Abstract
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 (IC50s 0.02–16 μM) overlapped with the top six antiproliferative KKRs against LNCaP (IC50s ~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 (Kis ≤ 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.
Highlights
Prostate cancer (PCa) is the second most common malignancy among males
With multiple various in vitro screens conducted, we evaluate whether all monoamine oxidase (MAO)-Is can have anti-PCa effects
We established the basis for which the flavone, chalcone, and chromone synthetic structures might work as a treatment option for PCa patients with depression by reversibly inhibiting MAO-A and reducing oxidative stress
Summary
Prostate cancer (PCa) is the second most common malignancy among males. The high incidence, economic burden, and fatality rate makes PCa a global health issue [1,2,3]. PCa patients commonly experience depression and sometimes major depressive disorder (MDD). Recent estimates showed that 60% men with PCa experience depression, of which up to 40% become clinically significant [2]. Emerging meta-analysis research highlighted the prevalence of depression in PCa patients and urged further investigation [1]. The actual causes of depression among PCa patients are unclear, PCa sufferers experience exhausting symptoms and mortality concerns, which is manifested by an increased suicide rate [2,3], low quality of life, poor adherence to treatment, and, the poorer prognosis of PCa [4]
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