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Plumbagin, derived from the medicinal plant Plumbago zeylanica, modulates cellular proliferation, carcinogenesis, and radioresistance, all known to be regulated by the activation of the transcription factor NF-κB, suggesting plumbagin might affect the NF-κB activation pathway. We found that plumbagin inhibited NF-κB activation induced by TNF, and other carcinogens and inflammatory stimuli (e.g. phorbol 12-myristate 13-acetate, H2O2, cigarette smoke condensate, interleukin-1β, lipopolysaccharide, and okadaic acid). Plumbagin also suppressed the constitutive NF-κB activation in certain tumor cells. The suppression of NF-κB activation correlated with sequential inhibition of the tumor necrosis factor (TNF)-induced activation of IκBα kinase, lκBα phosphorylation, IκBα degradation, p65 phosphorylation, p65 nuclear translocation, and the NF-κB-dependent reporter gene expression activated by TNF, TNFR1, TRAF2, NIK, IKK-β, and the p65 subunit of NF-κB. Plumbagin also suppressed the direct binding of nuclear p65 and recombinant p65 to the DNA, and this binding was reversed by dithiothreitol both in vitro and in vivo. However, plumbagin did not inhibit p65 binding to DNA when cells were transfected with the p65 plasmid containing cysteine 38 mutated to serine. Plumbagin down-regulated the expression of NF-κB-regulated anti-apoptotic (IAP1, IAP2, Bcl-2, Bcl-xL, cFLIP, Bfl-1/A1, and survivin), proliferative (cyclin D1 and COX-2), and angiogenic (matrix metalloproteinase-9 and vascular endothelial growth factor) gene products. This led to potentiation of apoptosis induced by TNF and paclitaxel and inhibited cell invasion. Overall, our results indicate that plumbagin is a potent inhibitor of the NF-κB activation pathway that leads to suppression of NF-κB-regulated gene products. This may explain its cell growth modulatory, anticarcinogenic, and radiosensitizing effects previously described. [ABSTRACT FROM AUTHOR]

Compounds isolated from members of the Zingiberaceae family are traditionally used as a medicine against inflammatory diseases, but little is known about the mechanism. Here, we report the isolation and structural identification of coronarin D [E-labda-8(17),12-diene-15-ol], a labdane-type diterpene, from Hedychium coronarium and delineate its mechanism of action. Because the transcription factor nuclear factor-kappaB (NF-kappaB) is a key mediator of inflammation, apoptosis, invasion, and osteoclastogenesis, we investigated the effect of coronarin D on NF-kappaB activation pathway, NF-kappaB-regulated gene products, and NF-kappaB-regulated cellular responses. The coronarin D inhibited NF-kappaB activation induced by different inflammatory stimuli and carcinogens. This labdane also suppressed constitutive NF-kappaB activity in different cell lines and inhibited IkappaBalpha kinase activation, thus leading to the suppression of IkappaBalpha phosphorylation, degradation, p65 nuclear translocation, and reporter gene transcription. Coronarin D also inhibited the NF-kappaB-regulated gene products involved in cell survival (inhibitor of apoptosis protein 1, Bcl-2, survivin, and tumor necrosis factor receptor-associated factor-2), proliferation (c-myc, cyclin D1, and cyclooxygenase-2), invasion (matrix metalloproteinase-9), and angiogenesis (vascular endothelial growth factor). Suppression of these gene products by the diterpene enhanced apoptosis induced by TNF and chemotherapeutic agents, suppressed TNF-induced cellular invasion, and abrogated receptor activator of NF-kappaB ligand-induced osteoclastogenesis. Coronarin D was found to be more potent than its analogue coronarin D acid. Overall, our results show that coronarin D inhibited NF-kappaB activation pathway, which leads to inhibition of inflammation, invasion, and osteoclastogenesis, as well as potentiation of apoptosis.

