Helenalin bypasses Bcl-2-mediated cell death resistance by inhibiting NF-κB and promoting reactive oxygen species generation

Abstract

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractEvasion 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 ( 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.

Chronic Inflammation in Cancer Development

“…We found that the combined administration of celecoxib and EGCG can induce synergistic cancer preventive effects in pancreatic cancer cells by down-regulating tumorigenic factors and inducing apoptosis (Härdtner et al, 2009). Previous investigations of our group and others revealed anti-proliferative and apoptosis-inducing effects of EGCG and celecoxib in pancreatic cancer cells (Chen and Zhang, 2007; Inaba et al, 2008; Xu et al, 2008; Hoffmann et al, 2011). The anti-proliferative properties of NSAID such as celecoxib are related to effects on the cell cycle (Xiong, 2004) including changes in gene expression that favor cell cycle arrest (Yip-Schneider et al, 2001; Tseng et al, 2002).…”

“…Leukocytes are the main source of RNS and ROS acting as chemical effectors in inflammation-driven carcinogenesis (Kundu and Surh, 2008). We identified a constitutively enhanced expression of PGHS-2 in human pancreatic adenocarcinoma cells that is further increased in the presence of IL-1 (Bauer et al, 2009; Hoffmann et al, 2011). The constitutive production of PGHS-2 and its key product PGE 2 in the microenvironment of pancreatic carcinomas accounts for an enhanced malignancy of pancreatic tumor cells which is caused by inhibition of apoptosis, increase in cell proliferation, induction of angiogenesis, and invasion of malignant cells into surrounding tissue (Merati et al, 2001; Kong et al, 2002; Garcea et al, 2005).…”

High-Throughput Screen of Natural Product Libraries for Hsp90 Inhibitors

“…Compound 9 , helenalin, suppresses NF-κB activation, promotes ROS generation, and induces apoptosis by bypassing Bcl-2 function [47]. Helenalin is cytotoxic against a number of cancer cells, and it also manifests immunosuppressant and anti-inflammatory activity [48].…”

Development of Anticancer Agents from Plant-Derived Sesquiterpene Lactones

“…A mechanistic study showed that helenalin ( 22 ) induced HL-60 cell differentiation via the protein kinase C (PKC)/extracellular signal-regulated kinase (ERK) signaling pathway and inhibition of NF-κB activity [149]. It was found to reverse Bcl-2-mediated chemoresistance in tumor cells by inhibition of Bcl-2-induced upregulation of NF-κB activity [150]. Also, this compound induced cell death and abrogated clonal survival in the highly apoptosis-resistant Bcl-2-overexpressing Jurkat cell line and other two Bcl-2-overexpressing solid MCF-7 mammary and L6.3pl pancreatic tumor cell lines [150].…”