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1.  Delivery of anti-inflammatory nutraceuticals by nanoparticles for the prevention and treatment of cancer 
Biochemical pharmacology  2010;80(12):1833-1843.
Extensive research within the last two decades has revealed that most chronic illnesses, including cancer, diabetes, and cardiovascular and pulmonary diseases, are mediated through chronic inflammation. Thus, suppressing chronic inflammation has the potential to delay, prevent, and even treat various chronic diseases, including cancer. Various nutraceuticals from fruits, vegetables, vitamins, spices, legumes, and traditional Chinese and Ayurvedic medicine have been shown to safely suppress proinflammatory pathways; however, their low bioavailability in vivo limits their use in preventing and treating cancer. We describe here the potential of nanotechnology to fill this gap. Several nutraceuticals, including curcumin, green tea polyphenols, coenzyme Q, quercetin, thymoquinone and others, have been packaged as nanoparticles and proven to be useful in “nano-chemoprevention” and “nano-chemotherapy.”
PMCID: PMC2974020  PMID: 20654584
Inflammation; diabetes; cancer; NF-κB; curcumin; nutraceuticals; nanotechnology
2.  Nimbolide, a Limonoid Triterpene, Inhibits Growth of Human Colorectal Cancer Xenografts by Suppressing the Proinflammatory Microenvironment 
Extensive research over the past decade has revealed that the proinflammatory microenvironment plays a critical role in the development of colorectal cancer (CRC). Whether nimbolide, a limonoid triterpene, can inhibit the growth of CRC was investigated in the present study.
Experimental Design
The effect of nimbolide on proliferation of CRC cell lines was examined by MTT assay, apoptosis by caspase activation and poly-ADP ribose polymerase cleavage, nuclear factor-kappa B (NF-kB) activation by DNA-binding assay, and protein expression by Western blotting. The effect of nimbolide on the tumor growth in vivo was examined in CRC xenografts in a nude mouse model.
Nimbolide inhibited proliferation, induced apoptosis, and suppressed NF-κB activation and NF-κB–regulated tumorigenic proteins in CRC cells. The suppression of NF-κB activation by nimbolide was caused by sequential inhibition of IκB kinase (IKK) activation, IκBα phosphorylation, and p65 nuclear translocation. Furthermore, the effect of nimbolide on IKK activity was found to be direct. In vivo, nimbolide (at 5 and 20 mg/kg body weight), injected intraperitoneally after tumor inoculation, significantly decreased the volume of CRC xenografts. The limonoid-treated xenografts exhibited significant down-regulation in the expression of proteins involved in tumor cell survival (Bcl-2, Bcl-xL, c-IAP-1, survivin, Mcl-1), proliferation (c-Myc, cyclin D1), invasion (MMP-9, ICAM-1), metastasis (CXCR4), and angiogenesis (VEGF). The limonoid was found to be bioavailable in the blood plasma and tumor tissues of treated mice.
Our studies provide evidence that nimbolide can suppress the growth of human CRC through modulation of the proinflammatory microenvironment.
PMCID: PMC4220790  PMID: 23766363
Colorectal cancer; Inflammation; Limonoid; Nimbolide; NF-κB
3.  Curcumin: an orally bioavailable blocker of TNF and other pro-inflammatory biomarkers 
British Journal of Pharmacology  2013;169(8):1672-1692.
TNFs are major mediators of inflammation and inflammation-related diseases, hence, the United States Food and Drug Administration (FDA) has approved the use of blockers of the cytokine, TNF-α, for the treatment of osteoarthritis, inflammatory bowel disease, psoriasis and ankylosis. These drugs include the chimeric TNF antibody (infliximab), humanized TNF-α antibody (Humira) and soluble TNF receptor-II (Enbrel) and are associated with a total cumulative market value of more than $20 billion a year. As well as being expensive ($15 000–20 000 per person per year), these drugs have to be injected and have enough adverse effects to be given a black label warning by the FDA. In the current report, we describe an alternative, curcumin (diferuloylmethane), a component of turmeric (Curcuma longa) that is very inexpensive, orally bioavailable and highly safe in humans, yet can block TNF-α action and production in in vitro models, in animal models and in humans. In addition, we provide evidence for curcumin's activities against all of the diseases for which TNF blockers are currently being used. Mechanisms by which curcumin inhibits the production and the cell signalling pathways activated by this cytokine are also discussed. With health-care costs and safety being major issues today, this golden spice may help provide the solution.
Linked Articles
This article is part of a themed section on Emerging Therapeutic Aspects in Oncology. To view the other articles in this section visit
PMCID: PMC3753829  PMID: 23425071
bioavailability; chronic diseases; curcumin; inflammation; TNF blockers; TNF
5.  ERRATUM: Author-Reported Correction of Western Blot Data: Kim JH, Park B, Gupta SC, Kannappan R, Sung B, and Aggarwal BB. Antioxid Redox Signal 16:413–427, 2012 
Antioxidants & Redox Signaling  2013;18(2):219-220.