Recent statistics indicate that the overall cancer incidence in the United States, in spite of billions of dollars spent on research each year, has not changed significantly in the last half-century. Cancers of the prostate, breast, lung, and colon, although most common in the Western world, are least common in the Eastern world. Allopathic medicine commonly practiced currently is only 100 years old. Although traditional medicine has been around for thousands of years, no integration exists between it and allopathic medicine. Ayurveda, the science of long life and one of the most ancient medical systems still practiced on the Indian subcontinent, can be used in combination with modern medicine to provide better treatment of cancer. This review focuses on the ayurvedic concept of the causes of cancer and its linkage with inflammation, diagnosis, prevention, and treatment. How ayurvedic medicine can be integrated with allopathic medicine is also discussed in this review.

Zyflamend, a polyherbal preparation, was designed based on constituents that exhibit antiproliferative, antiinflammatory, antioxidant, antiangiogenic, and apoptotic activities through a mechanism that is not well defined. Because the nuclear factor (NF)-kappaB has been shown to regulate proliferation, invasion, and metastasis of tumor cells, we postulated that Zyflamend modulates the activity of NF-kappa B. To test this hypothesis, we examined the effect of this preparation on NF-kappaB and NF-kappaB-regulated gene products. We found that Zyflamend inhibited receptor activator of NF-kappa B ligand-induced osteoclastogenesis, suppressed tumor necrosis factor (TNF)-induced invasion, and potentiated the cytotoxicity induced by TNF and chemotherapeutic agents, all of which are known to require NF-kappa B activation. Zyflamend suppressed NF-kappa B activation induced by both TNF and cigarette smoke condensate. The expression of NF-kappa B-regulated gene products involved in antiapoptosis (inhibitor-of-apoptosis protein 1/2, Bcl-2, Bcl-xL, FADD-like interleukin-1betaconverting enzyme/caspase-8 inhibitory protein, TNF receptor-associated factor-1, and survivin) and angiogenesis (vascular endothelial growth factor, cyclooxygenase-2, intercellular adhesion molecule, and matrix metalloproteinase-9) was also down-regulated by Zyflamend. This correlated with potentiation of cell death induced by TNF and chemotherapeutic agents. Overall, our results indicate that Zyflamend suppresses osteoclastogenesis, inhibits invasion, and potentiates cytotoxicity through down-regulation of NF-kappa B activation and NF-kappa B-regulated gene products.

Silymarin consists of a family of flavonoids (silybin, isosilybin, silychristin, silydianin and taxifoline) commonly found in the dried fruit of the milk thistle plant Silybum marianum. Although silymarin's role as an antioxidant and hepatoprotective agent is well known, its role as an anticancer agent has begun to emerge. Extensive research within the last decade has shown that silymarin can suppress the proliferation of a variety of tumor cells (e.g., prostate, breast, ovary, colon, lung, bladder); this is accomplished through cell cycle arrest at the G1/S-phase, induction of cyclin-dependent kinase inhibitors (such as p15, p21 and p27), down-regulation of anti-apoptotic gene products (e.g., Bcl-2 and Bcl-xL), inhibition of cell-survival kinases (AKT, PKC and MAPK) and inhibition of inflammatory transcription factors (e.g., NF-kappaB). Silymarin can also down-regulate gene products involved in the proliferation of tumor cells (cyclin D1, EGFR, COX-2, TGF-beta, IGF-IR), invasion (MMP-9), angiogenesis (VEGF) and metastasis (adhesion molecules). The antiinflammatory effects of silymarin are mediated through suppression of NF-kappaB-regulated gene products, including COX-2, LOX, inducible iNOS, TNF and IL-1. Numerous studies have indicated that silymarin is a chemopreventive agent in vivo against a variety of carcinogens/tumor promoters, including UV light, 7,12-dimethylbenz(a)anthracene (DMBA), phorbol 12-myristate 13-acetate (PMA) and others. Silymarin has also been shown to sensitize tumors to chemotherapeutic agents through down-regulation of the MDR protein and other mechanisms. It binds to both estrogen and androgen receptors, and down-regulates PSA. In addition to its chemopreventive effects, silymarin exhibits antitumor activity against human tumors (e.g., prostate and ovary) in rodents. Various clinical trials have indicated that silymarin is bioavailable and pharmacologically safe. Studies are now in progress to demonstrate the clinical efficacy of silymarin against various cancers.

