Cytotoxicity of three naturally occurring flavonoid derived compounds (artocarpesin, cycloartocarpesin and isobavachalcone) towards multi-factorial drug-resistant cancer cells

Victor Kuete; Armelle T Mbaveng; Maen Zeino; Christian D Fozing; Bathelemy Ngameni; Gilbert Deccaux W F Kapche; Bonaventure T Ngadjui; Thomas Efferth

doi:10.1016/j.phymed.2015.07.006

Cytotoxicity of three naturally occurring flavonoid derived compounds (artocarpesin, cycloartocarpesin and isobavachalcone) towards multi-factorial drug-resistant cancer cells

Phytomedicine. 2015 Nov 15;22(12):1096-102. doi: 10.1016/j.phymed.2015.07.006. Epub 2015 Aug 11.

Authors

Victor Kuete¹, Armelle T Mbaveng², Maen Zeino³, Christian D Fozing⁴, Bathelemy Ngameni⁵, Gilbert Deccaux W F Kapche⁶, Bonaventure T Ngadjui⁴, Thomas Efferth⁷

Affiliations

¹ 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.
² Department of Biochemistry, Faculty of Science, University of Dschang, Dschang, Cameroon.
³ Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55128 Mainz, Germany.
⁴ Department of Organic Chemistry, Faculty of Science, University of Yaoundé I, Yaoundé, Cameroon.
⁵ Department of Pharmacognosy and Pharmaceutical Chemistry, Faculty of Medicine and Biomedical Sciences, University of Yaoundé I, Yaoundé, Cameroon.
⁶ Department of Chemistry, Higher Teachers' Training College, University of Yaoundé I, Yaoundé, Cameroon.
⁷ Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55128 Mainz, Germany. Electronic address: efferth@uni-mainz.de.

PMID: 26547532
DOI: 10.1016/j.phymed.2015.07.006

Abstract

Introduction: Cancer remains an aggressive deadly disease, if drug resistance develops. This problem is aggravated by the fact that multiple rather than single mechanisms are involved in resistance and that multidrug resistance (MDR) phenomena cause inefficacy of many clinical established anticancer drugs. We are seeking for novel cytotoxic phytochemicals to combat drug-resistant tumour cells.

Methods: In the present study, we investigated the cytotoxicity of three naturally occurring flavonoids including two flavones artocarpesin (1) and cycloartocarpesin (2) and one chalcone, isobavachalcone (3) against 9 drug-sensitive and 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 analysed via flow cytometry.

Results: Flavones 1 and 2 as well as chalcone 3 displayed cytotoxic effects at various extent on all the 9 tested cancer cell lines with IC50 values respectively below 106 µM, 50 µM and 25 µM. The IC50 values for the three investigational flavonoids ranged from 23.95 µM (towards hepatocarcinoma HepG2 cells) to 105 µM [towards colon carcinoma HCT116 (p53(-/-)) cells] for 1, from 15.51 µM (towards leukemia CCRF-CEM cells) to 49.83 µM [towards glioblastoma U87MG.ΔEGFR cells] for 2 and from 2.30 µM (towards CCRF-CEM cells) to 23.80 µM [towards colon carcinoma HCT116 (p53(+/+)) cells] for 3 and from 0.20 µM (towards CCRF-CEM cells) to 195.12 µM (towards leukemia CEM/ADR5000 cells) for doxorubicin. Compounds 2 and 3 induced apoptosis in CCRF-CEM leukemia cells, mediated by caspase activation and the disruption of MMP.

Conclusions: The three tested flavonoids and mostly chalcone 3 are potential cytotoxic natural products that deserve more investigations to develop novel antineoplastic drugs against multifactorial drug-resistant cancers.

Keywords: Apoptosis; Cycloartocarpesin; Cytotoxicity; Flavonoids; Isobavachalcone; Multi-drug resistance.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents, Phytogenic / pharmacology*
Caspases / metabolism
Cell Cycle / drug effects
Cell Line, Tumor
Chalcones / pharmacology*
Drug Resistance, Multiple / drug effects*
Drug Resistance, Neoplasm / drug effects*
Flavones / pharmacology*
Humans
Inhibitory Concentration 50
Membrane Potential, Mitochondrial / drug effects
Molecular Structure
Reactive Oxygen Species / metabolism

Substances

Antineoplastic Agents, Phytogenic
Chalcones
Flavones
Reactive Oxygen Species
artocarpesin
cycloartocarpesin
isobavachalcone
Caspases