Wogonin sensitizes resistant malignant cells to TNFα- and TRAIL-induced apoptosis

Abstract

TNF␣ has previously been used in anticancer therapy. However, the therapeutic application of TNF␣ was largely limited due to its general toxicity and the fact that it activates the NF-B-family transcription factors, which are proinflammatory and antiapoptotic. To overcome this problem in vitro, specific NF-B inhibitors or transcription or protein synthesis inhibitors such as actinomycin D and cycloheximide are usually used in combination to increase TNF␣ killing of tumor cells. However, these agents also cause harmful side effects in vivo. We show here that wogonin, derived from the popular Chinese herb Huang-Qin, attenuates NF-B activity by shifting TNF␣-induced free radical ⅐O 2 ؊ to a more reduced nonradical product, H 2 O 2 , and thereby sensitizes TNF␣-resistant leukemia cells to TNF␣-induced apoptosis. Importantly, wogonin does not affect the viability of normal IntroductionTumor necrosis factor-alpha (TNF␣) was isolated in 1985 as the first mammalian protein with cytotoxicity to tumor cells and that induced tumor regression in mice. 1 It is now known that TNF signaling may either induce cellular activation, apoptosis, or necrosis. 2 TNF␣ was thought to be a potent anticancer agent due to its cytotoxicity against a number of tumor cell lines. However, the clinical use of TNF␣ is limited because of its systemic toxicity largely due to activation of the proinflammatory NF-B-family transcription factors. 3-5 NF-B, apart from its proinflammatory activity, is also a negative regulator that antagonizes TNF␣-induced killing. 4,6 Clinically, the only success in TNF␣ therapy has occurred with isolated limb perfusion for a limited subset of susceptible tumors, such as melanoma and sarcoma. 7 In general, TNF␣ is considered a key inducer of proinflammatory genes, and its primary role is to stimulate innate inflammatory responses to fight infections, whereas the function of its proapoptotic capability remains mysterious. 8 Apoptosis involves 2 main pathways: the extrinsic pathway, which is initiated by binding of ligands to specific death receptors on the cell surface, and the intrinsic pathway, which is initiated at the mitochondria. TNF␣ is an inducer of the extrinsic pathway. In mammalians, TNF␣ signals through 2 distinct receptors, TNF receptor 1 (TNF-R1), the primary receptor for soluble TNF␣, and TNF-R2, the main receptor for membrane-associated TNF␣. 5,9 The TNF-R1 signaling pathway can either trigger activation of NF-Bcrucial for TNF␣-mediated immunity, inflammation, and proliferation-or activation of apical caspases as well as the c-Jun-N-terminal kinase (JNK) cascade, which leads to programmed cell death. 2 TNF-R1 signaling can be divided into 2 distinct stages that sequentially activate NF-B and apical caspases. Within a few minutes after binding of TNF␣ to TNF-R1 (stage 1), a signaling complex containing the receptor itself and the adaptor proteins TRADD, TRAF2, and RIP1 but lacking the FAS/APO-1-associated death domain adaptor protein FADD forms and transduces signals that lead to activation of NF-B and t...

Infiltrating Macrophages Are Key to the Development of Seizures following Virus Infection

“…Whether wogonin targets activated TMEV-specific T cells is not known; however, due to the low concentration of wogonin administered, a certain percentage of activated TMEV-specific T cells may escape targeting and be sufficient for viral clearance. These results are in agreement with previous reports that demonstrated wogonin specifically targeted activated cells and not resting immune cells (36,53). Therefore, wogonin-treated mice are able to clear TMEV, even though wogonin inhibits activated macrophages.…”

“…The natural root extract wogonin and the antibiotic minocycline were used to inhibit macrophage activity. Wogonin has antioxidant properties and can induce apoptosis of cells that have been previously sensitized by TNF-␣ (36,37). Minocycline has anti-inflammatory properties that lead to lower CNS excitability (38).…”

Combination of wogonin and sorafenib effectively kills human hepatocellular carcinoma cells through apoptosis potentiation and autophagy inhibition

“…Multiple naturally occurring compounds from diets or medicinal plants can modulate different cellular survival pathways, thus potentiating the anticancer activity of drugs used in anticancer therapy (23,24). One of such compounds is wogonin (5,7-dihydroxy-8-methoxyflavone), a flavonoid derived from the root of the medicinal herb Scutellaria baicalensis Georgi (25). Wogonin has been shown to have antioxidant, antiviral, antithrombotic and anti-inflammatory activities in both in vitro and in vivo studies (26)(27)(28)(29).…”

Signalling Pathways Leading to TRAIL Resistance

“…Besides the use of a broad range of protein inhibitors, chemotherapeutic agents or irradiation to exert synergistic effects with TRAIL action (Mahalingam et al, 2009), more recently the use of natural compounds, including polyphenols, has gained increasing interest due to their relative safety and anti-tumour efficacy in preclinical models (Jacquemin et al, 2010). Actually, it has been demonstrated that a number of natural compounds are able to enhance TRAIL-induced apoptosis in leukaemia cells (Fas et al, 2006;Russo et al, 2007;Hussain et al, 2008;Sung et al 2010). In particular, it has been shown that wogonin, derived from a popular Chinese herb, attenuates NF-B activity (Fas et al, 2006), whereas curcumin, responsible for the yellow colour of the spice turmeric, upregulates TRAIL-R2 expression and inactivates NF-B in a ROS-dependent manner in a number of solid tumours including Burkitt's lymphoma (Hussain et al, 2008).…”

“…Actually, it has been demonstrated that a number of natural compounds are able to enhance TRAIL-induced apoptosis in leukaemia cells (Fas et al, 2006;Russo et al, 2007;Hussain et al, 2008;Sung et al 2010). In particular, it has been shown that wogonin, derived from a popular Chinese herb, attenuates NF-B activity (Fas et al, 2006), whereas curcumin, responsible for the yellow colour of the spice turmeric, upregulates TRAIL-R2 expression and inactivates NF-B in a ROS-dependent manner in a number of solid tumours including Burkitt's lymphoma (Hussain et al, 2008). Moreover, Russo et al (2007) reported that leukaemia cell lines were efficiently sensitized by quercetin and TRAIL co-treatment through the inhibition of the Akt pathway, while Sung et al, 2010 observed other survival proteins down-regulation after TRAIL and triterpenoids co-treatment.…”