Cytotoxicity of a naturally occurring furoquinoline alkaloid and four acridone alkaloids towards multi-factorial drug-resistant cancer cells

Introduction: Chemotherapy is one of the preferred mode of treatment of malignancies, but is complicated by the expression of diverse resistance mechanisms of cancer cells. Methods: In the present study, we investigated the cytotoxicity of five alkaloids including a furoquinoline montrofoline (1) and four acridones namely 1-hydroxy-4-methoxy-10-methylacridone (2), norevoxanthine (3), evoxanthine (4), 1,3-dimethoxy-10-methylacridone (5) against 9 drug-sensitive and multidrug-resistant (MDR) cancer cell lines. The resazurin reduction assay was used to evaluate the cytotoxicity of these compounds, whilst caspase-Glo assay was used to detect caspase activation. Cell cycle, mitochondrial membrane potential (MMP) and levels of reactive oxygen species (ROS) were all analyzed via flow cytometry. Results: Furoquinoline 1 as well as the acridone alkaloids 2-5 displayed cytotoxic effects with IC50 values below 138 mu M on all the 9 tested cancer cell lines. The IC50 values ranged from 41.56 mu M (towards hepatocarinoma HepG2 cells) to 90.66 mu M [towards colon carcinoma HCT116 (p53(-/-)) cells] for 1, from 6.78 mu M [towards HCT116 (p53(-/-)) cells) to 106.47 mu M [towards breast adenocarcinoma MDA-MB-231-pcDNA cells] for 2, from 5.72 mu M (towards gliobastoma U87MG.Delta EGFR cells) to 137.62 mu M (towards leukemia CCRF-CEM cells] for 3, from 6.11 mu M [towards HCT116 (p53(+/+)) cells] to 80.99 mu M (towards HepG2 cells] for 4, from 3.38 mu M (towards MDA-MB-231-BCRP cells) to 58.10 mu M (towards leukemia CEM/ADR5000 cells] for 5 and from 0.20 mu M (against CCRF-CEM cells) to 195.12 mu M (against CEM/ADR5000 cells) for doxorubicin. Acridone alkaloid 5 induced apoptosis in CCRF-CEM leukemia cells, mediated by increased ROS production. Conclusions: The five tested alkaloids and mostly acridone 5 are potential cytotoxic natural products that deserve more investigations to develop novel cytotoxic compounds against multifactorial drug-resistant cancers.