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Cis‐Nerolidol Induces Endoplasmic Reticulum Stress and Cell Death in Human Hepatocellular Carcinoma Cells through Extensive CYP2C19 and CYP1A2 Oxidation
Author(s) -
Biazi Bruna Isabela,
Zanetti Thalita Alves,
Baranoski Adrivanio,
Corveloni Amanda Cristina,
Mantovani Mário Sérgio
Publication year - 2017
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.12772
Subject(s) - biology , programmed cell death , cyclin a , unfolded protein response , endoplasmic reticulum , microbiology and biotechnology , cell cycle , cell cycle checkpoint , apoptosis , cancer research , cyclin , biochemistry
Of late, many studies are attempting to find new molecules with anticancer properties, especially those with the capability to inhibit cell growth. The aim of this work was to evaluate nerolidol, a plant‐based compound, as its cytotoxicity, genotoxicity, antiproliferative and apoptotic induction, cell cycle, mitochondrial membrane potential and RT ‐ qPCR of transcripts related to those pathways in the human hepatocellular carcinoma cell line (HepG2/C3A). Only cis‐nerolidol (C‐ NER ) demonstrated cytotoxicity (100–250 μM) activity and was selected to conduct the following experiments. C‐ NER did not show genotoxic activity, but altered the mitochondrial membrane potential, reduced cell proliferation by arresting cell cycle in G1 phase and induced cell death. RT ‐ qPCR showed that C‐ NER down‐regulated genes related to apoptosis ( BAK 1, BAX , CAPN 1, CASP 8, CASP 9, PARP 1 and TP 53 ), cell cycle ( CCND 1, CCNE 1, CDK 1 and CDK 2 ), xenobiotic metabolism ( CYP 2D6 and CYP 3A4 ) and paraptosis ( IGF 1R receptor). Up‐regulation was seen in case of genes related to cell survival ( BBC 3 and MYC ) and reticulum stress protein response ( EIF 2 AK 3 and ERN 1 ) and xenobiotic metabolism ( CYP 1A2 and CYP 2C19 ). We deduced that the antiproliferative activity of C‐ NER is attributable to its modulation of the cyclins and cyclin‐dependent kinases as these proteins are necessary for G1/S phase transition. EIF 2 AK 3 , ERN 1 , CYP 2C19 and CYP 1A2 up‐regulation suggests that endoplasmic reticulum stress was induced owing to the increased activity of cytochrome P450 enzymes. Caspase‐independent cell death was also observed, indicating that another type of cell death, paraptosis, was triggered. Our results indicate that C‐ NER has considerable potential in anticancer therapy because it modulates important molecular targets of cell survival and proliferation.