title: Helenalin bypasses Bcl-2-mediated cell death resistance by inhibiting NF-κB and promoting reactive oxygen species generation.
abstract: Evasion of cell death by overexpression of anti-apoptotic proteins, such as Bcl-2, is commonly observed in cancer cells leading to a lack of response to chemotherapy. Hence, there is a need to find new chemotherapeutic agents that are able to overcome chemoresistance mediated by Bcl-2 and to understand their mechanisms of action. Helenalin, a sesquiterpene lactone (STL), induces cell death and abrogates clonal survival in a highly apoptosis-resistant Bcl-2 overexpressing Jurkat cell line as well as in two other Bcl-2 overexpressing solid tumor cell lines (mammary MCF-7; pancreatic L6.3pl). This effect is not achieved by directly affecting the mitochondria-protective function of Bcl-2 in the intrinsic pathway of apoptosis since Bcl-2 overexpressing Jurkat cells do not show cytochrome c release and dissipation of mitochondrial membrane potential upon helenalin treatment. Moreover, helenalin induces an atypical form of cell death with necrotic features in Bcl-2 overexpressing cells, neither activating classical mediators of apoptosis (caspases, AIF, Omi/HtrA2, Apaf/apoptosome) nor ER-stress mediators (BiP/GRP78 and CHOP/GADD153), nor autophagy pathways (LC3 conversion). In contrast, helenalin was found to inhibit NF-κB activation that was considerably increased in Bcl-2 overexpressing Jurkat cells and promotes cell survival. Moreover, we identified reactive oxygen species (ROS) and free intracellular iron as mediators of helenalin-induced cell death whereas activation of JNK and abrogation of Akt activity did not contribute to helenalin-elicited cell death. Our results highlight the NF-κB inhibitor helenalin as a promising chemotherapeutic agent to overcome Bcl-2-induced cell death resistance.
authors.affiliation: Center for Drug Research, Pharmaceutical Biology, Ludwig-Maximilians-University, Butenandtstrasse 5-13, Munich, Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Hoffmann
authors.forename: Karin
authors.initials: K
authors.lastname: von Schwarzenberg
authors.forename: Nancy
authors.initials: N
authors.lastname: López-Antón
authors.forename: Anita
authors.initials: A
authors.lastname: Rudy
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wanner
authors.forename: Verena M
authors.initials: VM
authors.lastname: Dirsch
authors.forename: Angelika M
authors.initials: AM
authors.lastname: Vollmar
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D002478:Cells, Cultured; D019610:Cytoprotection; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012717:Sesquiterpenes / Q000494:pharmacology*; D045789:Sesquiterpenes, Guaiane
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes; D045789:Sesquiterpenes, Guaiane; C001329:helenalin