Purpose: Deoxyelephantopin (ESD) and isodeoxyelephantopin (ESI) are two sesquiterpene lactones derived from the medicinal plant Elephantopus scaber Linn. (Asteraceae). Although they are used for the treatment of a wide variety of proinflammatory diseases, very little is known about their mechanism of action. Because most genes that control inflammation are regulated by activation of the transcription factor nuclear factor-kappaB (NF-kappaB), we postulated that ESD and ESI mediate their activities through modulation of the NF-kappaB activation pathway., Experimental Design: We investigated the effect of ESI and ESD on NF-kappaB activation by electrophoretic mobility shift assay and NF-kappaB-regulated gene expression by Western blot analysis., Results: We found that ESI suppressed NF-kappaB activation induced by a wide variety of inflammatory agents, including tumor necrosis factor (TNF), interleukin-1beta, phorbol 12-myristate 13-acetate, and lipopolysaccharide. The suppression was not cell type specific, and both inducible and constitutive NF-kappaB activation was blocked. ESI did not interfere with the binding of NF-kappaB to DNA but rather inhibited IkappaBalpha kinase, IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 phosphorylation, and subsequent p65 nuclear translocation. ESI also suppressed the expression of TNF-induced NF-kappaB-regulated, proliferative, antiapoptotic, and metastatic gene products. These effects correlated with enhancement of apoptosis induced by TNF and suppression of TNF-induced invasion and receptor activator of NF-kappaB ligand-induced osteoclastogenesis., Conclusion: Our results indicate that ESI inhibits NF-kappaB activation and NF-kappaB-regulated gene expression, which may explain the ability of ESI to enhance apoptosis and inhibit invasion and osteoclastogenesis.

The plant Withania somnifera Dunal (Ashwagandha), also known as Indian ginseng, is widely used in the Ayurvedic system of medicine to treat tumors, inflammation, arthritis, asthma, and hypertension. Chemical investigation of the roots and leaves of this plant has yielded bioactive withanolides. Earlier studies showed that withanolides inhibit cyclooxygenase enzymes, lipid peroxidation, and proliferation of tumor cells. Because several genes that regulate cellular proliferation, carcinogenesis, metastasis, and inflammation are regulated by activation of nuclear factor-kappaB (NF-kappaB), we hypothesized that the activity of withanolides is mediated through modulation of NF-kappaB activation. For this report, we investigated the effect of the withanolide on NF-kappaB and NF-kappaB-regulated gene expression activated by various carcinogens. We found that withanolides suppressed NF-kappaB activation induced by a variety of inflammatory and carcinogenic agents, including tumor necrosis factor (TNF), interleukin-1beta, doxorubicin, and cigarette smoke condensate. Suppression was not cell type specific, as both inducible and constitutive NF-kappaB activation was blocked by withanolides. The suppression occurred through the inhibition of inhibitory subunit of IkappaB alpha kinase activation, IkappaB alpha phosphorylation, IkappaB alpha degradation, p65 phosphorylation, and subsequent p65 nuclear translocation. NF-kappaB-dependent reporter gene expression activated by TNF, TNF receptor (TNFR) 1, TNFR-associated death domain, TNFR-associated factor 2, and IkappaB alpha kinase was also suppressed. Consequently, withanolide suppressed the expression of TNF-induced NF-kappaB-regulated antiapoptotic (inhibitor of apoptosis protein 1, Bfl-1/A1, and FADD-like interleukin-1beta-converting enzyme-inhibitory protein) and metastatic (cyclooxygenase-2 and intercellular adhesion molecule-1) gene products, enhanced the apoptosis induced by TNF and chemotherapeutic agents, and suppressed cellular TNF-induced invasion and receptor activator of NF-kappaB ligand-induced osteoclastogenesis. Overall, our results indicate that withanolides inhibit activation of NF-kappaB and NF-kappaB-regulated gene expression, which may explain the ability of withanolides to enhance apoptosis and inhibit invasion and osteoclastogenesis.

