title: Cytotoxicity of a naturally occurring furoquinoline alkaloid and four acridone alkaloids towards multi-factorial drug-resistant cancer cells.
abstract: BACKGROUND
  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 µM on all the 9 tested cancer cell lines. The IC50 values ranged from 41.56 µM (towards hepatocarinoma HepG2 cells) to 90.66 µM [towards colon carcinoma HCT116 (p53(-/-)) cells] for 1, from 6.78 µM [towards HCT116 (p53(-/-)) cells) to 106.47 µM [towards breast adenocarcinoma MDA-MB-231-pcDNA cells] for 2, from 5.72 µM (towards gliobastoma U87MG.ΔEGFR cells) to 137.62 µM (towards leukemia CCRF-CEM cells] for 3, from 6.11 µM [towards HCT116 (p53(+/+)) cells] to 80.99 µM (towards HepG2 cells] for 4, from 3.38 µM (towards MDA-MB-231-BCRP cells) to 58.10 µM (towards leukemia CEM/ADR5000 cells] for 5 and from 0.20 µM (against CCRF-CEM cells) to 195.12 µM (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.
authors: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55128, Mainz, Germany; Department of Biochemistry, Faculty of Science, University of Dschang, Dschang,Cameroon.
authors: Victor
authors: V
authors: Kuete
authors: Department of Organic Chemistry, Faculty of Science, University of Yaoundé I, Yaoundé, Cameroon.
authors: Hugues
authors: H
authors: Fouotsa
authors: Department of Biochemistry, Faculty of Science, University of Dschang, Dschang,Cameroon.
authors: Armelle T
authors: AT
authors: Mbaveng
authors: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55128, Mainz, Germany.
authors: Benjamin
authors: B
authors: Wiench
authors: Department of Organic Chemistry, Faculty of Science, University of Yaoundé I, Yaoundé, Cameroon.
authors: Augustin E
authors: AE
authors: Nkengfack
authors: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55128, Mainz, Germany. Electronic address: efferth@uni-mainz.de.
authors: Thomas
authors: T
authors: Efferth
mesh_terms: D054831:Acridones / Q000737:chemistry / Q000494:pharmacology*; D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D020128:Inhibitory Concentration 50; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D015394:Molecular Structure; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D054831:Acridones; D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D017382:Reactive Oxygen Species; D020169:Caspases
keywords: 1,3-Dimethoxy-10-methylacridone; Acridone; Apoptosis; Cytotoxicity; Furoquinoline; Multi-drug resistance