8,8-bis-(Dihydroconiferyl)-diferulate displayed impressive cytotoxicity towards a panel of human and animal cancer cells

Armelle T Mbaveng; Francois Damen; Michel-Gael F Guefack; Simplice Beaudelaire Tankeo; Sara Abdelfatah; Gabin T M Bitchagno; İlhami Çelik; Victor Kuete; Thomas Efferth

doi:10.1016/j.phymed.2020.153215

8,8-bis-(Dihydroconiferyl)-diferulate displayed impressive cytotoxicity towards a panel of human and animal cancer cells

Phytomedicine. 2020 Apr 15:70:153215. doi: 10.1016/j.phymed.2020.153215. Epub 2020 Apr 20.

Authors

Armelle T Mbaveng¹, Francois Damen², Michel-Gael F Guefack³, Simplice Beaudelaire Tankeo¹, Sara Abdelfatah⁴, Gabin T M Bitchagno², İlhami Çelik⁵, Victor Kuete⁶, 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, P.O. Box 67, Dschang, Cameroon.
² Department of Chemistry, Faculty of Science, University of Dschang, P.O. Box 67, Dschang, Cameroon.
³ Department of Biochemistry, Faculty of Science, University of Dschang, P.O. Box 67, Dschang, Cameroon.
⁴ Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55128 Mainz, Germany.
⁵ Department of Chemistry, Faculty of Science, Eskisehir Technical University, 26470 Eskisehir, Turkey.
⁶ 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, P.O. Box 67, Dschang, Cameroon. Electronic address: kuetevictor@yahoo.fr.
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: 32388040
DOI: 10.1016/j.phymed.2020.153215

Abstract

Background: Recalcitrant cancers appear as a major obstacle to chemotherapy, prompting scientists to intensify the search for novel drugs to tackle the cell lines expressing multi-drug resistant (MDR) phenotypes.

Purpose: The purpose of this study was to evaluate the antiproliferative potential of a ferrulic acid derivative, 8,8-bis-(dihydroconiferyl)-diferulate (DHCF2) on a panel of 18 cancer cell lines, including various sensitive and drug-resistant phenotypes, belonging to human and animals. The mode of induction of cell death by this compound was further studied.

Methods: The antiproliferative activity, autophagy, ferroptotic and necroptotic cell death were evaluated by the resazurin reduction assay (RRA). CCRF-CEM leukemia cells were used for all mechanistic studies. A caspase-Glo assay was applied to evaluate the activity of caspases. Cell cycle analysis (PI staining), apoptosis (annexin V/PI staining), mitochondrial membrane potential (MMP) (JC-1) and reactive oxygen species (ROS) (H₂DCFH-DA) were assessed by flow cytometry.

Results: DHCF2 demonstrated impressive cytotoxic effects towards the 18 cancer cell lines tested, with IC₅₀ values all below 6.5 µM. The obtained IC₅₀ values were in the range of 1.17 µM (towards CCRF-CEM leukemia cells) to 6.34 µM (towards drug-resistant HCT116 p53^-/- human colon adenocarcinoma cells) for DHCF2 and from 0.02 µM (against CCRF-CEM cells) to 122.96 µM (against multidrug-resistant CEM/ADR5000 leukemia cells) for the reference drug, doxorubicin. DHCF2 had IC₅₀ values lower than those of doxorubicin, against CEM/ADR5000 cells and on some melanoma cell lines, such as MaMel-80a cells, Mel-2a cells, MV3 cells and SKMel-505 cells. DHCF2 induced autophagy as well as apoptosis in CCRF-CEM cells though caspases activation, MMP alteration and increase of ROS production.

Conclusion: The studied diferulic acid, DHCF2, is a promising antiproliferative compound. It deserves further indepth investigations with the ultimate aim to develop a novel drug to fight cancer drug resistance.

Keywords: 8, 8-bis-(dihydroconiferyl)-diferulate; Cell death; Diferulic acid; Multi-drug resistance; Natural product.

MeSH terms

Animals
Antineoplastic Agents, Phytogenic / pharmacology*
Antineoplastic Agents, Phytogenic / therapeutic use
Antineoplastic Agents, Phytogenic / toxicity*
Apoptosis / drug effects*
Cell Line, Tumor / drug effects*
Doxorubicin / pharmacology*
Doxorubicin / therapeutic use
Doxorubicin / toxicity
Drug Resistance, Multiple / drug effects
Drug Resistance, Neoplasm / drug effects*
Humans
Leukemia / drug therapy*
Mice
Plant Extracts / pharmacology
Plant Extracts / therapeutic use
Plant Extracts / toxicity

Substances

Antineoplastic Agents, Phytogenic
Plant Extracts
Doxorubicin