This is a non-peer-reviewed author-reported erratum addressing that Zyflamend sensitizes tumor cells to TRAIL-induced apoptosis through upregulation of death receptors and downregulation of survival proteins: role of reactive oxygen species-dependent CCAAT/enhancer-binding protein–homologous protein pathway. Kim JH, Park B, Gupta SC, Kannappan R, Sung B, and Aggarwal BB. Antioxid Redox Signal 16:413–427, 2012. The authors claim that Figure 7 reporting Western blot data was erroneous. Specifically, the β-actin panel of Fig. 7B was found to be switched with that of Fig. 7D. The corrected version is reported here. The authors claim that this correction does not influence the conclusion of the study.
PMCID: PMC3513985
6.  Recent Developments in Delivery, Bioavailability, Absorption and Metabolism of Curcumin: the Golden Pigment from Golden Spice 
Curcumin (diferuloylmethane) is a yellow pigment present in the spice turmeric (Curcuma longa) that has been associated with antioxidant, anti-inflammatory, anticancer, antiviral, and antibacterial activities as indicated by over 6,000 citations. In addition, over one hundred clinical studies have been carried out with curcumin. One of the major problems with curcumin is perceived to be the bioavailability. How curcumin should be delivered in vivo, how bioavailable is it, how well curcumin is absorbed and how it is metabolized, is the focus of this review. Various formulations of curcumin that are currently available are also discussed.
PMCID: PMC3918523  PMID: 24520218
Curcumin; Nano-formulation; Biological availability; Metabolism; Anticancer
7.  Cardamonin Inhibits Osteoclastogenesis Induced by Tumor Cells Through Interruption of the Signaling Pathway Activated by Receptor Activator of NF-κB Ligand 
Cancer letters  2011;10.1016/j.canlet.2011.12.011.
Bone loss/resorption or osteoporosis is a disease that is accelerated with aging and age-associated chronic diseases such as cancer. Bone loss has been associated with human multiple myeloma, breast cancer, and prostate cancer and is usually treated with a bisphosphonate. Because of the numerous side effects of the currently available drugs, the search continues for safe and effective therapies for bone loss. Recently, receptor activator of NF-κB ligand (RANKL), a member of the TNF superfamily, has emerged as a major mediator of bone loss via activation of osteoclastogenesis. We have identified cardamonin, a chalcone first isolated from grass cardamom (Alpinia katsumadai Hayata), that can affect osteoclastogenesis through modulation of RANKL. We found that treatment of monocytes with cardamonin suppressed RANKL-induced NF-κB activation and this suppression correlated with inhibition of IκBα kinase and of phosphorylation and degradation of IκBα, an inhibitor of NF-κB. Cardamonin suppressed the differentiation of monocytes to osteoclasts in a dose-dependent and time-dependent manner. We also found that an NF-κB–specific inhibitory peptide blocked RANKL-induced osteoclastogenesis, indicating a direct link with NF-κB. Finally, osteoclastogenesis induced by human breast cancer cells or human multiple myeloma cells was completely suppressed by cardamonin. Collectively, our results indicate that cardamonin suppresses osteoclastogenesis induced by RANKL and tumor cells by suppressing activation of the NF-κB pathway.
PMCID: PMC3769506  PMID: 22182452
Osteoclastogenesis; RANKL; NF-κB; Cancer; Cardamonin
8.  Zyflamend Suppresses Growth and Sensitizes Human Pancreatic Tumors to Gemcitabine in an Orthotopic Mouse Model Through Modulation of Multiple Targets 
Agents that can potentiate the efficacy of standard chemotherapy against pancreatic cancer are of great interest. Because of their low cost and safety, patients commonly use a variety of dietary supplements, although evidence of their efficacy is often lacking. One such commonly used food supplement, Zyflamend, is a polyherbal preparation with potent anti-inflammatory activities, and preclinical efficacy against prostate and oral cancer. Whether Zyflamend has any efficacy against human pancreatic cancer alone or in combination with gemcitibine, a commonly used agent, was examined in cell cultures and in an orthotopic mouse model. In vitro, Zyflamend inhibited the proliferation of pancreatic cancer cell lines regardless of p53 status and also enhanced gemcitabine-induced apoptosis. This finding correlated with inhibition of NF-κB activation by Zyflamend and suppression of cyclin D1, c-myc, COX-2, Bcl-2, IAP, survivin, VEGF, ICAM-1, and CXCR4. In nude mice, oral administration of Zyflamend alone significantly inhibited the growth of orthotopically transplanted human pancreatic tumors, and when combined with gemcitabine, further enhanced the antitumor effects. Immunohistochemical and Western blot analyses of tumor tissue showed that the suppression of pancreatic cancer growth correlated with inhibition of proliferation index marker (Ki-67), COX-2, MMP-9, NF-κB, and VEGF. Overall, these results suggest that the concentrated multiherb product Zyflamend alone can inhibit the growth of human pancreatic tumors and, in addition, can sensitize pancreatic cancers to gemcitabine through the suppression of multiple targets linked to tumorigenesis.