Osteoclastogenesis is commonly associated with various age-related diseases, including cancer. A member of the tumor necrosis factor superfamily, receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL), has been shown to play a critical role in osteoclast formation and bone resorption. Thus, agents that suppress RANKL signaling have a potential to suppress bone loss. In this report, we investigated the effect of 1'-acetoxychavicol acetate (ACA), a component of Alpina galanga, on RANKL signaling and consequent osteoclastogenesis in RAW 264.7 cells, a murine monocytic cell line. Treatment of these cells with RANKL activated NF-kappaB, and coexposure of the cells to ACA completely suppressed RANKL-induced NF-kappaB activation in a time- and concentration-dependent manner. The suppression of NF-kappaB by ACA was mediated through suppression of RANKL-induced activation of IkappaBalpha kinase, IkappaBalpha phosphorylation, and IkappaBalpha degradation. Furthermore, incubation of monocytic cells with RANKL induced osteoclastogenesis, and ACA suppressed it. Inhibition of osteoclastogenesis was maximal when cells were simultaneously exposed to ACA and RANKL and minimum when ACA was added 2 days after RANKL. ACA also inhibited the osteoclastogenesis induced by human breast cancer MCF-7 cells, multiple myeloma MM1 cells, and head and neck squamous cell carcinoma LICR-LON-HN5 cells. These results indicate that ACA is an effective blocker of RANKL-induced NF-kappaB activation and of osteoclastogenesis induced by RANKL and tumor cells, suggesting its potential as a therapeutic agent for osteoporosis and cancer-associated bone loss.

Because of its ability to suppress tumor cell proliferation, angiogenesis, and inflammation, the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) is currently in clinical trials. How SAHA mediates its effects is poorly understood. We found that in several human cancer cell lines, SAHA potentiated the apoptosis induced by tumor necrosis factor (TNF) and chemotherapeutic agents and inhibited TNF-induced invasion and receptor activator of NF-kappaB ligand-induced osteoclastogenesis, all of which are known to require NF-kappaB activation. These observations corresponded with the down-regulation of the expression of anti-apoptotic (IAP1, IAP2, X chromosome-linked IAP, Bcl-2, Bcl-x(L), TRAF1, FLIP, and survivin), proliferative (cyclin D1, cyclooxygenase 2, and c-Myc), and angiogenic (ICAM-1, matrix metalloproteinase-9, and vascular endothelial growth factor) gene products. Because several of these genes are regulated by NF-kappaB, we postulated that SAHA mediates its effects by modulating NF-kappaB and found that SAHA suppressed NF-kappaB activation induced by TNF, IL-1beta, okadaic acid, doxorubicin, lipopolysaccharide, H(2)O(2), phorbol myristate acetate, and cigarette smoke; the suppression was not cell type-specific because both inducible and constitutive NF-kappaB activation was inhibited. We also found that SAHA had no effect on direct binding of NF-kappaB to the DNA but inhibited sequentially the TNF-induced activation of IkappaBalpha kinase, IkappaBalpha phosphorylation, IkappaBalpha ubiquitination, IkappaBalpha degradation, p65 phosphorylation, and p65 nuclear translocation. Furthermore, SAHA inhibited the NF-kappaB-dependent reporter gene expression activated by TNF, TNFR1, TRADD, TRAF2, NF-kappaB-inducing kinase, IkappaBalpha kinase, and the p65 subunit of NF-kappaB. Overall, our results indicated that NF-kappaB and NF-kappaB-regulated gene expression inhibited by SAHA can enhance apoptosis and inhibit invasion and osteoclastogenesis.

