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

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.

Exploring Amodiaquine’s Repurposing Potential in Breast Cancer Treatment—Assessment of In-Vitro Efficacy & Mechanism of Action

“…We profiled the activity of AQ, in terms of cell viability inhibition, cell migration and colony growth inhibition. Cell viability is an important toxicity assay parameter and is directly associated with the toxic effects of a drug [ 47 ]. AQ induced a reduction in cell viability in different breast cancer cells (MCF-7, MDAMB-231, SK-BR-3 and BT-549).…”

Quinacrine Has Preferential Anticancer Effects on Mesothelioma Cells With Inactivating NF2 Mutations

“…A recent report was published with preclinical evidence supporting the use of quinacrine in pleural mesothelioma, but without any focus on NF2 mutations ( Kulkarni et al, 2020 ). This report suggested the potential mechanism of action for quinacrine autophagy inhibition and apoptotic induction.…”

Development and Characterization of Folic Acid-Conjugated Amodiaquine-Loaded Nanoparticles–Efficacy in Cancer Treatment

“…In earlier work from our group, we demonstrated the feasibility of drug repurposing for various cancers’ treatments, together with non-small cell lung cancer (NSCLC), breast cancer, and mesothelioma [ 7 , 8 , 9 , 10 ]. We have shown that previous FDA-approved drugs can be successfully repurposed for the treatment of various aggressive cancer phenotypes with great success [ 7 , 11 , 12 ]. However, most repurposed therapies work by poly-pharmacology, and may have adverse effects in healthy tissues if given by systemic routes [ 13 ].…”