PMCID: PMC3288649  PMID: 21935918
Zyflamend; pancreatic cancer; inflammation
9.  Evidence for the Critical Roles of NF-κB p65 and Specificity Proteins in the Apoptosis-Inducing Activity of Proteasome Inhibitors in Leukemia Cells 
Biochimica et biophysica acta  2012;10.1016/j.bbadis.2012.01.002.
Although proteasome inhibitors, such as Bortezomib, have been approved for the treatment of multiple myeloma and mantle cell lymphoma, the mechanism by which they induce apoptosis is still incompletely understood. In the present study, we demonstrate that genetic deletion of the NF-κB p65 subunit abolished the ability of Bortezomib to induce apoptosis, indicating that p65 is needed for apoptosis. Although Bortezomib inhibited TNF–induced NF-κB activation through suppression of IκBα degradation, it also induced proteolytic degradation of constitutive NF-κB proteins, including p65, IκBα and p105. These effects were also observed with two other proteasome inhibitors, N-acetyl-leucylleucyl-norleucinal (ALLN) and MG132. The p65 is known to be linked with Specific proteins (Sp), and we found that proteasome inhibition also induced degradation of Sp-1, Sp-3, and Sp-4 proteins. Bortezomib induced apoptosis in cells expressing caspase-3 but not in cells that lack caspase-3, indicating the critical role for this enzyme in the apoptotic action of Bortezomib. Furthermore, inhibition of pan-caspases abolished Bortezomib-induced degradation of p65, p105 and Sp proteins, but not that of IκBα. Overall, our results demonstrate for the first time a critical role for the degradation of NF-κB and Sp proteins by caspases in the apoptosis-inducing activity of proteasome inhibitors, such as Bortezomib.
PMCID: PMC3340479
10.  Upsides and Downsides of Reactive Oxygen Species for Cancer: The Roles of Reactive Oxygen Species in Tumorigenesis, Prevention, and Therapy 
Antioxidants & Redox Signaling  2012;16(11):1295-1322.
Significance: Extensive research during the last quarter century has revealed that reactive oxygen species (ROS) produced in the body, primarily by the mitochondria, play a major role in various cell-signaling pathways. Most risk factors associated with chronic diseases (e.g., cancer), such as stress, tobacco, environmental pollutants, radiation, viral infection, diet, and bacterial infection, interact with cells through the generation of ROS. Recent Advances: ROS, in turn, activate various transcription factors (e.g., nuclear factor kappa-light-chain-enhancer of activated B cells [NF-κB], activator protein-1, hypoxia-inducible factor-1α, and signal transducer and activator of transcription 3), resulting in the expression of proteins that control inflammation, cellular transformation, tumor cell survival, tumor cell proliferation and invasion, angiogenesis, and metastasis. Paradoxically, ROS also control the expression of various tumor suppressor genes (p53, Rb, and PTEN). Similarly, γ-radiation and various chemotherapeutic agents used to treat cancer mediate their effects through the production of ROS. Interestingly, ROS have also been implicated in the chemopreventive and anti-tumor action of nutraceuticals derived from fruits, vegetables, spices, and other natural products used in traditional medicine. Critical Issues: These statements suggest both “upside” (cancer-suppressing) and “downside” (cancer-promoting) actions of the ROS. Thus, similar to tumor necrosis factor-α, inflammation, and NF-κB, ROS act as a double-edged sword. This paradox provides a great challenge for researchers whose aim is to exploit ROS stress for the development of cancer therapies. Future Directions: The various mechanisms by which ROS mediate paradoxical effects are discussed in this article. The outstanding questions and future directions raised by our current understanding are discussed. Antioxid. Redox Signal. 16, 1295–1322.
PMCID: PMC3324815  PMID: 22117137
11.  Boswellic Acid Inhibits Growth and Metastasis of Human Colorectal Cancer in Orthotopic Mouse Model By Downregulating Inflammatory, Proliferative, Invasive, and Angiogenic Biomarkers 
Numerous cancer therapeutics were originally identified from natural products used in traditional medicine. One such agent is acetyl-11-keto-beta-boswellic acid (AKBA), derived from the gum resin of the Boswellia serrata known as Salai guggal or Indian frankincense. Traditionally it has been used in Ayurvedic medicine to treat proinflammatory conditions. In the present report, we hypothesized that AKBA can affect the growth and metastasis of colorectal cancer (CRC) in orthotopically-implanted tumors in nude mice. We found that the oral administration of AKBA (50-200 mg/kg) dose-dependently inhibited the growth of CRC tumors in mice, resulting in decrease in tumor volumes than those seen in vehicle-treated mice without significant decreases in body weight. In addition, we observed that AKBA was highly effective in suppressing ascites and distant metastasis to the liver, lungs, and spleen in orthotopically-implanted tumors in nude mice. When examined for the mechanism, we found that markers of tumor proliferation index Ki-67 and the microvessel density CD31; were significantly downregulated by AKBA treatment. We also found that AKBA significantly suppressed NF-κB activation in the tumor tissue and expression of pro-inflammatory (COX2), tumor survival (bcl-2, bcl-xL, IAP-1, survivin), proliferative (cyclin D1), invasive (ICAM-1, MMP-9) and angiogenic (CXCR4 and VEGF) biomarkers. When examined for serum and tissue levels of AKBA, a dose-dependent increase in the levels of the drug was detected, indicating its bioavailability. Thus, our findings suggest that this boswellic acid analogue can inhibit the growth and metastasis of human CRC in vivo through downregulation of cancer-associated biomarkers.
