In Vitro and In Vivo Antitumor Effects of Pyrimethamine on Non-small Cell Lung Cancers

• Published in: Anticancer research 2018-06, Vol.38 (6), p.3435-3445
• Main Authors: Lin, Meng-Xian, Lin, Sheng-Hao, Lin, Chi-Chen, Yang, Ching-Chieh, Yuan, Sheau-Yun
• Format: Article
• Language: English
• Subjects: A549 Cells; Animals; Annexin V; Anticancer properties; Antineoplastic Agents - pharmacology; Antitumor activity; Apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins - metabolism; Bcl-2 protein; Cancer; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Caspase; Caspase-9; Cell cycle; Cell Cycle Checkpoints - drug effects; Cell Cycle Proteins - metabolism; Cell Proliferation - drug effects; Cyclin-dependent kinase 2; Cyclin-dependent kinase 4; Cyclin-dependent kinases; Cyclins; Dimethyl sulfoxide; Female; Flow cytometry; Humans; Kinases; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lungs; Membrane potential; Membrane Potential, Mitochondrial - drug effects; Mice, Inbred BALB C; Mice, Nude; Mitochondria; Molecular modelling; Non-small cell lung carcinoma; Proteins; Pyrimethamine; Pyrimethamine - pharmacology; Tumors; Western blotting; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation
• ISSN: 0250-7005; 1791-7530
• DOI: 10.21873/anticanres.12612

Pyrimethamine (PYR), an anti-malarial drug is known to inhibit various types of human cancer cells. The aim of this study was to investigate the anti-tumour effects of pyrimethamine (PYR) and its underlying molecular mechanisms using the human NSCLC cell line A549. PYR was dissolved in dimethyl sulfoxide to determine its apoptotic activity on A549 cells. Cell viability was determined by the MTT assay. Cell cycle, mitochondrial membrane potential, and Annexin V-FITC early apoptosis detection were evaluated by flow cytometry. Cyclin-dependent kinase (CDK) and Bcl-2 family protein expression was determined by western blotting. PYR reduced cell viability percentage and induced G /G arrest, which was associated with down-regulation of cyclins D1 and E, CDK4, and CDK2, and up-regulation of p21. PYR induced sub-G accumulation, Annexin-V binding, caspase-9 and -3 activation, poly (ADPribose) polymerase cleavage, and mitochondrial dysfunction in A549 cells. Moreover, PYR effectively inhibited NSCLC tumour growth in an A549 xenograft model. PYR demonstrated anti-tumour effects on NSCLC in vitro and in vivo, indicating its therapeutic potential against human NSCLC.