Abstract Objective To investigate the possible mechanism through which Artemisinin induced apoptosis in pancreatic cell line.
Methods Column chromatography, thin layer chromatography (TLC) and proton NMR spectroscopy were used to purify Artemisinin. The flowcytometry was employed to detect apoptosis and reactive oxygen species (ROS).
Results The results indicated that 50% inhibiting concentration (IC50 value) for pancreatic cell line (RIN) was 45 μmol/L of Artemisinin. Artemisinin had no cytotoxic effect on the growth of peripheral blood lymphocytes. The mechanism of apoptosis was evaluated by measuring intracellular ROS. It was shown that Artemisinin-induced apoptosis occurred independently of the binding of CD95L to CD95 receptor in the RIN cells. Moreover, Artemisinin, in a dose-dependent manner, could significantly increase the level of ROS.
Conclusion Artemisinin can induce apoptosis in the RIN cells via the generation of ROS and triggering the intrinsic pathway of cell death.
Bitter melon juice activates cellular energy sensor AMPactivated protein kinase causing apoptotic death of human pancreatic carcinoma cells
Prognosis of pancreatic cancer is extremely poor, suggesting critical needs for additional drugs to improve disease outcome. Here, we examined efficacy and associated mechanism of a novel agent bitter melon juice (BMJ) against pancreatic carcinoma cells both in culture and nude mice. BMJ anticancer efficacy was analyzed in human pancreatic carcinoma BxPC-3, MiaPaCa-2, AsPC-1 and Capan-2 cells by MTT, cell death ELISA and annexin/PI assays. BMJ effect on apoptosis regulators was assessed by immunoblotting. In vivo BMJ efficacy was evaluated against MiaPaCa-2 tumors in nude mice, and xenograft analyzed for biomarkers by immunohistochemistry (IHC). Results showed that BMJ (2-5% v/v) decreases cell viability in all four pancreatic carcinoma cell lines by inducing strong apoptotic death. At molecular level, BMJ caused caspases activation, altered expression of Bcl2 family members, and cytochrome-c release into the cytosol. Additionally, BMJ decreased survivin and XIAP but increased p21, CHOP and phosphorylated MAPKs (ERK1/2 and p38) levels. Importantly, BMJ activated AMPactivated protein kinase (AMPK); a biomarker for cellular energy status, and an AMPK inhibitor (Compound C) reversed BMJ-induced caspase 3 activation suggesting activated-AMPK involvement in BMJ-induced apoptosis. In vivo, oral administration of lyophilized BMJ (5 mg in 100 µl water/day/mouse) for 6 weeks inhibited MiaPaCa-2 tumor xenograft growth by 60% (p<0.01) without noticeable toxicity in nude mice. IHC analyses of MiaPaCa-2 xenografts showed that BMJ also inhibits proliferation, induces apoptosis and activates AMPK in vivo. Overall, BMJ exerts strong anti-cancer efficacy against human pancreatic carcinoma cells, both in vitro and in vivo, suggesting its clinical usefulness
Abstract Pancreatic cancer remains one of the leading causes of cancer-related deaths, due to aggressive growth, high metastatic rates during the early stage and the lack of an effective therapeutic approach. We previously showed that Qingyihuaji (QYHJ), a seven-herb Chinese medicine formula, exhibited significant anti-cancer effects in pancreatic cancer, associated with modifications in the tumor microenvironment, particularly the inhibition of cancer-associated fibroblast (CAF) activation. In the present study, we generated CAF and paired normal fibroblast (NF) cultures from resected human pancreatic cancer tissues. We observed that CAFs exhibited an enhanced capacity for inducing pancreatic cancer cell migration and invasion compared with NFs, while QYHJ-treated CAFs exhibited decreased migration and invasion-promoting capacities in vitro. The results of further analyses indicated that compared with NFs, CAFs exhibit increased CXCL1, 2 and 8 expression, contributing to the enhanced invasion-promoting capacities of these cells, while QYHJ treatment significantly suppressed CAF proliferation activities and the production of CAF-derived CXCL1, 2 and 8. These in vitro observations were confirmed in mice models of human pancreatic cancer. Taken together, these results suggested that suppressing the tumor-promoting capacity of CAFs through Chinese herbal medicine attenuates pancreatic cancer cell invasion.
