inducer, stimulating HO-1 gene expression through the modulation of specific transcription factors ( 19 ).…”

Section: Introductionmentioning

confidence: 99%

Targeting heme degradation pathway augments prostate cancer cell sensitivity to docetaxel-induced apoptosis and attenuates migration

Salloom,

Ahmad,

Abdalla

2024

Front. Oncol.

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IntroductionChemotherapy, notably docetaxel (Doc), stands as the primary treatment for castration-resistant prostate cancer (CRPC). However, its efficacy is hindered by side effects and chemoresistance. Hypoxia in prostate cancer (PC) correlates with chemoresistance to Doc-induced apoptosis via Heme Oxygenase-1 (HO-1) modulation, a key enzyme in heme metabolism. This study investigated targeting heme degradation pathway via HO-1 inhibition to potentiate the therapeutic efficacy of Doc in PC.MethodsUtilizing diverse PC cell lines, we evaluated HO-1 inhibition alone and with Doc on viability, apoptosis, migration, and epithelial- to- mesenchymal transition (EMT) markers and elucidated the underlying mechanisms.ResultsHO-1 inhibition significantly reduced PC cell viability under hypoxic and normoxic conditions, enhancing Doc-induced apoptosis through interconnected mechanisms, including elevated reactive oxygen species (ROS) levels, glutathione cycle disruption, and modulation of Signal Transducer and Activator of Transcription 1 (STAT1) pathway. The interplay between STAT1 and HO-1 suggests its reliance on HO-1 activation. Additionally, a decrease in cell migration and downregulation of EMT markers (vimentin and snail) were observed, indicating attenuation of mesenchymal phenotype.DiscussionIn conclusion, the combination of HO-1 inhibition with Doc holds promise for improving therapeutic outcomes and advancing clinical management in PC.

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Section: Introductionmentioning

confidence: 99%

Targeting heme degradation pathway augments prostate cancer cell sensitivity to docetaxel-induced apoptosis and attenuates migration

Salloom,

Ahmad,

Abdalla

2024

Front. Oncol.

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Catalpol Exerts Antidepressant-Like Effects by Enhancing Anti-oxidation and Neurotrophy and Inhibiting Neuroinflammation via Activation of HO-1

Liu

Wang

et al. 2022

Neurochem Res

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Synthesis and Molecular Dynamic Simulation of Novel Cationic and Non-cationic Pyrimidine Derivatives as Potential G-quadruplex-ligands

Atapour-Mashhad,

Soukhtanloo,

Golmohammadzadeh

et al. 2024

ACAMC

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Background:: Drug resistance has been a problem in cancer chemotherapy, which often causes shortterm effectiveness. Further, the literature indicates that telomere G-quadruplex could be a promising anti-cancer target. Objective:: We synthesized and characterized two new pyrimidine derivatives as ligands for G-quadruplex DNA Methods:: The interaction of novel non-cationic and cationic pyrimidine derivatives (3a, b) with G-quadruplex DNA (1k8p and 3qsc) was explored by circular dichroism (CD) and ultraviolet-visible spectroscopy and polyacrylamide gel electrophoresis (PAGE) methods. The antiproliferative activity of desired compounds was evaluated by the MTT assay. Apoptosis induction was assessed by Propidium iodide (P.I.) staining and flow cytometry. Computational molecular modeling (CMM) and molecular dynamics simulation (MD) were studied on the complexes of 1k8p and 3qsc with the compounds. The van der Waals, electrostatic, polar solvation, solventaccessible surface area (SASA), and binding energies were calculated and analyzed. method: The interaction of novel non-cationic and cationic pyrimidine derivatives (3a, b) with G-quadruplex DNA (1k8p and 3qsc) was explored by circular dichroism (CD) and ultraviolet-visible spectroscopy and polyacrylamide gel electrophoresis (PAGE) methods. The antiproliferative activity of desired compounds was evaluated by the MTT assay. Apoptosis induction was assessed by Propidium iodide (P.I.) staining and flow cytometry. Computational molecular modeling (CMM) and molecular dynamics simulation (MD) were studied on the complexes of 1k8p and 3qsc with the compounds. The van der Waals, electrostatic, polar solvation, solvent-accessible surface area (SASA), and binding energies were calculated and analyzed. Results:: The experimental results confirmed that both compounds 3a and 3b interacted with 1k8p and 3qsc and exerted cytotoxic and proapoptotic effects on cancer cells. The number of hydrogen bonds and the RMSD values increased in the presence of the ligands, indicating stronger binding and suggesting increased structural dynamics. The electrostatic contribution to binding energy was higher for the cationic pyrimidine 3b, indicating more negative binding energies. Conclusion:: Both experimental and MD results confirmed that 3b was more prone to form a complex with DNA G-quadruplex (1k8p and 3qsc), inhibit cell growth, and induce apoptosis, compared to the non-cationic pyrimidine 3a.

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Zinc protoporphyrin binding to telomerase complexes and inhibition of telomerase activity*

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 3 publications

References 60 publications

Targeting heme degradation pathway augments prostate cancer cell sensitivity to docetaxel-induced apoptosis and attenuates migration

Targeting heme degradation pathway augments prostate cancer cell sensitivity to docetaxel-induced apoptosis and attenuates migration

Catalpol Exerts Antidepressant-Like Effects by Enhancing Anti-oxidation and Neurotrophy and Inhibiting Neuroinflammation via Activation of HO-1

Synthesis and Molecular Dynamic Simulation of Novel Cationic and Non-cationic Pyrimidine Derivatives as Potential G-quadruplex-ligands

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