NF-κB p65 repression by the sesquiterpene lactone, Helenalin, contributes to the induction of autophagy cell death

Abstract

BackgroundNumerous studies have demonstrated that autophagy plays a vital role in maintaining cellular homeostasis. Interestingly, several anticancer agents were found to exert their anticancer effects by triggering autophagy. Emerging data suggest that autophagy represents a novel mechanism that can be exploited for therapeutic benefit. Pharmacologically active natural compounds such as those from marine, terrestrial plants and animals represent a promising resource for novel anticancer drugs. There are several prominent examples from the past proving the success of natural products and derivatives exhibiting anticancer activity. Helenalin, a sesquiterpene lactone has been demonstrated to have potent anti-inflammatory and antitumor activity. Albeit previous studies demonstrating helenalin’s multi modal action on cellular proliferative and apoptosis, the mechanisms underlying its action are largely unexplained.MethodsTo deduce the mechanistic action of helenalin, cancer cells were treated with the drug at various concentrations and time intervals. Using western blot, FACS analysis, overexpression and knockdown studies, cellular signaling pathways were interrogated focusing on apoptosis and autophagy markers.ResultsWe show here that helenalin induces sub-G1 arrest, apoptosis, caspase cleavage and increases the levels of the autophagic markers. Suppression of caspase cleavage by the pan caspase inhibitor, Z-VAD-fmk, suppressed induction of LC3-B and Atg12 and reduced autophagic cell death, indicating caspase activity was essential for autophagic cell death induced by helenalin. Additionally, helenalin suppressed NF-κB p65 expression in a dose and time dependent manner. Exogenous overexpression of p65 was accompanied by reduced levels of cell death whereas siRNA mediated suppression led to augmented levels of caspase cleavage, autophagic cell death markers and increased cell death.ConclusionsTaken together, these results show that helenalin mediated autophagic cell death entails inhibition of NF-κB p65, thus providing a promising approach for the treatment of cancers with aberrant activation of the NF-κB pathway.

Pikuni-Blackfeet traditional medicine: Neuroprotective activities of medicinal plants used to treat Parkinson’s disease-related symptoms

“…Arnica preparations examined in randomized double-blind human clinical trials exhibited a potent analgesic effect in patients suffering from osteoarthritis (Knuesel et al, 2002; Widrig et al, 2007). A sesquiterpene lactone isolated from Arnica flowers, helenalin, showed anti-inflammatory activity by inhibiting NFκB (Lim et al, 2012; Lyss et al, 1997), a transcription factor involved in inflammatory responses, suggesting that this constituent could be involved in Arnica’s medicinal activity.…”

Natural sesquiterpene lactones induce programmed cell death in Trypanosoma cruzi: A new therapeutic target?

“…In activated CD4+ T cells, Hln induces cell death by triggering the mitochondrial apoptotic pathway by rapid stabilization of p53, nuclear localization of p53 and AIF, and an increase in ROS production that results in loss of mitochondrial membrane potential (Berges et al 2009). In addition, it has been described that Hln mediates autophagic cell death by inhibition of NF-B p65 in other cancer cell lines, specifically in A2780 (human ovarian cancer cell line), RKO (colon carcinoma cancer cell line) and MCF-7 (breast adenocarcinoma cancer cell line) (Lim et al 2012). It has been previously shown that STLs reduce the glutathione content and increase the production of ROS in trypanosomatids (Barrera et al 2013) and that the cytotoxic effect of the STLs can be prevented by adding reducing agents like DTT or GSH (Brengio et al 2000;Jimenez-Ortiz et al 2005).…”

A triterpenoid saponin from Adenophora triphylla var. japonica suppresses the growth of human gastric cancer cells via regulation of apoptosis and autophagy

“…NF-κB functions to block cell death through transcriptional induction of antiapoptotic proteins and inhibits autophagy by activating mTOR [30]. Other study also demonstrated that NF-κB p65 repression contributes to the induction of autophagy [31]. Compound 1 dosedependently reduced the DNA-binding activity of NF-κB, suggesting that compound 1 has been shown to exert its effect via inhibition of NF-κB activation.…”