Antitumor Effect of Water Decoctions of Taxus Cuspidate on Pancreatic Cancer Chao Qu1,2 and Zhen Chen1,2
1Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
The Taxus cuspidate has been used as a traditional Chinese medicinal herb and considered to affect various physiological functions in the body for thousands of years. As we know that taxol isolated from the Taxus cuspidate has been approved for the treatment of ovarian cancer, it has also shown its antitumor abilities against other kinds of cancers. But the antitumor activity of other components which are free of paclitaxel and hydrophilic paclitaxel derivatives from Taxus cuspidate has not been fully understood. In this study, we investigated the effect of the water decoctions from the leaves of Taxus cuspidate on pancreatic cancer cell proliferation and the potential mechanism(s); though its antitumor activity and mechanism in vitro remain to be elucidated, the water soluble constituents from Taxus cuspidate could be used in clinical for cancer patients.
......According to our results, the water decoction of Taxus cuspidate attenuates the inflammatory activation by downregulating the two important factors, but without affecting the stimulating inflammatory cytokines. In conclusion, traditional Chinese medicine could be used alone, or as an adjuvant in combination with chemotherapeutic drugs for cancer treatment, including Taxus cuspidate. There are many difficulties in studying the molecular mechanisms of water decoction of TCM which are totally different from the extract agent. Though the underlying antitumor mechanisms of water decoction from TCM are still unclear, future studies in vitro will be helpful to uncover it.
Notch-1 down-regulation by curcumin is associated with the inhibition of cell growth and the induction of apoptosis in pancreatic cancer cells. Wang Z, Zhang Y, Banerjee S, Li Y, Sarkar FH.
Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
AbstractBACKGROUND: Notch signaling plays a critical role in maintaining the balance between cell proliferation, differentiation, and apoptosis, and thereby may contribute to the development of pancreatic cancer. Therefore, the down-regulation of Notch signaling may be a novel approach for pancreatic cancer therapy. It has been reported that curcumin down-regulates many genes that are known to promote survival and also up-regulates genes that are known promoters of apoptosis in pancreatic cancer cells in vitro. It also has been reported that there is cross-talk between Notch-1 and another major cell growth and apoptotic regulatory pathway, the nuclear factor kappaB (NF-kappaB) pathway, which is down-regulated by both curcumin and reduction of Notch-1 levels. However, to the authors' knowledge to date, no studies have determined whether the down-regulation of Notch-1 signaling, resulting in the inactivation of NF-kappaB activity, contributes to curcumin-induced cell growth inhibition and apoptosis in pancreatic cancer cells.
METHODS: The authors used multiple molecular approaches, such as the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, an apoptosis assay, gene transfection, real-time reverse transcriptase-polymerase chain reaction analysis, Western blot analysis, and an electrophoretic mobility shift assay to measure the DNA binding activity of NF-kappaB.
RESULTS: Curcumin inhibited cell growth and induced apoptosis in pancreatic cancer cells. Notch-1, Hes-1, and Bcl-XL expression levels concomitantly were down-regulated by curcumin treatment. These results correlated with the inactivation of NF-kappaB activity and increased apoptosis induced by curcumin. The down-regulation of Notch-1 by small-interfering RNA prior to curcumin treatment resulted in enhanced cell growth inhibition and apoptosis.
CONCLUSIONS: The current results provide the first demonstration to the authors' knowledge that the Notch-1 signaling pathway is associated mechanistically with NF-kappaB activity during curcumin-induced cell growth inhibition and apoptosis of pancreatic cells. These results suggest that the down-regulation of Notch signaling by curcumin may be a novel strategy for the treatment of patients with pancreatic cancer.
Abstract Gambogic acid (GA), a potent anticancer agent, is limited in clinical administration due to its poor water solubility. The aim of this study was to explore a drug delivery system based on magnetic Fe3O4 nanoparticles (MNP-Fe3O4) conjugated with GA to increase water solubility of the drug and enhance its chemotherapeutic efficiency for pancreatic cancer.