PMCID: PMC3246525  PMID: 21702037
AKBA; colorectal cancer; NF-κB; growth; metastasis
12.  Age-Associated Chronic Diseases Require Age-Old Medicine: Role of Chronic Inflammation 
Preventive Medicine  2011;54(Suppl):S29-S37.
Most chronic diseases - such as cancer, cardiovascular disease (CVD), Alzheimer disease, Parkinson disease, arthritis, diabetes and obesity - are becoming leading causes of disability and death all over the world. Some of the most common causes of these age-associated chronic diseases are lack of physical activity, poor nutrition, tobacco use, and excessive alcohol consumption. All the risk factors linked to these chronic diseases have been shown to up-regulate inflammation. Therefore, downregulation of inflammation-associated risk factors could prevent or delay these age-associated diseases. Although modern science has developed several drugs for treating chronic diseases, most of these drugs are enormously expensive and are associated with serious side effects and morbidity. In this review, we present evidence on how chronic inflammation leads to age-associated chronic disease. Furthermore, we discuss diet and lifestyle as solutions for age-associated chronic disease.
PMCID: PMC3340492  PMID: 22178471
chronic disease; aging; inflammation; diet; life style
13.  Thiocolchicoside suppresses osteoclastogenesis induced by RANKL and cancer cells through inhibition of inflammatory pathways: a new use for an old drug 
British Journal of Pharmacology  2012;165(7):2127-2139.
Most patients with cancer die not because of the tumour in the primary site, but because it has spread to other sites. Common tumours, such as breast, multiple myeloma, and prostate tumours, frequently metastasize to the bone. To search for an inhibitor of cancer-induced bone loss, we investigated the effect of thiocolchicoside, a semi-synthetic colchicoside derived from the plant Gloriosa superba and clinically used as a muscle relaxant, on osteoclastogenesis induced by receptor activator of NF-κB ligand (RANKL) and tumour cells.
We used RAW 264.7 (murine macrophage) cells, a well-established system for osteoclastogenesis, and evaluated the effect of thiocolchicoside on RANKL-induced NF-κB signalling and osteoclastogenesis as well as on osteoclastogenesis induced by tumour cells.
Thiocolchicoside suppressed osteoclastogenesis induced by RANKL, and by breast cancer and multiple myeloma cells. Inhibition of the NF-κB pathway was responsible for this effect since the colchicoside inhibited RANKL-induced NF-κB activation, activation of IκB kinase (IKK) and suppressed inhibitor of NF-κBα (IκBα) phosphorylation and degradation, an inhibitor of NF-κB. Furthermore, an inhibitor of the IκBα kinase γ or NF-κB essential modulator, the regulatory component of the IKK complex, demonstrated that the NF-κB signalling pathway is mandatory for osteoclastogenesis induced by RANKL.
Together, these data suggest that thiocolchicoside significantly suppressed osteoclastogenesis induced by RANKL and tumour cells via the NF-κB signalling pathway. Thus, thiocolchicoside, a drug that has been used for almost half a century to treat muscle pain, may also be considered as a new treatment for bone loss.
This article is commented on by Micheau et al., pp. 2124–2126 of this issue. To view this commentary visit
PMCID: PMC3413851  PMID: 21955206
thiocolchicoside; osteoclastogenesis; cancer; RANKL; NF-κB
14.  Turmeric (Curcuma longa) inhibits inflammatory nuclear factor (NF)-κB and NF-κB-regulated gene products and induces death receptors leading to suppressed proliferation, induced chemosensitization, and suppressed osteoclastogenesis 
The incidence of cancer is significantly lower in regions where turmeric is heavily consumed. Whether lower cancer incidence is due to turmeric was investigated by examining its effects on tumor cell proliferation, on pro-inflammatory transcription factors NF-κB and STAT3, and on associated gene products.
