Repurposing Quinacrine for Treatment of Malignant Mesothelioma: In-Vitro Therapeutic and Mechanistic Evaluation.

Nishant S. Kulkarni,Vineela Parvathaneni,Bhuvaneshwar Vaidya,Vivek Gupta,Debarati Bhanja

doi:10.3390/ijms21176306

Abstract

Malignant mesothelioma (MM) is a rare type of cancer primarily affecting mesothelial cells lining the pleural cavity. In this study, we propose to repurpose quinacrine (QA), a widely approved anti-malarial drug, for Malignant Pleural Mesothelioma (MPM) treatment. QA demonstrates high degree of cytotoxicity against both immortalized and primary patient-derived cell lines with sub-micromolar 50% inhibitory concentration (IC50) values ranging from 1.2 µM (H2452) to 5.03 µM (H28). Further, QA also inhibited cellular migration and colony formation in MPM cells, demonstrated using scratch and clonogenic assays, respectively. A 3D-spheroid cell culture experiment was performed to mimic in-vivo tumor conditions, and QA was reported to be highly effective in this simulated cellular model. Anti-angiogenic properties were also discovered for QA. Autophagy inhibition assay was performed, and results revealed that QA successfully inhibited autophagy process in MPM cells, which has been cited to be one of the survival pathways for MPM. Annexin V real-time apoptosis study revealed significant apoptotic induction in MPM cells following QA treatment. Western blots confirmed inhibition of autophagy and induction of apoptosis. These studies highlight anti-mesothelioma efficacy of QA at low doses, which can be instrumental in developing it as a stand-alone treatment strategy for MPM.

Highlights

Malignant mesothelioma (MM) is a type of cancer that affects the mesothelium tissue lining found around major bodily organs like lungs, liver, heart, etc. [1,2] MM can be classified based on its type and location in the body
Malignant Pleural Mesothelioma (MPM) is the cancer that affects the pleural lining of the lungs, peritoneal mesothelioma affects the abdominal linings, whereas pericardial mesothelioma affects the lining of the heart [3,4,5]
QA was compared with cisplatin (CA), a common drug used in platinum-based therapy of MPM

Summary

Introduction

Malignant mesothelioma (MM) is a type of cancer that affects the mesothelium tissue lining found around major bodily organs like lungs, liver, heart, etc. [1,2] MM can be classified based on its type and location in the body. Malignant mesothelioma (MM) is a type of cancer that affects the mesothelium tissue lining found around major bodily organs like lungs, liver, heart, etc. Malignant Pleural Mesothelioma (MPM) is the cancer that affects the pleural lining of the lungs, peritoneal mesothelioma affects the abdominal linings, whereas pericardial mesothelioma affects the lining of the heart [3,4,5]. Even though all bodily tissues are at risk, majority of the diagnosed cases reveal that lungs and chest wall are the most susceptible to MM. MM occurring in the chest wall is often referred to as pleural mesothelioma (MPM; pleura is a thin layer of tissue lining the lungs) and is predominantly seen to occur in geriatric patients with an average age of occurrence being 72 years [6].

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