Methods GA was conjugated with the MNP-Fe3O4 colloidal suspension by mechanical absorption polymerization to construct GA-loaded MNP-Fe3O4, which acted as a drug delivery system.
Results Combination therapy with GA and MNP-Fe3O4 induced remarkable improvement in anticancer activity, which was demonstrated by optical microscopic observations, MTT assay, and nuclear DAPI staining. Furthermore, the possible signaling pathway was explored by Western blot. In Capan-1 pancreatic cancer cells, our observations demonstrated that this strategy could enhance potential anticancer efficiency by inducing apoptosis. The mechanisms of the synergistic effect may be due to reducing protein expression of Bcl-2 and enhancing that of Bax, caspase 9, and caspase 3.
Conclusion These findings demonstrate that a combination of GA and MNPs-Fe3O4 represents a promising approach to the treatment of pancreatic cancer.
Cytotoxicity Effects of Amoora rohituka and chittagonga on Breast and Pancreatic Cancer Cells Leo L. Chan,1 Sherine George,2 Irfan Ahmad,3 Saujanya L. Gosangari,4,5 Atiya Abbasi,6 Brian T. Cunningham,1,2 and Kenneth L. Watkin4,5,7
1Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA 2Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA 3Micro and Nanotechnology Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA 4Bioimaging Science and Technology Group, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA 5College of Applied Health Science, University of Illinois at Urbana-Champaign, Champaign, IL 61820, USA 6Medical Imaging Research Laboratory, Department of Speech and Hearing Science, University of Jllinois at Urbana-Champaign, Urbana, IL 61801, USA 7International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
Abstract Chemotherapeutic agents for cancer are highly toxic to healthy tissues and hence alternative medicine avenues are widely researched. Majority of the recent studies on alternative medicine suggested that Amoora rohituka possesses considerable antitumor and antibacterial properties. In this work, rohituka and chittagonga, fractionated with petroleum ether, dichloromethane, and ethanol, were explored for their anticancer potential against two breast cancer (MCF-7 and HTB-126) and three pancreatic cancer (Panc-1, Mia-Paca2, and Capan1). The human foreskin fibroblast, Hs68, was also included. Cytotoxicity of each extract was analyzed using the MTT assay and label-free photonic crystal biosensor assay. A concentration series of each extract was performed on the six cell lines. For MCF-7 cancer cells, the chittagonga (Pet-Ether and CH2Cl2) and rohituka (Pet-Ether) extracts induced cytotoxicity; the chittagonga (EtoAC) and rohituka (MeOH) extracts did not induce cytotoxicity. For HTB126, Panc-1, Mia-Paca2, and Capan-1 cancer cells, only the chittagonga CH2Cl2 extract showed a significant cytotoxic effect. The extracts were not cytotoxic to normal fibroblast Hs68 cells, which may be correlated to the specificity of Amoora extracts in targeting cancerous cells. Based on these results, further examination of the potential anticancer properties Amoora species and the identification of the active ingredients of these extracts is warranted.
Source : Evidence-Based Complementary and Alternative Medicine Volume 2011 (2011), Article ID 860605, 8 pages doi:10.1155/2011/860605 Link to Full Article
Psorinum Therapy in Treating Stomach, Gall Bladder, Pancreatic, and Liver Cancers: A Prospective Clinical Study Aradeep Chatterjee,1 Jaydip Biswas,2 Ashim Chatterjee,1 Sudin Bhattacharya,2 Bishnu Mukhopadhyay,3 and Syamsundar Mandal2
1Critical Cancer Management Research Centre & Clinic, 381 S K Deb Road, West Bengal, Kolkata 700 048, India 2Chittaranjan National Cancer Institute, Kolkata 700 026, India 3National Institute of Technology, Durgapur 713209, India
We prospectively studied the clinical efficacy of an alternative cancer treatment “Psorinum Therapy” in treating stomach, gall bladder, pancreatic and liver cancers. Our study was observational, open level and single arm. The participants' eligibility criteria included histopathology/cytopathology confirmation of malignancy, inoperable tumor, and no prior chemotherapy or radiation therapy. The primary outcome measures of the study were (i) to assess the radiological tumor response (ii) to find out how many participants survived at least 1 year, 2 years, 3 years, 4 years and finally 5 years after the beginning of the study considering each type of cancer. Psorinum-6x was administered orally to all the participants up to 0.02 ml/Kg body weight as a single dose in empty stomach per day for 2 years along with allopathic and homeopathic supportive cares. 158 participants (42 of stomach, 40 of gall bladder, 44 of pancreatic, 32 of liver) were included in the final analysis of the study. Complete tumor response occurred in 28 (17.72%) cases and partial tumor response occurred in 56 (35.44%) cases. Double-blind randomized controlled clinical trial should be conducted for further scientific exploration of this alternative cancer treatment.