Methods and results
Cell proliferation and cell cytotoxicity were measured by the MTT method, NF-κB activity by EMSA, protein expression by Western blot analysis, ROS generation by FACS analysis, and osteoclastogenesis by TRAP assay. Turmeric inhibited NF-κB activation and down-regulated NF-κB-regulated gene products linked to survival (Bcl-2, cFLIP, XIAP, and cIAP1), proliferation (cyclin D1 and c-Myc), and metastasis (CXCR4) of cancer cells. The spice suppressed the activation of STAT3, and induced the death receptors (DR)4 and DR5. Turmeric enhanced the production of ROS, and suppressed the growth of tumor cell lines. Furthermore, turmeric sensitized the tumor cells to chemotherapeutic agents capecitabine and taxol. Turmeric was found to be more potent than pure curcumin for cell growth inhibition. Turmeric also inhibited NF-κB activation induced by RANKL that correlated with the suppression of osteoclastogenesis.
Our results indicate that turmeric can effectively block the proliferation of tumor cells through the suppression of NF-κB and STAT3 pathways.
PMCID: PMC3392043  PMID: 22147524
Death receptor; NF-κB; Osteoclastogenesis; STAT3; Turmeric
15.  Zyflamend Sensitizes Tumor Cells to TRAIL-Induced Apoptosis Through Up-Regulation of Death Receptors and Down-Regulation of Survival Proteins: Role of ROS-Dependent CCAAT/Enhancer-Binding Protein-Homologous Protein Pathway 
Antioxidants & Redox Signaling  2012;16(5):413-427.
Aim: TNF (tumor necrosis factor)-related apoptosis-inducing ligand (TRAIL), is a selective killer of tumor cells, although its potential is limited by the development of resistance. In this article, we investigated whether the polyherbal preparation Zyflamend® can sensitize tumor cells to TRAIL. Results: We found that Zyflamend potentiated TRAIL-induced apoptosis in human cancer cells. Zyflamend manifested its effects through several mechanisms. First, it down-regulated the expression of cell survival proteins known to be linked to resistance to TRAIL. Second, Zyflamend up-regulated the expression of pro-apoptotic protein, Bax. Third, Zyflamend up-regulated the expression of death receptors (DRs) for TRAIL. Up-regulation of DRs was critical as gene-silencing of these receptors significantly reduced the effect of Zyflamend on TRAIL-induced apoptosis. The up-regulation of DRs was dependent on CCAAT/enhancer-binding protein-homologous protein (CHOP), as Zyflamend induced CHOP, its gene-silencing abolished the induction of receptors, and mutation of the CHOP binding site on DR5 promoter abolished Zyflamend-mediated DR5 transactivation. Zyflamend mediated its effects through reactive oxygen species (ROS), as ROS quenching reduced its effect. Further, Zyflamend induced DR5 and CHOP and down-regulated the expression of cell survival proteins in nude mice bearing human pancreatic cancer cells. Innovation: Zyflamend can sensitize tumor cells to TRAIL through modulation of multiple cell signaling mechanisms that are linked to ROS. Conclusion: Zyflamend potentiates TRAIL-induced apoptosis through the ROS-CHOP-mediated up-regulation of DRs, increase in pro-apoptotic protein and down-regulation of cell survival proteins. Antioxid. Redox Signal. 16, 413–427.
PMCID: PMC3261028  PMID: 22004570
16.  Discovery of Curcumin, a Component of the Golden Spice, and Its Miraculous Biological Activities 
1. Curcumin is the active ingredient of the dietary spice turmeric and has been consumed for medicinal purposes for thousands of years. Modern science has shown that curcumin modulates various signaling molecules, including inflammatory molecules, transcription factors, enzymes, protein kinases, protein reductases, carrier proteins, cell survival proteins, drug resistance proteins, adhesion molecules, growth factors, receptors, cell-cycle regulatory proteins, chemokines, DNA, RNA, and metal ions.
2. Because of this polyphenol's potential to modulate multiple signaling molecules, it has been reported to possess pleiotropic activities. First shown to have anti-bacterial activity in 1949, curcumin has since been shown to have anti-inflammatory, anti-oxidant, pro-apoptotic, chemopreventive, chemotherapeutic, anti-proliferative, wound healing, anti-nociceptive, anti-parasitic, and anti-malarial properties as well. Animal studies have suggested that curcumin may be active against a wide range of human diseases, including diabetes, obesity, neurologic and psychiatric disorders, and cancer, as well as chronic illnesses affecting the eyes, lungs, liver, kidneys, and gastrointestinal and cardiovascular systems.
3. Although many clinical trials evaluating curcumin's safety and efficacy against human ailments have already been completed, others are still ongoing. Moreover, curcumin is used as a supplement in several countries, including India, Japan, the United States, Thailand, China, Korea, Turkey, South Africa, Nepal, and Pakistan. Although inexpensive, apparently well tolerated, and potentially active, curcumin has yet not been approved for treatment of any human disease.
4. In this article, we discuss the discovery and key biological activities of curcumin, with a particular emphasis on its activities at the molecular, cellular, animal, and human levels.
PMCID: PMC3288651  PMID: 22118895
17.  Cancer and diet: How are they related? 
Free radical research  2011;45(8):864-879.
