title: Cis-Nerolidol Induces Endoplasmic Reticulum Stress and Cell Death in Human Hepatocellular Carcinoma Cells through Extensive CYP2C19 and CYP1A2 Oxidation.
abstract: 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 (BAK1, BAX, CAPN1, CASP8, CASP9, PARP1 and TP53), cell cycle (CCND1, CCNE1, CDK1 and CDK2), xenobiotic metabolism (CYP2D6 and CYP3A4) and paraptosis (IGF1R receptor). Up-regulation was seen in case of genes related to cell survival (BBC3 and MYC) and reticulum stress protein response (EIF2AK3 and ERN1) and xenobiotic metabolism (CYP1A2 and CYP2C19). 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. EIF2AK3, ERN1, CYP2C19 and CYP1A2 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.
authors.affiliation: Laboratory of Toxicological Genetics, Department of General Biology, Biological Sciences Center, State University of Londrina - UEL, Londrina, Paraná, Brazil.
authors.forename: Bruna Isabela
authors.initials: BI
authors.lastname: Biazi
authors.affiliation: Laboratory of Toxicological Genetics, Department of General Biology, Biological Sciences Center, State University of Londrina - UEL, Londrina, Paraná, Brazil.
authors.forename: Thalita Alves
authors.initials: TA
authors.lastname: Zanetti
authors.affiliation: Laboratory of Toxicological Genetics, Department of General Biology, Biological Sciences Center, State University of Londrina - UEL, Londrina, Paraná, Brazil.
authors.forename: Adrivanio
authors.initials: A
authors.lastname: Baranoski
authors.affiliation: Laboratory of Toxicological Genetics, Department of General Biology, Biological Sciences Center, State University of Londrina - UEL, Londrina, Paraná, Brazil.
authors.forename: Amanda Cristina
authors.initials: AC
authors.lastname: Corveloni
authors.affiliation: Laboratory of Toxicological Genetics, Department of General Biology, Biological Sciences Center, State University of Londrina - UEL, Londrina, Paraná, Brazil.
authors.forename: Mário Sérgio
authors.initials: MS
authors.lastname: Mantovani
mesh_terms: D065767:Activation, Metabolic; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D065731:Cytochrome P-450 CYP2C19 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010084:Oxidation-Reduction; D012717:Sesquiterpenes / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D012717:Sesquiterpenes; C504573:CYP1A2 protein, human; C045793:CYP2C19 protein, human; D019388:Cytochrome P-450 CYP1A2; D065731:Cytochrome P-450 CYP2C19; C037055:nerolidol