Cytotoxicity of seven naturally occurring phenolic compounds towards multi-factorial drug-resistant cancer cells.
BACKGROUND
In medical oncology, multi-drug resistance (MDR) of cancer cells continues to be a major impediment. We are in quest of novel anti-proliferative agents to overcome drug-resistant tumor cells.


METHODS
In the present study, we investigated the cytotoxicity of 7 naturally occurring phenolic compounds including two isoflavonoids alpinumisoflavone (1) and laburnetin (2), one biflavonoid amentoflavone (3), three lignans pycnanthulignene A (4), pycnanthulignene B (5), and syringaresinol (7) and one xanthone, euxanthone (6) 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 analyzed via flow cytometry.


RESULTS
The IC50 values for the investigational phenolics ranged from 5.91 µM (towards leukemia CEM/ADR5000 cells) to 65.65 µM (towards drug-resistant breast adenocarcinoma MDA-MB-231-BCRP cells) for 1, 27.63 µM (towards leukemia CCRF-CEM cells) to 107.57 µM (towards MDA-MB-231-pcDNA cells) for 2, from 5.84 µM (towards CEM/ADR5000 cells) to 65.32 µM (towards colon carcinoma HCT116 (p53(-/-)) cells) for 4 and 0.20 µM (towards CCRF-CEM cells) to 195.12 µM (towards leukemia CEM/ADR5000) for doxorubicin. Phenolics 3, 5, 6 and 7 displayed selectivity cytotoxic effects on cancer cells lines. Compounds 1 and 4 induced apoptosis in CCRF-CEM cells, mediated by loss of MMP and increase ROS production.


CONCLUSIONS
The studied phenolics and mostly isoflavonoid 1 and lignan 4 are potential cytotoxic natural products that deserve more investigations to develop novel antineoplastic drugs against multifactorial drug-resistant cancers.
Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz 55128, Germany; Department of Biochemistry, Faculty of Science, University of Dschang, Dschang, Cameroon.
Victor
V
Kuete
Department of Biochemistry, Faculty of Science, University of Dschang, Dschang, Cameroon.
Armelle T
AT
Mbaveng
Department of Organic Chemistry, Faculty of Science, University of Yaoundé I, Yaoundé, Cameroon.
Eric C N
EC
Nono
Department of Organic Chemistry, Faculty of Science, University of Yaoundé I, Yaoundé, Cameroon.
Christophe C
CC
Simo
Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz 55128, Germany.
Maen
M
Zeino
Department of Organic Chemistry, Faculty of Science, University of Yaoundé I, Yaoundé, Cameroon.
Augustin E
AE
Nkengfack
Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz 55128, Germany. Electronic address: efferth@uni-mainz.de.
Thomas
T
Efferth
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010078:Oxazines / Q000737:chemistry; D010636:Phenols / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014966:Xanthenes / Q000737:chemistry
D000972:Antineoplastic Agents, Phytogenic; D010078:Oxazines; D010636:Phenols; D017382:Reactive Oxygen Species; D014966:Xanthenes; C005843:resazurin; D020169:Caspases
Alpinumisoflavone; Apoptosis; Cytotoxicity; Multi-drug resistance; Phenolic compounds; Pycnanthulignene