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: Ruth Hoffmann, Karin von Schwarzenberg, Nancy López-Antón, Anita Rudy, Gerhard Wanner, Verena M Dirsch, Angelika M Vollmar
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 82 Issue 5 Pg. 453-63 (Sep 01 2011) ISSN: 1873-2968 [Electronic] England
• PMID: 21669190 (Publication Type: Journal Article)
• Copyright: Copyright © 2011. Published by Elsevier Inc.

Chemical References

• Antineoplastic Agents, Phytogenic
• Endoplasmic Reticulum Chaperone BiP
• HSPA5 protein, human
• NF-kappa B
• Proto-Oncogene Proteins c-bcl-2
• Reactive Oxygen Species
• Sesquiterpenes
• Sesquiterpenes, Guaiane
• helenalin

Topics

• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis
• Cells, Cultured
• Cytoprotection
• Endoplasmic Reticulum (metabolism)
• Endoplasmic Reticulum Chaperone BiP
• Humans
• Membrane Potential, Mitochondrial (drug effects)
• NF-kappa B (antagonists & inhibitors, physiology)
• Proto-Oncogene Proteins c-bcl-2 (physiology)
• Reactive Oxygen Species (metabolism)
• Sesquiterpenes (pharmacology)
• Sesquiterpenes, Guaiane