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

Abstract

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 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: Victor Kuete, Hugues Fouotsa, Armelle T Mbaveng, Benjamin Wiench, Augustin E Nkengfack, Thomas Efferth
• Journal: Phytomedicine : international journal of phytotherapy and phytopharmacology (Phytomedicine) Vol. 22 Issue 10 Pg. 946-51 (Sep 15 2015) ISSN: 1618-095X [Electronic] Germany
• PMID: 26321744 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier GmbH. All rights reserved.

Chemical References

• Acridones
• Alkaloids
• Antineoplastic Agents, Phytogenic
• Reactive Oxygen Species
• Caspases

Topics

• Acridones (chemistry, pharmacology)
• Alkaloids (chemistry, pharmacology)
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects)
• Caspases (metabolism)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• Humans
• Inhibitory Concentration 50
• Membrane Potential, Mitochondrial (drug effects)
• Molecular Structure
• Reactive Oxygen Species (metabolism)