Near-Infrared MAO A Inhibitor (NMI) Outperformed FDA-Approved Chemotherapeutic Agents in Brain and Other Cancers: A Bioinformatic Analysis of NCI60 Screening Data.

Qianhua Feng,Yihan Qian,Yuxuan Lian,Jean C Shih

doi:10.3390/brainsci11101318

Abstract

Our previous work has shown that monoamine oxidase A (MAO A) is overexpressed in glioma and prostate cancer. Near-infrared dye conjugate MAO A Inhibitor (NMI) inhibited the growth of these cancers. This study investigated the effects of NMI on other cancers by NCI60 screening. Our results showed that 48 out of 59 screened cell lines from nine types of cancer had 100% growth inhibition at 10 μM NMI treatment. The in vitro efficacy of NMI determined by growth inhibition (GI50 and TGI) and lethal doses (LC50) has been further studied in various cell lines of CNS cancer, prostate cancer, and non-small cell lung cancer (NSCLC), these three cancers showed increased MAO A expression in tumors compared to normal tissues. Based on the waterfall plots and the 3D scatter plot of GI50, TGI, and LC50 data, NMI showed higher potency to several CNS cancer and NSCLC cell lines than prostate cancer cell lines. In vitro efficacy of NMI outperformed FDA-approved drugs for CNS cancer, prostate cancer, and NSCLC, respectively. The Pairwise Pearson Correlation Coefficient (PCC) showed that NMI has a unique mechanism compared to the existing anticancer drugs. This study shows that NMI is a novel theragnostic drug with high potency and unique mechanisms for brain, prostate, NSCLC, and other cancers.

Highlights

Monoamine oxidase A (MAO A) is a mitochondrial enzyme that degrades monoamine neurotransmitters and dietary monoamines via oxidative deamination [1,2]
The drug efficacy of Near-infrared dye conjugate MAO A Inhibitor (NMI) was determined by the values of these three parameters, the higher drug efficacy required a lower concentration in GI50, TGI, and LC50
These results showed that NMI had better inhibition of cancer growth than most of these drugs in non-small cell lung cancer (NSCLC) cell lines, indicating that NMI is a potential anticancer drug for NSCLC

Summary

Introduction

Monoamine oxidase A (MAO A) is a mitochondrial enzyme that degrades monoamine neurotransmitters and dietary monoamines via oxidative deamination [1,2]. Our previous studies have shown that MAO A expression is increased in glioma [3] and prostate cancer [4]. Mice bearing glioma treated with MAO A inhibitors showed a significant increase in macrophages and TNF-α expression, resulting in the reduction in tumor progression [3]. MAO A expression promotes reactive oxygen species (ROS) production, epithelial-tomesenchymal transition (EMT), and tumor hypoxia, resulting in prostate tumorigenesis, progression, and metastasis [4]. NMI (near-infrared (NIR) dye conjugated with a MAO A specific inhibitor, clorgyline, targets tumors by activating the HIF1α/OATPs signaling axis in mitochondria [5]. In vivo study showed that NMI alone or in combination with temozolomide (TMZ) increases the survival of U251R (TMZ-resistant) tumor-bearing nude mice [3]

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