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...
Main Authors: | , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
MDPI AG
2020-05-01
|
Series: | Molecules |
Subjects: | |
Online Access: | https://www.mdpi.com/1420-3049/25/9/2257 |
id |
doaj-9c68ac8eec39457fb4e3c6180b336314 |
---|---|
record_format |
Article |
spelling |
doaj-9c68ac8eec39457fb4e3c6180b3363142020-11-25T02:04:35ZengMDPI AGMolecules1420-30492020-05-01252257225710.3390/molecules25092257The Antiproliferative Effects of Flavonoid MAO Inhibitors on Prostate Cancer CellsNajla O. Zarmouh0Samia S. Messeha1Nelly Mateeva2Madhavi Gangapuram3Kacy Flowers4Suresh V. K. Eyunni5Wang Zhang6Kinfe K. Redda7Karam F. A. Soliman8College of Pharmacy & Pharmaceutical Sciences, College of Medical Technology-Misurata; Libyan National Board for Technical & Vocational Education, Misrata, LibyaCollege of Pharmacy & Pharmaceutical Sciences, Florida A & M University, Tallahassee, FL 32307, USACollege of Science and Technology, Florida A & M University, Tallahassee, FL 32307, USACollege of Pharmacy & Pharmaceutical Sciences, Florida A & M University, Tallahassee, FL 32307, USACollege of Pharmacy & Pharmaceutical Sciences, Florida A & M University, Tallahassee, FL 32307, USACollege of Pharmacy & Pharmaceutical Sciences, Florida A & M University, Tallahassee, FL 32307, USACollege of Pharmacy & Pharmaceutical Sciences, Florida A & M University, Tallahassee, FL 32307, USACollege of Pharmacy & Pharmaceutical Sciences, Florida A & M University, Tallahassee, FL 32307, USACollege of Pharmacy & Pharmaceutical Sciences, Florida A & M University, Tallahassee, FL 32307, USAProstate 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<sub>50</sub>s 0.02–16 μM) overlapped with the top six antiproliferative KKRs against LNCaP (IC<sub>50</sub>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<sub>i</sub>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 [(<i>E</i>)-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.https://www.mdpi.com/1420-3049/25/9/2257flavonoid derivativesMAO-A and MAO-BLNCaPDU145prostate cancerdepression |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Najla O. Zarmouh Samia S. Messeha Nelly Mateeva Madhavi Gangapuram Kacy Flowers Suresh V. K. Eyunni Wang Zhang Kinfe K. Redda Karam F. A. Soliman |
spellingShingle |
Najla O. Zarmouh Samia S. Messeha Nelly Mateeva Madhavi Gangapuram Kacy Flowers Suresh V. K. Eyunni Wang Zhang Kinfe K. Redda Karam F. A. Soliman The Antiproliferative Effects of Flavonoid MAO Inhibitors on Prostate Cancer Cells Molecules flavonoid derivatives MAO-A and MAO-B LNCaP DU145 prostate cancer depression |
author_facet |
Najla O. Zarmouh Samia S. Messeha Nelly Mateeva Madhavi Gangapuram Kacy Flowers Suresh V. K. Eyunni Wang Zhang Kinfe K. Redda Karam F. A. Soliman |
author_sort |
Najla O. Zarmouh |
title |
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_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_sort |
antiproliferative effects of flavonoid mao inhibitors on prostate cancer cells |
publisher |
MDPI AG |
series |
Molecules |
issn |
1420-3049 |
publishDate |
2020-05-01 |
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<sub>50</sub>s 0.02–16 μM) overlapped with the top six antiproliferative KKRs against LNCaP (IC<sub>50</sub>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<sub>i</sub>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 [(<i>E</i>)-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. |
topic |
flavonoid derivatives MAO-A and MAO-B LNCaP DU145 prostate cancer depression |
url |
https://www.mdpi.com/1420-3049/25/9/2257 |
work_keys_str_mv |
AT najlaozarmouh theantiproliferativeeffectsofflavonoidmaoinhibitorsonprostatecancercells AT samiasmesseha theantiproliferativeeffectsofflavonoidmaoinhibitorsonprostatecancercells AT nellymateeva theantiproliferativeeffectsofflavonoidmaoinhibitorsonprostatecancercells AT madhavigangapuram theantiproliferativeeffectsofflavonoidmaoinhibitorsonprostatecancercells AT kacyflowers theantiproliferativeeffectsofflavonoidmaoinhibitorsonprostatecancercells AT sureshvkeyunni theantiproliferativeeffectsofflavonoidmaoinhibitorsonprostatecancercells AT wangzhang theantiproliferativeeffectsofflavonoidmaoinhibitorsonprostatecancercells AT kinfekredda theantiproliferativeeffectsofflavonoidmaoinhibitorsonprostatecancercells AT karamfasoliman theantiproliferativeeffectsofflavonoidmaoinhibitorsonprostatecancercells AT najlaozarmouh antiproliferativeeffectsofflavonoidmaoinhibitorsonprostatecancercells AT samiasmesseha antiproliferativeeffectsofflavonoidmaoinhibitorsonprostatecancercells AT nellymateeva antiproliferativeeffectsofflavonoidmaoinhibitorsonprostatecancercells AT madhavigangapuram antiproliferativeeffectsofflavonoidmaoinhibitorsonprostatecancercells AT kacyflowers antiproliferativeeffectsofflavonoidmaoinhibitorsonprostatecancercells AT sureshvkeyunni antiproliferativeeffectsofflavonoidmaoinhibitorsonprostatecancercells AT wangzhang antiproliferativeeffectsofflavonoidmaoinhibitorsonprostatecancercells AT kinfekredda antiproliferativeeffectsofflavonoidmaoinhibitorsonprostatecancercells AT karamfasoliman antiproliferativeeffectsofflavonoidmaoinhibitorsonprostatecancercells |
_version_ |
1724942413347160064 |