Extensive research in the past decade has revealed cancer to be a multigenic disease caused by perturbation of multiple cell signalling pathways and dysregulation of numerous gene products, all of which have been linked to inflammation. It is also becoming evident that various lifestyle factors, such as tobacco and alcohol use, diet, environmental pollution, radiation and infections, can cause chronic inflammation and lead to tumourigenesis. Chronic diseases caused by ongoing inflammation therefore require chronic, not acute, treatment. Nutraceuticals, compounds derived from fruits, vegetables, spices and cereals, can be used chronically. This study discusses the molecular targets of some nutraceuticals that happen to be markers of chronic inflammation and how they can prevent or treat cancer. These naturally-occurring agents in the diet have great potential as anti-cancer drugs, thus proving Hippocrates, who proclaimed 25 centuries ago, ‘Let food be thy medicine and medicine be thy food’.
PMCID: PMC3564493  PMID: 21651450
Dietary agents; inflammation; cancer
18.  Cardamonin sensitizes tumour cells to TRAIL through ROS- and CHOP-mediated up-regulation of death receptors and down-regulation of survival proteins 
British Journal of Pharmacology  2012;165(3):741-753.
TNF-related apoptosis-inducing ligand (TRAIL) is currently in clinical trials as a treatment for cancer, but development of resistance is a major drawback. Thus agents that can overcome resistance to TRAIL are urgently needed. Cardamonin (2′,4′-dihydroxy-6′-methoxychalcone) has been shown to affect cell growth by modulating various cell signalling pathways. Hence, we investigated the effect of cardamonin on the actions of TRAIL.
The effect of cardamonin on TRAIL was measured by plasma membrane integrity, phosphatidylserine exposure, mitochondrial activity, and activation of caspase-8, caspase-9, and caspase-3 in human colon cancer cells.
Cardamonin potentiated TRAIL-induced apoptosis and this correlated with up-regulation of both the TRAIL death receptor (DR) 4, 5 at mRNA and protein levels. TRAIL-decoy receptor DcR1 was down-regulated by cardamonin. Induction of DRs by cardamonin occurred in a variety of cell types. Gene silencing of the DRs by small interfering RNA (siRNA) abolished the effect of cardamonin on TRAIL-induced apoptosis, suggesting that sensitization was mediated through the DR. Induction of the DR by cardamonin was p53-independent but required CCAAT/enhancer binding protein homologous protein (CHOP); cardamonin induced CHOP, and its silencing by siRNA eliminated the induction of DR5. Cardamonin increased the production of reactive oxygen species (ROS) and quenching ROS abolished its induction of receptors and enhancement of TRAIL-induced apoptosis. Cardamonin also decreased the expression of various cell survival proteins.
Cardamonin potentiates TRAIL-induced apoptosis through ROS-CHOP-mediated up-regulation of DRs, decreased expression of decoy receptor and cell survival proteins. Thus, cardamonin has the potential to make TRAIL more effective as an anticancer therapy.
PMCID: PMC3315045  PMID: 21797841
Cardamonin; TRAIL; apoptosis; death receptors; ROS
19.  Cancer-linked targets modulated by curcumin 
In spite of major advances in oncology, the World Health Organization predicts that cancer incidence will double within the next two decades. Although it is well understood that cancer is a hyperproliferative disorder mediated through dysregulation of multiple cell signaling pathways, most cancer drug development remains focused on modulation of specific targets, mostly one at a time, with agents referred to as “targeted therapies,” “smart drugs,” or “magic bullets.” How many cancer targets there are is not known, and how many targets must be attacked to control cancer growth is not well understood. Although more than 90% of cancer-linked deaths are due to metastasis of the tumor to vital organs, most drug targeting is focused on killing the primary tumor. Besides lacking specificity, the targeted drugs induce toxicity and side effects that sometimes are greater problems than the disease itself. Furthermore, the cost of some of these drugs is so high that most people cannot afford them. The present report describes the potential anticancer properties of curcumin, a component of the Indian spice turmeric (Curcuma longa), known for its safety and low cost. Curcumin can selectively modulate multiple cell signaling pathways linked to inflammation and to survival, growth, invasion, angiogenesis, and metastasis of cancer cells. More clinical trials of curcumin are needed to prove its usefulness in the cancer setting.
PMCID: PMC3533886  PMID: 23301199
Curcumin; cancer targets
20.  Suppression of pro-inflammatory and proliferative pathways by diferuloylmethane (curcumin) and its analogues dibenzoylmethane, dibenzoylpropane, and dibenzylideneacetone: role of Michael acceptors and Michael donors 
Biochemical pharmacology  2011;82(12):1901-1909.
