Purpose: Pancreatic cancer is almost always lethal, and the only U.S. Food and Drug Administration^approved therapies for it, gemcitabine and erlotinib, produce objective responses in <10% of patients.We evaluated the clinical biological effects of curcumin (diferuloylmethane), a plant-derived dietary ingredient with potent nuclear factor-nB (NF-nB) and tumor inhibitory properties, against advanced pancreatic cancer. Experimental Design: Patients received 8 g curcumin by mouth daily until disease progression, with restaging every 2 months. Serum cytokine levels for interleukin (IL)-6, IL-8, IL-10, and IL-1 receptor antagonists and peripheral blood mononuclear cell expression of NF-nB and cyclooxygenase-2 were monitored. Results:Twenty-five patients were enrolled, with 21evaluable for response. Circulating curcumin was detectable as drug in glucuronide and sulfate conjugate forms, albeit at low steady-state levels, suggesting poor oral bioavailability. Two patients showed clinical biological activity. One had ongoing stable disease for >18 months; interestingly, one additional patient had a brief, but marked, tumor regression (73%) accompanied by significant increases (4-to 35-fold) in serum cytokine levels (IL-6, IL-8, IL-10, and IL-1 receptor antagonists). No toxicities were observed. Curcumin down-regulated expression of NF-nB, cyclooxygenase-2, and phosphorylated signal transducer and activator of transcription 3 in peripheral blood mononuclear cells from patients (most of whom had baseline levels considerably higher than those found in healthy volunteers). Whereas there was considerable interpatient variation in plasma curcumin levels, drug levels peaked at 22 to 41ng/mL and remained relatively constant over the first 4 weeks. Conclusions: Oral curcumin is well tolerated and, despite its limited absorption, has biological activity in some patients with pancreatic cancer.

IntroductionCurcumin is a polyphenolic compound derived from the plant Curcuma Long Lin that has been demonstrated to have antioxidant and anti-inflammatory effects as well as effects on reducing beta-amyloid aggregation. It reduces pathology in transgenic models of Alzheimer's disease (AD) and is a promising candidate for treating human AD. The purpose of the current study is to generate tolerability and preliminary clinical and biomarker efficacy data on curcumin in persons with AD.MethodsWe performed a 24-week randomized, double blind, placebo-controlled study of Curcumin C3 Complex® with an open-label extension to 48 weeks. Thirty-six persons with mild-to-moderate AD were randomized to receive placebo, 2 grams/day, or 4 grams/day of oral curcumin for 24 weeks. For weeks 24 through 48, subjects that were receiving curcumin continued with the same dose, while subjects previously receiving placebo were randomized in a 1:1 ratio to 2 grams/day or 4 grams/day. The primary outcome measures were incidence of adverse events, changes in clinical laboratory tests and the Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) at 24 weeks in those completing the study. Secondary outcome measures included the Neuropsychiatric Inventory (NPI), the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scale, levels of Aβ1-40 and Aβ1-42 in plasma and levels of Aβ1-42, t-tau, p-tau181 and F2-isoprostanes in cerebrospinal fluid. Plasma levels of curcumin and its metabolites up to four hours after drug administration were also measured.ResultsMean age of completers (n = 30) was 73.5 years and mean Mini-Mental Status Examination (MMSE) score was 22.5. One subject withdrew in the placebo (8%, worsened memory) and 5/24 subjects withdrew in the curcumin group (21%, 3 due to gastrointestinal symptoms). Curcumin C3 Complex® was associated with lowered hematocrit and increased glucose levels that were clinically insignificant. There were no differences between treatment groups in clinical or biomarker efficacy measures. The levels of native curcumin measured in plasma were low (7.32 ng/mL).ConclusionsCurcumin was generally well-tolerated although three subjects on curcumin withdrew due to gastrointestinal symptoms. We were unable to demonstrate clinical or biochemical evidence of efficacy of Curcumin C3 Complex® in AD in this 24-week placebo-controlled trial although preliminary data suggest limited bioavailability of this compound.Trial registrationClinicalTrials.gov Identifier: NCT00099710.