.....The limitation of this study is that it did not have any placebo or treatment control arm; therefore, it cannot be concluded that Psorinum Therapy is effective in improving the survival and the quality of life of the participants due to the academic rigours of the scientific clinical trials. This study also cannot rule out the effects of the implemented allopathic and homeopathic supportive measures in the observed results. However, the results of the study showed a fair number of complete and partial tumor responses along with impressive survival outcomes in difficult to treat cancer types. Therefore, randomized double-blind clinical trial, detailed molecular, pharmacokinetics, and pharmacodynamics studies should be conducted for further scientific exploration of this alternative cancer treatment to determine if it can be integrated into the mainstream oncology.
Source : Evidence-Based Complementary and Alternative Medicine Volume 2011 (2011), Article ID 724743, 7 pages doi:10.1155/2011/724743 LINK TO FULL ARTICLE
Cytotoxicity screening of Bangladeshi medicinal plant extracts on pancreatic cancer cells
Sherine George1, Siddharth V. Bhalerao2, Erich A. Lidstone1, Irfan S. Ahmad3,4, Atiya Abbasi5, Brian T. Cunningham1,2,3, Kenneth L. Watkin3,6*
1Department of Bioengineering, University of Illinois at Urbana Champaign, USA 2Department of Electrical and Computer Engineering, University of Illinois at Urbana Champaign, USA 3Center for Nanoscale Science and Technology, Micro and Nanotechnology Laboratory, University of Illinois at Urbana Champaign, USA 4Agricultural and Biological Engineering, University of Illinois at Urbana Champaign, USA 5International Center for Chemical and Biological Sciences, University of Karachi, Pakistan 6Beckman Institute for Advanced Science and Technology, Bio-Imaging Science and Technology Group, University of Illinois at Urbana Champaign, USA
Pancreatic cancer is the fourth leading cause of cancer-related death in both sexes in the United States . Although Gemcitabine is the current first-line chemotherapeutic administered for metastatic pancreatic cancer, this line of treatment has been met with limited survival and symptomatic outcomes [2, 3] resulting in research interest in exploring new alternatives for treatment and prevention. Natural products play a dominant role in the discovery of such new drugs, as over 60% of approved drugs or those in late stages of development (during 1989-1995) are of natural origin . Examples of clinically useful antitumor agents derived from plants include paclitaxel, vincristine, and camptothecin. Many of these plant-derived anticancer agents have been discovered through large-scale screening programs . Furthermore, the broadreaching support and continuation of studies of plant extracts with implications in pancreatic cancer treatment are indicative of the continued role that natural products play in the drug discovery process [6, 7].
This study provides data on the cytotoxic potential of 56 extracts derived from 44 different plants used in Bangladeshi folk medicine. A three-tiered screening system was designed, in which all extracts were first screened for their ability to induce death in the Panc-1 cell line using a label-free photonic crystal (PC) biosensor assay. These experiments generated biosensor images of attached cells which were used to quantify cell proliferation changes in treated versus untreated cultures. Next, extracts that showed significant cytotoxicity to Panc-1 cells (>80% cell death at a testing concentration of 100 μg/mL) in the PC biosensor assay were tested using a colorimetric MTT assay on two additional pancreatic cell lines (Mia-Paca2, and Capan-1). Toxicity to a normal foreskin Hs68 fibroblast cell line was studied as a control Finally, the extract showing the highest cytotoxicity in all three cancer cell lines was evaluated for its apoptotic activity via a caspase-3 quantification assay.
