MicroRNA-Mediated Drug Repurposing Unveiled Potential Candidate Drugs for Prolactinoma Treatment

Abstract

Introduction: Prolactinomas, also called lactotroph adenomas, are the most encountered type of hormone-secreting pituitary neuroendocrine tumors (PitNET) in the clinic. The preferred first-line therapy is a medical treatment with dopamine agonists (DA), mainly cabergoline, to reduce serum prolactin levels, tumor volume, and mass effect. However, in some cases, patients have displayed DA-resistance with aggressive tumor behavior or are faced with recurrence after drug withdrawal. Also, currently used therapeutics have notorious side effects and impair the life quality of the patients. Methods: Since the amalgamation of clinical and laboratory data besides tumor histopathogenesis and transcriptional regulatory features of the tumor emerge to exhibit essential roles in the behavior and progression of prolactinomas, in this work, we integrated mRNA and microRNA (miRNA) level transcriptome data that exploit disease-specific signatures in addition to biological and pharmacological data to elucidate a rational prioritization of pathways and drugs in prolactinoma. Results: We identified eight drug candidates through drug repurposing based on mRNA-miRNA level data integration and evaluated their potential through in vitro assays in the MMQ cell line. Seven re-purposed drugs including 5-flourocytosine, nortriptyline, neratinib, puromycin, taxifolin, vorinostat, and zileuton were proposed as potential drug candidates for the treatment of prolactinoma. We further hypothesized possible mechanisms of drug action on MMQ cell viability through analyzing PI3K/Akt signaling pathway and cell cycle arrest via flow cytometry and western blotting. Discussion: We presented the transcriptomic landscape of prolactinoma through miRNA and mRNA level data integration and proposed repurposed drug candidates based on this integration. We validated our findings through testing cell viability, cell cycle phases, and PI3K/Akt protein expressions. Effects of the drugs on cell cycle phases and inhibition of PI3K/Akt pathway by all drugs gave us promising output for further studies using these drugs in the treatment of prolactinoma. This is the first study that reports miRNA-mediated repurposed drugs for prolactinoma treatment via in vitro experiments.

Treatment Strategies for Dopamine Agonist-Resistant and Aggressive Prolactinomas: A Comprehensive Analysis of the Literature

“…miRNA Based Analyses Reveal the Potential for Drug Repurposal for Aggressive Prolactinomas Aydin et al analyzed the transcriptomic features of prolactinoma through mRNA and miRNA level data integration and repurposed novel drugs based on this integration [44]. They repurposed 7 drugs including 5-flourocytosine (an antifungal agent), nortriptyline (an antidepressant), neratinib (an antineoplastic used for breast cancer), puromycin (an aminonucleoside antibiotic), taxifolin (an anticancer flavonolol), vorinostat (an antineoplastic histone deacetylase inhibitor), and zileuton (an anti-asthmatic 5-lipoxygenase inhibitor) for the treatment of resistant prolactinoma [44]. They also analyzed effects of these drugs MMQ cell vitality via investigating PI3-Kinase/Akt signaling pathway and arrest of cell cycle via western blotting and flow cytometry [44].…”

Molecular Pathways in Prolactinomas: Translational and Therapeutic Implications

“…Aydin et al [84] studied the miRNA-mediated drug repositioning (transcriptome data that exploit disease-specific signatures in addition to biological and pharmacological data to elucidate a rational prioritisation of pathways and drugs) in 17 prolactinomas. The group found seven drugs including 5-fluorocytosine, nortriptyline, neratinib, puromycin, taxifolin, vorinostat, and zileuton as potential candidates for the treatment of prolactinoma.…”

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“…They repurposed 7 drugs including 5-flourocytosine (an antifungal agent), nortriptyline (an antidepressant), neratinib (an antineoplastic used for breast cancer), puromycin (an aminonucleoside antibiotic), taxifolin (an anticancer flavonolol), vorinostat (an antineoplastic histone deacetylase inhibitor), and zileuton (an anti-asthmatic 5-lipoxygenase inhibitor) for the treatment of resistant prolactinoma [44]. They also analyzed effects of these drugs MMQ cell vitality via investigating PI3-Kinase/Akt signaling pathway and arrest of cell cycle via western blotting and flow cytometry [44].…”