Curcumin, a component of turmeric (Curcuma longa), has been shown to exhibit chemopreventive activity. Whether analogs of curcumin (Cur), such as demethoxycurcumin (DMC), bisdemethoxycurcumin (BDMC), tetrahydrocurcumin (THC) and turmerones, modulate inflammatory signaling and cell proliferation signaling to same extent as curcumin was investigated. The results indicate that the relative potency for suppression of tumor necrosis factor (TNF)-induced nuclear factor-kappaB (NF-kappaB) activation was Cur > DMC > BDMC; thus suggesting the critical role of methoxy groups on the phenyl ring. THC, which lacks the conjugated bonds in the central seven-carbon chain, was completely inactive for suppression of the transcription factor. Turmerones also failed to inhibit TNF-induced NF-kappaB activation. The suppression of NF-kappaB activity correlated with inhibition of NF-kappaB reporter activity and with down-regulation of cyclooxygenase-2, cyclin D1 and vascular endothelial growth factor, all regulated by NF-kappaB. In contrast to NF-kappaB activity, the suppression of proliferation of various tumor cell lines by Cur, DMC and BDMC was found to be comparable; indicating the methoxy groups play minimum role in the growth-modulatory effects of curcumin. THC and turmerones were also found to be active in suppression of cell growth but to a much lesser extent than curcumin, DMC and BDMC. Whether suppression of NF-kappaB or cell proliferation, no relationship of any of the curcuminoid was found with reactive oxygen species (ROS) production. Overall, our results demonstrated that different analogs of curcumin present in turmeric exhibit variable anti-inflammatory and anti-proliferative activities, which do not correlate with their ability to modulate the ROS status.

Curcumin has a potent antiproliferative activity and can also potentiate the antitumor effect of gemcitabine. This study was undertaken to evaluate the activity and feasibility of gemcitabine in combination with curcumin in patients with advanced pancreatic cancer. Seventeen patients were enrolled in the study and received 8,000 mg of curcumin by mouth daily, concurrently with gemcitabine 1,000 mg/m(2) IV weekly × 3 of 4 wk; 5 patients (29%) discontinued curcumin after a few days to 2 wk due to intractable abdominal fullness or pain, and the dose of curcumin was reduced to 4,000 mg/day because of abdominal complaints in 2 other patients. One of 11 evaluable patients (9%) had partial response, 4 (36%) had stable disease, and 6 (55%) had tumor progression. Time to tumor progression was 1-12 mo (median 2½), and overall survival was 1-24 mo (median 5). Low compliance for curcumin at a dose of 8,000 mg/day, when taken together with systemic gemcitabine, may prevent the use of high doses of oral curcumin needed to achieve systemic effect. Further studies should be conducted to evaluate the ability of other formulations of curcumin to enhance the effect of chemotherapy in cancer patients.

Ginger, the rhizome of the plant Zingiber officinale, has received extensive attention due to its antioxidant, anti-inflammatory, and anti-tumor activities. Most researchers have considered gingerols as the active principles and have paid little attention to shogaols, the dehydration products of corresponding gingerols during storage or thermal processing. In this study, we have purified and identified eight major components including three major gingerols and corresponding shogaols from ginger extract and compared their anti-carcinogenic and anti-inflammatory activities. Our results showed that shogaols ([6]-, [8]-, and [10]-) had much stronger growth inhibitory effects than gingerols ([6]-, [8]-, and [10]-) on H-1299 human lung cancer cells and HCT-116 human colon cancer cells, especially when comparing [6]-shogaol with [6]-gingerol (IC50: ~8 µM vs. ~150 µM). In addition, we found that [6]-shogaol had much stronger inhibitory effects on arachidonic acid release and nitric oxide (NO) synthesis than [6]-gingerol.