Methods: 56 extracts of 44 unique medicinal plants were studied. The extracts were screened for cytotoxicity against the pancreatic adenocarcinoma cell line Panc-1, using a label-free biosensor assay. The top cytotoxic extracts identified in this screen were tested on two additional pancreatic cancer cell lines (Mia-Paca2 and Capan-1) and a fibroblast cell line (Hs68) using an MTT proliferation assay. Finally, one of the most promising extracts was studied using a caspase-3 colorimetric assay to identify induction of apoptosis.
Results: Crude extracts of Petunia punctata, Alternanthera sessilis, and Amoora chittagonga showed cytotoxicity to three cancer cell lines with IC50 values ranging between 20.3 – 31.4 μg/mL, 13.08 – 34.9 μg/mL, and 42.8 – 49.8 μg/mL, respectively. Furthermore, treatment of Panc-1 cells with Petunia punctata was shown to increase caspase-3 activity, indicating that the observed cytotoxicity was mediated via apoptosis. Only Amoora chittagonga showed low cytotoxicity to fibroblast cells with an IC50 value > 100 μg/mL.
Conclusion: Based upon the initial screening work reported here, further studies aimed at the identification of active components of these three extracts and the elucidation of their mechanisms as cancer therapeutics are warranted
Apoptosis of human pancreatic cancer cells induced by Triptolide Guo-Xiong Zhou, Xiao-Ling Ding, Jie-Fei Huang, Hong Zhang, Sheng-Bao Wu, Jian-Ping Cheng, and Qun Wei Guo-Xiong Zhou, Xiao-Ling Ding, Jie-Fei Huang, Hong Zhang, Sheng-Bao Wu, Jian-Ping Cheng, Qun Wei, Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, ChinaAuthor contributions: Zhou GX, Ding XL contributed equally to this work; Zhou GX, Ding XL, Huang JF, Zhang H and Wu SB designed research; Ding XL, Zhang H, Wu SB, Cheng JP and Wei Q performed research; Zhou GX, Ding XL and Zhang H analyzed data; Zhou GX and Ding XL wrote the paper.
Pancreatic adenocarcinoma is characterized by a poor prognosis and lack of response to conventional therapy. The incidence has shown that no significant sign of decline throughout the past 20 years and almost equals its mortality[1–3]. The 5-year survival rate for this disease is less than 4% and the median survival time after diagnosis is less than 6 mo[2,3]. Surgical resection of the tumor is still the only effective treatment option, although only 20% of carcinomas of the head of the pancreas are resectable.Furthermore, the median survival even after apparent curative resection is only 20 mo, because of early tumor recurrence or rapid metastatic spread[2,4]. Other treatment options, such as chemotherapy or radiation therapy, provide limited palliation without significant improvement of survival in patients with unresectable pancreatic cancer. Therefore; new targets for chemo-preventive and therapeutic agents need to be identified.Triptolide (TL), extracts of the Chinese herb Tripterygium Wilfordii hook have potent anti-inflammatory and immunosuppressive properties and have been used successfully in traditional Chinese medicine for the treatment of rheumatoid arthritis and lupus erythematosus[5,6]. It has been recently reported that TL possesses anti-tumor and proapoptotic activities in many different tumor cell lines, including breast, prostate, lung, and leukemia cells lines[7–13]. TL was also shown to sensitize cells to death induced by a variety of agents, such as Apo2/Trail, TNF-α, and different chemotherapeutic agents[14–16]. In this study, we provide evidence that TL potently inhibits human pancreatic cancer cell lines growth in vitro, suggesting that TL could be used to prevent or treat pancreatic cancer in the future. Considerable studies indicated that TL functioned through a p53-dependent or independent way[11,14,17,18]. Recently, Bing et al suggested that TL induced caspase-dependent cell death via the mitochondrial pathway in leukemia cells. However, the cellular and molecular mechanisms underlying TL-induced apoptosis in tumor cells are not fully understood.The purpose of this study is to investigate the inhibitory effects of TL on apoptosis and angiogenesis of pancreatic cancer in vitro and further to explore whether TL exerts clinical therapeutic value for patients with pancreatic cancer.
