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The Antiproliferative Effects of Flavonoid MAO Inhibitors on Prostate Cancer Cells

Prostate cancer (PCa) patients commonly experience clinical depression. Recent reports indicated that monoamine oxidase-A (MAO-A) levels elevate in PCa, and antidepressant MAO-Is show anti-PCa properties. In this work, we aimed to find potential drugs for PCa patients suffering from depression by es...

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Autores principales: Zarmouh, Najla O., Messeha, Samia S., Mateeva, Nelly, Gangapuram, Madhavi, Flowers, Kacy, Eyunni, Suresh V. K., Zhang, Wang, Redda, Kinfe K., Soliman, Karam F. A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7249060/
https://www.ncbi.nlm.nih.gov/pubmed/32403270
http://dx.doi.org/10.3390/molecules25092257
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author Zarmouh, Najla O.
Messeha, Samia S.
Mateeva, Nelly
Gangapuram, Madhavi
Flowers, Kacy
Eyunni, Suresh V. K.
Zhang, Wang
Redda, Kinfe K.
Soliman, Karam F. A.
author_facet Zarmouh, Najla O.
Messeha, Samia S.
Mateeva, Nelly
Gangapuram, Madhavi
Flowers, Kacy
Eyunni, Suresh V. K.
Zhang, Wang
Redda, Kinfe K.
Soliman, Karam F. A.
author_sort Zarmouh, Najla O.
collection PubMed
description Prostate cancer (PCa) patients commonly experience clinical depression. Recent reports indicated that monoamine oxidase-A (MAO-A) levels elevate in PCa, and antidepressant MAO-Is show anti-PCa properties. In this work, we aimed to find potential drugs for PCa patients suffering from depression by establishing novel anti-PCa reversible monoamine oxidase-A inhibitors (MAO-AIs/RIMA); with an endeavor to understand their mechanism of action. In this investigation, twenty synthesized flavonoid derivatives, defined as KKR compounds were screened for their inhibitory potentials against human MAO-A and MAO-B isozymes. Meanwhile, the cytotoxic and antiproliferative effects were determined in three human PCa cell lines. MAO-A-kinetics, molecular docking, SAR, cell morphology, and cell migration were investigated for the most potent compounds. The screened KKRs inhibited MAO-A more potently than MAO-B, and non-toxically inhibited LNCaP cell proliferation more than the DU145 and PC3 cell lines, respectively. The results showed that the three top MAO-AI KKRs compounds (KKR11, KKR20, and KKR7 (IC(50)s 0.02–16 μM) overlapped with the top six antiproliferative KKRs against LNCaP (IC(50)s ~9.4 μM). While KKR21 (MAO-AI) and KKR2A (MAO-I) were ineffective against the PCa cells. Furthermore, KKR21 and KKR11 inhibited MAO-A competitively (K(i)s ≤ 7.4 nM). Molecular docking of the two compounds predicted shared hydrophobic and distinctive hydrophilic interactions—between the KKR molecule and MAO-A amino acid residues—to be responsible for their reversibility. The combined results and SAR observations indicated that the presence of specific active groups—such as chlorine and hydroxyl groups—are essential in certain MAO-AIs with anti-PCa effects. Additionally, MAO-A inhibition was found to be associated more with anti-PCa property than MAO-B. Distinctively, KKR11 [(E)-3-(3,4-dichlorophenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one] exhibited anti-metastatic effects on the DU145 cell line. The chlorine substitution groups might play vital roles in the KKR11 multiple actions. The obtained results indicated that the flavonoid derivative KKR11 could present a novel candidate for PCa patients with depression, through safe non-selective potent inhibition of MAOs.
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spelling pubmed-72490602020-06-10 The Antiproliferative Effects of Flavonoid MAO Inhibitors on Prostate Cancer Cells Zarmouh, Najla O. Messeha, Samia S. Mateeva, Nelly Gangapuram, Madhavi Flowers, Kacy Eyunni, Suresh V. K. Zhang, Wang Redda, Kinfe K. Soliman, Karam F. A. Molecules Article Prostate cancer (PCa) patients commonly experience clinical depression. Recent reports indicated that monoamine oxidase-A (MAO-A) levels elevate in PCa, and antidepressant MAO-Is show anti-PCa properties. In this work, we aimed to find potential drugs for PCa patients suffering from depression by establishing novel anti-PCa reversible monoamine oxidase-A inhibitors (MAO-AIs/RIMA); with an endeavor to understand their mechanism of action. In this investigation, twenty synthesized flavonoid derivatives, defined as KKR compounds were screened for their inhibitory potentials against human MAO-A and MAO-B isozymes. Meanwhile, the cytotoxic and antiproliferative effects were determined in three human PCa cell lines. MAO-A-kinetics, molecular docking, SAR, cell morphology, and cell migration were investigated for the most potent compounds. The screened KKRs inhibited MAO-A more potently than MAO-B, and non-toxically inhibited LNCaP cell proliferation more than the DU145 and PC3 cell lines, respectively. The results showed that the three top MAO-AI KKRs compounds (KKR11, KKR20, and KKR7 (IC(50)s 0.02–16 μM) overlapped with the top six antiproliferative KKRs against LNCaP (IC(50)s ~9.4 μM). While KKR21 (MAO-AI) and KKR2A (MAO-I) were ineffective against the PCa cells. Furthermore, KKR21 and KKR11 inhibited MAO-A competitively (K(i)s ≤ 7.4 nM). Molecular docking of the two compounds predicted shared hydrophobic and distinctive hydrophilic interactions—between the KKR molecule and MAO-A amino acid residues—to be responsible for their reversibility. The combined results and SAR observations indicated that the presence of specific active groups—such as chlorine and hydroxyl groups—are essential in certain MAO-AIs with anti-PCa effects. Additionally, MAO-A inhibition was found to be associated more with anti-PCa property than MAO-B. Distinctively, KKR11 [(E)-3-(3,4-dichlorophenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one] exhibited anti-metastatic effects on the DU145 cell line. The chlorine substitution groups might play vital roles in the KKR11 multiple actions. The obtained results indicated that the flavonoid derivative KKR11 could present a novel candidate for PCa patients with depression, through safe non-selective potent inhibition of MAOs. MDPI 2020-05-11 /pmc/articles/PMC7249060/ /pubmed/32403270 http://dx.doi.org/10.3390/molecules25092257 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zarmouh, Najla O.
Messeha, Samia S.
Mateeva, Nelly
Gangapuram, Madhavi
Flowers, Kacy
Eyunni, Suresh V. K.
Zhang, Wang
Redda, Kinfe K.
Soliman, Karam F. A.
The Antiproliferative Effects of Flavonoid MAO Inhibitors on Prostate Cancer Cells
title The Antiproliferative Effects of Flavonoid MAO Inhibitors on Prostate Cancer Cells
title_full The Antiproliferative Effects of Flavonoid MAO Inhibitors on Prostate Cancer Cells
title_fullStr The Antiproliferative Effects of Flavonoid MAO Inhibitors on Prostate Cancer Cells
title_full_unstemmed The Antiproliferative Effects of Flavonoid MAO Inhibitors on Prostate Cancer Cells
title_short The Antiproliferative Effects of Flavonoid MAO Inhibitors on Prostate Cancer Cells
title_sort antiproliferative effects of flavonoid mao inhibitors on prostate cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7249060/
https://www.ncbi.nlm.nih.gov/pubmed/32403270
http://dx.doi.org/10.3390/molecules25092257
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