Acetyl-11-keto-β-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-κB ligand-induced osteoclastogenesis, all of which are known to require NF-κB activation. These observations corresponded with the down-regulation of the expression of NF-κB-regulated antiapoptotic, proliferative, and angiogenic gene products. As examined by DNA binding, AKBA suppressed both inducible and constitutive NF-κB activation in tumor cells. It also abrogated NF-κB activation induced by TNF, IL-1β, okadaic acid, doxorubicin, LPS, H2O2, PMA, and cigarette smoke. AKBA did not directly affect the binding of NF-κB to the DNA but inhibited sequentially the TNF-induced activation of IκBα kinase (IKK), IκBα phosphorylation, IκBα ubiquitination, IκBα 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-κB-dependent reporter gene expression activated by TNFR type 1, TNFR-associated death domain protein, TNFR-associated factor 2, NF-κB-inducing kinase, and IKK, but not that activated by the p65 subunit of NF-κB. Overall, our results indicated that AKBA enhances apoptosis induced by cytokines and chemotherapeutic agents, inhibits invasion, and suppresses osteoclastogenesis through inhibition of NF-κB-regulated gene expression.

Pterostilbene, an active constituent of blueberries, is known to possess anti-inflammatory activity and also induces apoptosis in various types of cancer cells. Here, the effects of pterostilbene on cell viability in human gastric carcinoma AGS cells were investigated. This study demonstrated that pterostilbene was able to inhibit cell proliferation and induce apoptosis in a concentration- and time-dependent manner. Pterostilbene-induced cell death was characterized with changes in nuclear morphology, DNA fragmentation, and cell morphology. The molecular mechanism of pterostilbene-induced apoptosis was also investigated. The results show the caspase-2, -3, -8, and -9 are all activated by pterostilbene, together with cleavage of the downstream caspase-3 target DNA fragmentation factor (DFF-45) and poly(ADP-riobse) polymerase. Moreover, the results indicate that the Bcl-family of proteins, the mitochondrial pathway, and activation of the caspase cascade are responsible for pterostilbene-induced apoptosis. Pterostilbene markedly enhanced the expression of growth arrest DNA damage-inducible gene 45 and 153 (GADD45 and GADD153) in a time-dependent manner. Flow cytometric analysis indicated that pterostilbene blocked cell cycle progression at G1 phase in a dose- and time-dependent manner. Pterostilbene increased the p53, p21, p27, and p16 proteins and decreased levels of cyclin A, cyclin E, cyclin-dependent kinase 2 (Cdk2), Cdk4, and Cdk6, but the expression of cyclin D1 was not affected. Over a 24 h exposure to pterostilbene, the degree of phosphorylation of Rb was decreased after 6 h. In summary, pterostilbene induced apoptosis in AGS cells through activating the caspase cascade via the mitochondrial and Fas/FasL pathway, GADD expression, and by modifying cell cycle progress and changes in several cycle-regulating proteins. The induction of apoptosis by pterostilbene may provide a pivotal mechanism of the antitumor effects and for treatment of human gastric cancer.

Pterostilbene, a natural dimethylated analog of resveratrol, is known to have diverse pharmacologic activities including anticancer, anti-inflammation, antioxidant, apoptosis, anti-proliferation and analgesic potential. However, the effects of pterostilbene in preventing invasion of cancer cells have not been studied. Here, we report our finding that pterostilbene significantly suppressed 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced invasion, migration and metastasis of human hepatoma cells (HepG(2) cells). Increase in the enzyme activity, protein and messenger RNA levels of matrix metalloproteinase (MMP)-9 were observed in TPA-treated HepG(2) cells, and these were blocked by pterostilbene. In addition, pterostilbene can inhibit TPA-induced expression of vascular endothelial growth factor, epidermal growth factor and epidermal growth factor receptor. Transient transfection experiments also showed that pterostilbene strongly inhibited TPA-stimulated nuclear factor kappa B (NF-kappaB) and activator protein-1 (AP-1)-dependent transcriptional activity in HepG(2) cells. Moreover, pterostilbene can suppress TPA-induced activation of extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, c-Jun N-terminal kinases 1/2 and phosphatidylinositol 3-kinase/Akt and protein kinase C that are upstream of NF-kappaB and AP-1. Significant therapeutic effects were further demonstrated in vivo by treating nude mice with pterostilbene (50 and 250 mg/kg intraperitoneally) after inoculation with HepG(2) cells into the tail vein. Presented data reveal that pterostilbene is a novel, effective, anti-metastatic agent that functions by downregulating MMP-9 gene expression.