Acetyl-11-keto-beta-boswellic acid (AKBA), a component of an Ayurvedic therapeutic plant Boswellia serrata, is a pentacyclic terpenoid active against a large number of inflammatory diseases, including cancer, arthritis, chronic colitis, ulcerative colitis, Crohn's disease, and bronchial asthma, but the mechanism is poorly understood. We found that AKBA potentiated the apoptosis induced by TNF and chemotherapeutic agents, suppressed TNF-induced invasion, and inhibited receptor activator of NF-kappaB ligand-induced osteoclastogenesis, all of which are known to require NF-kappaB activation. These observations corresponded with the down-regulation of the expression of NF-kappaB-regulated antiapoptotic, proliferative, and angiogenic gene products. As examined by DNA binding, AKBA suppressed both inducible and constitutive NF-kappaB activation in tumor cells. It also abrogated NF-kappaB activation induced by TNF, IL-1beta, okadaic acid, doxorubicin, LPS, H2O2, PMA, and cigarette smoke. AKBA did not directly affect the binding of NF-kappaB to the DNA but inhibited sequentially the TNF-induced activation of IkappaBalpha kinase (IKK), IkappaBalpha phosphorylation, IkappaBalpha ubiquitination, IkappaBalpha degradation, p65 phosphorylation, and p65 nuclear translocation. AKBA also did not directly modulate IKK activity but suppressed the activation of IKK through inhibition of Akt. Furthermore, AKBA inhibited the NF-kappaB-dependent reporter gene expression activated by TNFR type 1, TNFR-associated death domain protein, TNFR-associated factor 2, NF-kappaB-inducing kinase, and IKK, but not that activated by the p65 subunit of NF-kappaB. Overall, our results indicated that AKBA enhances apoptosis induced by cytokines and chemotherapeutic agents, inhibits invasion, and suppresses osteoclastogenesis through inhibition of NF-kappaB-regulated gene expression.

Bone resorption is commonly associated with aging and with certain types of cancer, including multiple myeloma and breast cancer. What induces bone resorption is not fully understood, but the role of osteoclasts is well established. Recently, receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL), a member of the tumor necrosis factor superfamily, was implicated as a major mediator of bone resorption, suggesting that agents that can suppress RANKL signaling have the potential to inhibit bone resorption or osteoclastogenesis. Guggulsterone [4,17(20)-pregnadiene-3,16-dione], isolated from the guggul tree Commiphora mukul and used to treat osteoarthritis and bone fractures, was recently shown to antagonize the farnesoid X receptor, decrease the expression of bile acid-activated genes, and suppress the NF-kappaB activation induced by various carcinogens. We investigated whether guggulsterone could modulate RANKL signaling and osteoclastogenesis induced by RANKL or tumor cells. We found that treatment of monocytes with guggulsterone suppressed RANKL-activated NF-kappaB activation (as indicated by gel-shift assay) and that this suppression correlated with inhibition of IkappaBalpha kinase and phosphorylation and degradation of IkappaBalpha, an inhibitor of NF-kappaB. Guggulsterone also suppressed the differentiation of monocytes to osteoclasts in a dose-dependent and time-dependent manner. Suppression of osteoclastogenesis by the NF-kappaB-specific inhibitory peptide implies a link between NF-kappaB and osteoclastogenesis. Finally, differentiation to osteoclasts induced by coincubating human breast tumor cells (MDA-MB-468) or human multiple myeloma (U266) cells with monocytes was also completely suppressed by guggulsterone. Collectively, our results indicate that guggulsterone suppresses RANKL and tumor cell-induced osteoclastogenesis by suppressing the activation of NF-kappaB.