RESULTS: TL inhibited the growth of human pancreatic cancer cells in a dose-and time-dependent manner. TL induced human pancreatic cancer cells to undergo apoptosis with typically apoptotic characteristics. TUNEL assay showed that after the treatment of human pancreatic cancer cells with 40 ng/mL TL for 12 h and 24 h, the apoptotic rates of human pancreatic cancer cells increased significantly. RT-PCR demonstrated that caspase-3 and bax were significantly up-regulated in SW1990 cells treated with TL while bcl-2 mRNA was not.
CONCLUSION: TL is able to induce the apoptosis in human pancreatic cancer cells. This apoptosis may be mediated by up-regulating the expression of apoptosis-associated caspase-3 and bax gene.
Effects of Qingyi Huaji decoction on serum levels of interleukin-6, interleukin-8 and tumor necrosis factor-α in nude mice bearing pancreatic tumours
1. Hua-qiang Ouyang (Department of Integrated Traditional Chinese and Western Medicine, Cancer Hospital, Fudan University, Shanghai 200032, China ) 2. Lu-ming Liu (Department of Integrated Traditional Chinese and Western Medicine, Cancer Hospital, Fudan University, Shanghai 200032, China 3. Zhen Chen (Department of Integrated Traditional Chinese and Western Medicine, Cancer Hospital, Fudan University, Shanghai 200032, China ) 4. Jian-min Luo (Department of Integrated Traditional Chinese and Western Medicine, Cancer Hospital, Fudan University, Shanghai 200032, China ) 5. Er-xin Yu (Department of Integrated Traditional Chinese and Western Medicine, Cancer Hospital, Fudan University, Shanghai 200032, China )
Abstract Objective: To investigate the effects of Qingyi Huaji (QYHJ) decoction, a compound traditional Chinese herbal medicine, on tumor inhibition rate and serum levels of interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor-α (TNF-α) in nude mice with transplanted tumors of human pancreatic cancer.
Methods: The tumor-bearing mice model was established by subcutaneously inoculating with xenografts of pancreatic cancer into the right armpit of 40 BALB/c nude mice. After successful modeling, the mice were randomly divided into untreated group (Arabic gum), capecitabine group, low-dose QYHJ decoction group (36 g/kg) and high-dose QYHJ decoction group (72 g/kg), with 10 mice in each group. Citrate buffer solution (containing 5% Arabic gum), capecitabine suspension and QYHJ decoction were administered to four groups by gavage respectively. After 5-week treatment, the concentrations of serum IL-6, IL-8 and TNF-α were examined by enzyme-linked immunosorbent assay (ELISA) using blood sample from eye socket. Then the mice were euthanized by cervical dislocation. Tumor weight and the tumor inhibition rate were calculated.
Results: Tumor weight in the low-dose QYHJ decoction group decreased significantly as compared with the untreated group (P<0.05). Serum levels of IL-6 and TNF-α in low- and high-dose QYHJ groups were extremely significantly lower than those in the untreated group (P<0.01). Serum level of IL-8 in the low-dose QYHJ group was significantly lower than that in the untreated group (P<0.05). Correlation analysis showed that transplanted tumor weight of the mice was linearly positively correlated with serum levels of IL-6, IL-8 or TNF-α (P<0.01).
Conclusion: Conventional dose of QYHJ decoction is effective in suppressing pancreatic carcinoma in nude mice. The mechanism may be related to down-regulation of serum cytokines such as IL-6, IL-8 and TNF-α.
Source: Journal of Chinese Integrative Medicine: 2010; 8(7): 655-661 DOI: 10.3736/jcim20100709 LINK TO FULL ARTICLE
Phase II Trial of Curcumin in Patients with Advanced Pancreatic Cancer
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-κB (NF-κB) 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-κB and cyclooxygenase-2 were monitored.
Results: Twenty-five patients were enrolled, with 21 evaluable 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-κB, 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 41 ng/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.