Curcumin, a diferuloylmethane, has been shown to exhibit anti-inflammatory and anti-proliferative activities. Whereas curcumin has both a Michael acceptor and a Michael donor units, its analogues dibenzoylmethane (DBM, a component of licorice) and dibenzoylpropane (DBP) have a Michael donor but not a Michael acceptor unit, and the analogue dibenzylideneacetone (DBA) has a Michael acceptor unit. In the current report, we investigated the potency of DBM, DBP, and DBA in relation to curcumin for their ability to suppress TNF-induced NF-κB activation, NF-κB-regulated gene products, and cell proliferation. We found that all four agents were active in suppressing NF-κB activation; curcumin was most active and DBM was least active. When examined for its ability to inhibit the direct DNA binding activity of p65, a subunit of NF-κB, only DBP inhibited the binding. For inhibition of TNF-induced IKK activation, DBA was most active. For suppression of TNF-induced expression of NF-κB regulated gene products such as COX-2 (inflammation marker), cyclin D1 (proliferation marker), and VEGF (angiogenesis marker), DBA and curcumin were more active than DBM. Similarly for suppression of proliferation of leukemia (KBM-5), T cell leukemia (Jurkat), prostate (DU145), and breast (MDA-MB-231) cancer cells, curcumin and DBA were most active and DBP was least active. Overall, our results indicate that although curcumin and its analogues exhibit activities to suppress inflammatory pathways and cellular proliferation, a lack of Michael acceptor units in DBM and DBP can reduce their activities.
PMCID: PMC3216474  PMID: 21924245
Curcumin analogues; NF-κB; cell proliferation; Michael acceptor
21.  NF-κB in cancer: A Matter of Life and Death 
Cancer discovery  2011;1(6):469-471.
Activation of NF-κB has been linked to various cellular processes in cancer, including inflammation, transformation, proliferation, angiogenesis, invasion, metastasis, chemoresistance, and radioresistance. Although acute inflammation mediates innate and humoral immunity, chronic inflammation has been linked to tumorigenesis. Thus, inhibition of NF-κB has therapeutic potential in sensitization of tumors to chemotherapeutic agents; however, generalized suppression of NF-κB can result in serious host toxicity with minimum effect on the tumor.
PMCID: PMC3392037  PMID: 22586649
22.  Curcumin suppresses proliferation and induces apoptosis in human biliary cancer cells through modulation of multiple cell signaling pathways 
Carcinogenesis  2011;32(9):1372-1380.
Cholangiocarcinoma (CCA) is a tumor with poor prognosis that is resistant to all currently available treatments. Whether curcumin, a nutraceutical derived from turmeric (Curcuma longa), has potential therapeutic activity against human CCA was investigated using three CCA cell lines (KKU100, KKU-M156 and KKU-M213). Examination of mitochondrial dehydrogenase activity, phosphatidylserine externalization, esterase staining, caspase activation and poly-adenosine diphosphate ribose polymerase cleavage demonstrated that curcumin inhibited proliferation of and induced apoptosis in these biliary cancer cells. Colony-formation assay confirmed the growth-inhibitory effect of curcumin on CCA cells. When examined for the mechanism, curcumin was found to activate multiple cell signaling pathways in these cells. First, all CCA cells exhibited constitutively active nuclear factor (NF)-κB, and treatment with curcumin abolished this activation as indicated by DNA binding, nuclear translocation and p65 phosphorylation. Second, curcumin suppressed activation of signal transducer and activator of transcription-3 as indicated by decreased phosphorylation at both tyrosine705 and serine727 and inhibition of janus kinase-1 phosphorylation. Third, curcumin induced expression of peroxisome proliferator-activated receptor gamma. Fourth, curcumin upregulated death receptors, DR4 and DR5. Fifth, curcumin suppressed the Akt activation pathway. Sixth, curcumin inhibited expression of cell survival proteins such as B-cell lymphoma-2, B-cell leukemia protein xL, X-linked inhibitor of apoptosis protein, c-FLIP, cellular inhibitor of apoptosis protein (cIAP)-1, cIAP-2 and survivin and proteins linked to cell proliferation, such as cyclin D1 and c-Myc. Seventh, the growth inhibitory effect of curcumin was enhanced in the IκB kinase-deficient cells, the enzyme required for nuclear factor-kappaB activation. Overall, our results indicate that curcumin mediates its antiproliferative and apoptotic effects through activation of multiple cell signaling pathways, and thus, its activity against CCA should be further investigated.
PMCID: PMC3165121  PMID: 21325634
23.  Acetyl-11-keto-β-Boswellic Acid Suppresses Invasion of Pancreatic Cancer Cells Through The Downregulation of CXCR4 Chemokine Receptor Expression 
Ninety percent of cancer-mediated deaths are due to metastasis of the tumor, but the mechanisms controlling metastasis remain poorly understood. Thus, no therapy targeting this process has yet been approved. Chemokines and their receptors are mediators of chronic inflammation and have been linked to the metastasis of numerous cancers. More recently, the CXC chemokine receptor 4 (CXCR4) has emerged as a key mediator of tumor metastasis; therefore, identification of inhibitors of this receptor has the potential to abrogate metastasis. In this report, we demonstrate that acetyl-11-keto-β-boswellic acid (AKBA), a component of the therapeutic plant Boswellia serrata, can downregulate CXCR4 expression in pancreatic cancer cells. The reduction in CXCR4 induced by this terpenoid was found to be cell-type specific, as its expression was also abrogated in leukemia, myeloma, and breast cancer cell lines. Neither proteasome inhibitors nor lysosomal stabilization could prevent the AKBA-induced reduction in CXCR4 expression, and downregulation occurred at the transcriptional level. Suppression of CXCR4 by AKBA was accompanied by the inhibition of pancreatic cancer cell invasion, which is induced by CXCL12, the ligand for CXCR4. In addition, abrogation of the expression of chemokine receptor by AKBA was found in human pancreatic tissues from orthotopic animal model. AKBA also abolished breast tumor cell invasion, and this effect correlated with the disappearance of both the CXCR4 mRNA and CXCR4 protein. Overall, our results show that AKBA is a novel inhibitor of CXCR4 expression and, thus, has the potential to suppress the invasion and metastasis of cancer cells.