1'-Acetoxychavicol acetate (ACA), extracted from rhizomes of the commonly used ethno-medicinal plant Languas galanga, has been found to suppress chemical- and virus-induced tumor initiation and promotion through a poorly understood mechanism. Because several genes that regulate cellular proliferation, carcinogenesis, metastasis, and survival are regulated by activation of the transcription factor NF-kappaB, we postulated that ACA might mediate its activity through modulation of NF-kappaB activation. For this report, we investigated the effect of ACA on NF-kappaB and NF-kappaB-regulated gene expression activated by various carcinogens. We found that ACA suppressed NF-kappaB activation induced by a wide variety of inflammatory and carcinogenic agents, including TNF, IL-1beta, PMA, LPS, H(2)O(2), doxorubicin, and cigarette smoke condensate. Suppression was not cell type specific, because both inducible and constitutive NF-kappaB activations were blocked by ACA. ACA did not interfere with the binding of NF-kappaB to the DNA, but, rather, inhibited IkappaBalpha kinase activation, IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 phosphorylation, and subsequent p65 nuclear translocation. ACA also inhibited NF-kappaB-dependent reporter gene expression activated by TNF, TNFR1, TNFR-associated death domain protein, TNFR-associated factor-2, and IkappaBalpha kinase, but not that activated by p65. Consequently, ACA suppressed the expression of TNF-induced NF-kappaB-regulated proliferative (e.g., cyclin D1 and c-Myc), antiapoptotic (survivin, inhibitor of apoptosis protein-1 (IAP1), IAP2, X-chromosome-linked IAP, Bcl-2, Bcl-x(L), Bfl-1/A1, and FLIP), and metastatic (cyclooxygenase-2, ICAM-1, vascular endothelial growth factor, and matrix metalloprotease-9) gene products. ACA also enhanced the apoptosis induced by TNF and chemotherapeutic agents and suppressed invasion. Overall, our results indicate that ACA inhibits activation of NF-kappaB and NF-kappaB-regulated gene expression, which may explain the ability of ACA to enhance apoptosis and inhibit invasion.

The inducible transcription factor nuclear factor-kappa B (NF-kappaB) plays a central role in regulation of many immune, inflammatory and carcinogenic responses. While normal activation of NF-kappaB is required for cell survival and immunity, aberrant regulation of NF-kappaB leads to development of many pathological states especially those involved in acute inflammation. Recent advances in our knowledge of the signaling mechanisms those control the activation of NF-kappaB highlights the intriguing aspect of NF-kappaB regulation, namely the ability of many different signal transduction pathways originating from a wide variety of inducing mechanisms to converge on a single target, the NF-kappaB/IkappaB complex. In this review we summarize our current understanding of the NF-kappaB signaling pathways, their role in various cellular responses and the potential of using NF-kappaB as a therapeutic target in modern medicine.

The preventive effects of Shengmai San (SMS), a traditional Chinese herbal medicine (TCM), was studied on cerebral ischemia-reperfusion injury in rats as a model of antioxidant-based composite therapy. Two biochemical indicators of oxidative damage, thiobarbituric acid reactive substance (TBARS) formation and glutathione peroxidase (GPX) loss were measured in the brain after forebrain ischemia-reperfusion treatment and both were inhibited in all rats administered SMS (15 g original herbs/kg) 2 h before the ischemia-reperfusion. Histochemical study of the brain slice using TTC staining revealed that the SMS effectively reduced infarct area caused by the cerebral ischemia-reperfusion. The antioxidant potentials of SMS preparations were determined in vitro by five different assay methods and were related to the in vivo effectiveness of SMS in protection against brain damage. Inhibitory effect on TBARS formation in vivo showed better correlation with superoxide radical scavenging and DPPH quenching activity in vitro rather than with the other in vitro antioxidant indicators. On the other hand, the in vivo prevention of GPX activity loss showed better correlation with in vitro crocin bleaching inhibition than with the other in vitro antioxidant indicators. It was also suggested that the in vitro TBARS inhibitory activty of SMS is not a good indication to predict the in vivo effectiveness of SMS on inhibition of either TBARS formation or GPX activity loss.