Abstract
Monoamine oxidase A (MAOA) is an important mitochondria-bound enzyme that catalyzes the oxidative deamination of monoamine neurotransmitters. Accumulating evidence suggests a significant association of increased MAOA expression and advanced high-grade prostate cancer (PCa) progression and metastasis. Herein, a series of novel conjugates combining the MAOA inhibitor isoniazid (INH) and tumor-targeting near-infrared (NIR) heptamethine cyanine dyes were designed and synthesized. The synthesized compounds G1–G13 were evaluated in vitro for their cytotoxicity against PC-3 cells using the MTT assay, and molecular docking studies were performed. Results showed that most tested compounds exhibited improved antitumor efficacy compared with INH. Moreover, conjugates G10 and G11 showed potent anticancer activity with IC50 values (0.85 and 0.4 μM respectively) comparable to that of doxorubicin (DOX). This may be attributable to the preferential accumulation of these conjugates in tumor cells. G10, G11, and G12 also demonstrated moderate MAOA inhibitory activities. This result and the results of molecular docking studies were consistent with their cytotoxicity activities. Taken together, these data suggest that a combination of the MAOA inhibitor INH with tumor-targeting heptamethine cyanine dyes may prove to be a highly promising tool for the treatment of advanced prostate cancer.
Highlights
IntroductionGlobal prostate cancer (PCa) incidence and mortality have substantially increased, compounded by an increase in the proportion of the elderly population and in the frequency of diagnosis
Global prostate cancer (PCa) incidence and mortality have substantially increased, compounded by an increase in the proportion of the elderly population and in the frequency of diagnosis. the majority of cases with metastatic PCa respond to the available therapeutic modalities, hormone-refractory PCa and advanced metastatic PCa remain inevitable [1,2,3,4]
Monoamine oxidase A (MAOA) is an important mitochondria-bound enzyme that catalyzes the oxidative deamination of monoamine neurotransmitters including serotonin (5-hydroxytryptamine), catecholamines, and biogenic amines [5,6,7,8]
Summary
Global prostate cancer (PCa) incidence and mortality have substantially increased, compounded by an increase in the proportion of the elderly population and in the frequency of diagnosis. Monoamine oxidase A (MAOA) is an important mitochondria-bound enzyme that catalyzes the oxidative deamination of monoamine neurotransmitters including serotonin (5-hydroxytryptamine), catecholamines, and biogenic amines [5,6,7,8] This process subsequently generates their catalytic by-product hydrogen peroxide (H2 O2 ), a predominant source of reactive oxygen species (ROS), which may predispose cancer cells to DNA damage, leading to tumor initiation and progression. Wang et al confirmed that NIR heptamethine cyanine dyes IR-780 and MHI-148 could be retained in the mitochondria of tumor cells, increase ROS production, decrease mitochondrial membrane potential, and induce tumor cell apoptosis [36]. Taken together, these findings suggest that heptamethine carbocyanine dyes hold great promise for tumor targeting and to some extent possess antitumor efficacy. Molecules 2018, 23, x FOR PEER REVIEW was carried out
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