PMCID: PMC3082612  PMID: 21448932
CXCR4; CXCL12; AKBA; Metastasis
24.  Gambogic Acid Inhibits STAT3 Phosphorylation Through Activation of Protein Tyrosine Phosphatase SHP-1: Potential Role in Proliferation and Apoptosis 
The transcription factor, signal transducer and activator of transcription 3 (STAT3), is associated with proliferation, survival, and metastasis of cancer cells. We investigated whether gambogic acid (GA), a xanthone derived from the resin of traditional Chinese medicine, Gamboge hanburyi (mangosteen), can regulate the STAT3 pathway, leading to suppression of growth and sensitization of cancer cells. We found that GA induced apoptosis in human multiple myeloma cells that correlated with the inhibition of both constitutive and inducible STAT3 activation. STAT3 phosphorylation at both tyrosine residue 705 and serine residue 727 was inhibited by GA. STAT3 suppression was mediated through the inhibition of activation of the protein tyrosine kinases Janus-activated kinase (JAK) 1, and JAK2. Treatment with the protein tyrosine phosphatase (PTP) inhibitor pervanadate reversed the GA-induced down-regulation of STAT3, suggesting the involvement of a PTP. We also found that GA induced the expression of the PTP SHP-1. Deletion of the SHP-1 gene by small interfering RNA suppressed the ability of GA to inhibit STAT3 activation and to induce apoptosis, suggesting the critical role of SHP-1 in its action. Moreover, GA down-regulated the expression of STAT3-regulated antiapoptotic (Bcl-2, Bcl-xL, and Mcl-1), proliferative (cyclin D1), and angiogenic (VEGF) proteins, and this correlated with suppression of proliferation and induction of apoptosis. Overall, these results suggest that GA blocks STAT3 activation, leading to suppression of tumor cell proliferation and induction of apoptosis.
PMCID: PMC3131433  PMID: 21490133
Gambogic acid; STAT3; Apoptosis; Proliferation; Cancer
25.  Epidermal growth factor down-regulates the expression of neutrophil gelatinase-associated lipocalin (NGAL) through E-cadherin in pancreatic cancer cells 
Cancer  2010;117(11):10.1002/cncr.25803.
Our group previously reported that neutrophil gelatinase-associated lipocalin (NGAL) overexpression significantly blocked invasion and angiogenesis of pancreatic ductal adenocarcinoma (PDAC) and also demonstrated a loss of NGAL expression in the advanced stages of PDAC. However, little is known regarding mechanisms of NGAL regulation in PDAC. As EGF-EGFR axis is significantly upregulated in PDAC, we examined EGF-mediated NGAL regulation in these cells.
NGAL-positive AsPC-1 and BxPC-3 cells were used as model system. Quantitative RT-PCR, western blot analysis, and immunofluorescence studies were used to investigate EGF-mediated effects on NGAL expression. E-cadherin expression was manipulated using lentiviral overexpression or shRNA constructs. NGAL promoter activity was assessed by luciferase-reporter assay and electrophoretic mobility shift assay (EMSA).
NGAL expression was positively associated with tumor differentiation and was significantly downregulated after EGF treatment along with a concomitant reduction of E-cadherin expression in PDAC cells. E-cadherin downregulation was partly through the EGF receptor (EGFR)-dependent MEK-ERK signaling pathway. In addition, E-cadherin downregulation reduced NGAL expression in PDAC cells, whereas overexpression of E-cadherin led to increased NGAL expression and partly rescued inhibition of NGAL expression by EGF. Furthermore, EGF in part through E-cadherin reduced NGAL promoter activity by blocking NF-κB activation.
We demonstrated for the first time that EGF potently blocked NGAL expression in PDAC cells. This effect is partly mediated through activation of the EGFR-MEK-ERK signaling pathway, which in turn downregulated E-cadherin with a subsequent reduction in NF-κB activation. Our findings illustrate a novel mechanism by which EGF regulates NGAL expression in PDAC.
PMCID: PMC3134548  PMID: 24048788
neutrophil gelatinase associated lipocalin (NGAL); EGF; E-cadherin; nuclear factor-κB (NF-κB) and pancreatic cancer

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