ABSTRACT
A new unprecedented cinnamate derivative (1) was obtained from Erythrina excelsa (Leguminosae) and identified as nonadecyl para-hydroperoxycinnamate. This compound was isolated together with three known compounds, namely lupeol (2), mixture of sitosterol and stigmasterol (3), and isoneorautenol (4). Their structures were established on the basis of NMR and mass spectroscopic data in conjunction with those reported in the literature. Compound 1 was evaluated for its capability of inhibiting cancer cell lines and growth of a panel of microbial strains. It turned out that 1 is moderately to significantly cytotoxic against six cancer cell lines and shows weak to no antimicrobial activity.
Subject(s)
Anti-Bacterial Agents/chemistry , Antineoplastic Agents, Phytogenic/chemistry , Cinnamates/chemistry , Erythrina/chemistry , Anti-Bacterial Agents/isolation & purification , Antineoplastic Agents, Phytogenic/isolation & purification , Cell Line, Tumor , Cinnamates/isolation & purification , Drug Screening Assays, Antitumor , Humans , Magnetic Resonance Spectroscopy , Mass Spectrometry , Molecular Structure , Plant Bark/chemistry , Plant Extracts/chemistryABSTRACT
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.