Abstract | INTRODUCTION: Resistance of cancer cells to chemotherapy has become a worldwide concern. Naturally occuring isoflavonoids possess a variety of biological activities including anti- cancer effects. The present study was aimed at investigating the cytotoxicity and the modes of action of three naturally occuring isoflavonoids, neobavaisoflavone (1), sigmoidin H (2) and a pterocarpan that is a special type of isoflavonoid, isoneorautenol (3) against a panel of nine cancer cell lines, including various sensitive and drug-resistant phenotypes. METHODS: The cytotoxicity of the compounds was determined using a resazurin reduction assay, whereas the caspase-Glo assay was used to detect the activation of caspases 3/7, caspase 8 and caspase 9 in cells treated with compounds 3. Flow cytometry was used for cell cycle analysis and detection of apoptotic cells, analysis of mitochondrial membrane potential ( MMP) as well as measurement of reactive oxygen species (ROS). RESULTS: Compounds 3 showed significant cytotoxicity toward sensitive and drug-resistant cancer cell lines. Compounds 1 and 2 were selectively active, and IC50 values below 115 μM were obtained on 6/9 and 4/9 cell lines respectively with values ranging from 42.93 μM (toward CCRF-CEM cells) to 114.64 μM [against HCT116 (p53(+/+)) cells] for 1 and 25.59 μM (toward U87MG) to 110.51 μM [against HCT116 (p53(+/+)) cells] for 2. IC50 values ranging from 2.67 μM (against MDA-MB 237BCRP cells) to 21.84 (toward U87MG) were measured for compound 3 and between 0.20 μM (toward CCRF-CEM cells) and 195.12 μM (toward CEM/ADR5000 cells) for doxorubicin as control drug. BCRP-transfected MDA-MB-231 cells, HCT116 (p53(+/+)) and U87MG.ΔEGFR cells were hypersensitive (collateral sensitive) to compound 3 as compared to their counterpart cell lines. Compound 3 induced apoptosis in CCRF-CEM cells via activation of caspases 3/7, 8 and 9 as well as the loss of MMP and increased ROS production. CONCLUSIONS: The cytotoxicity of the studied isoflavonoids and especially the pterocarpan 3 deserve more detailed exploration in the future to develop novel anticancer drugs against sensitive and otherwise drug-resistant phenotypes.
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Authors | Victor Kuete, Louis P Sandjo, Guy M N Kwamou, Benjamin Wiench, Augustin E Nkengfack, Thomas Efferth |
Journal | Phytomedicine : international journal of phytotherapy and phytopharmacology
(Phytomedicine)
Vol. 21
Issue 5
Pg. 682-8
(Apr 15 2014)
ISSN: 1618-095X [Electronic] Germany |
PMID | 24252341
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2013 Elsevier GmbH. All rights reserved. |
Chemical References |
- Antineoplastic Agents, Phytogenic
- Benzofurans
- Benzopyrans
- Isoflavones
- Reactive Oxygen Species
- isoneorautenol
- neobavaisoflavone
- sigmoidin H
- Caspases
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Topics |
- Antineoplastic Agents, Phytogenic
(isolation & purification, pharmacology)
- Apoptosis
(drug effects)
- Benzofurans
(isolation & purification, pharmacology)
- Benzopyrans
(isolation & purification, pharmacology)
- Caspases
(metabolism)
- Cell Cycle
(drug effects)
- Drug Resistance, Neoplasm
- Drug Screening Assays, Antitumor
- Erythrina
(chemistry)
- HCT116 Cells
- Humans
- Isoflavones
(isolation & purification, pharmacology)
- Membrane Potential, Mitochondrial
(drug effects)
- Reactive Oxygen Species
(metabolism)
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