curcumin and Lymphoma--T-Cell

Inhibition of carcinogenesis may be a consequence of attenuation of oxidative stress via activation of antioxidant defence system, restoration and stabilization of tumour suppressor proteins along with modulation of inflammatory mediators. Previously we have delineated significant role of curcumin during its long term effect in regulation of glycolytic pathway and angiogenesis, which in turn results in prevention of cancer via modulation of stress activated genes. Present study was designed to investigate long term effect of curcumin in regulation of Nrf2 mediated phase-II antioxidant enzymes, tumour suppressor p53 and inflammation under oxidative tumour microenvironment in liver of T-cell lymphoma bearing mice. Inhibition of Nrf2 signalling observed during lymphoma progression, resulted in down regulation of phase II antioxidant enzymes, p53 as well as activation of inflammatory signals. Curcumin potentiated significant increase in Nrf2 activation. It restored activity of phase-II antioxidant enzymes like GST, GR, NQO1, and tumour suppressor p53 level. In addition, curcumin modulated inflammation via upregulation of TGF-β and reciprocal regulation of iNOS and COX2. The study suggests that during long term effect, curcumin leads to prevention of cancer by inducing phase-II antioxidant enzymes via activation of Nrf2 signalling, restoration of tumour suppressor p53 and modulation of inflammatory mediators like iNOS and COX2 in liver of lymphoma bearing mice.

Topics: Animals; Anticarcinogenic Agents; Antioxidants; Consensus Sequence; Curcumin; Cyclooxygenase 2; Glutathione Reductase; Glutathione Transferase; Inflammation Mediators; Liver; Lymphoma, T-Cell; Male; Mice; Mice, Inbred AKR; NAD(P)H Dehydrogenase (Quinone); NF-E2-Related Factor 2; Nitric Oxide Synthase Type II; Protein Binding; RNA, Messenger; Signal Transduction; Transforming Growth Factor beta1; Tumor Microenvironment; Tumor Suppressor Protein p53

Oxidative stress, an important factor in modulation of glycolytic pathway and induction of stress activated genes, is further augmented due to reduced antioxidant defense system, which promotes cancer progression via inducing angiogenesis. Curcumin, a naturally occurring chemopreventive phytochemical, is reported to inhibit carcinogenesis in various experimental animal models. However, the underlying mechanism involved in anticarcinogenic action of curcumin due to its long term effect is still to be reported because of its rapid metabolism, although metabolites are accumulated in tissues and remain for a longer time. Therefore, the long term effect of curcumin needs thorough investigation. The present study aimed to analyze the anticarcinogenic action of curcumin in liver, even after withdrawal of treatment in Dalton's lymphoma bearing mice. Oxidative stress observed during lymphoma progression reduced antioxidant enzyme activities, and induced angiogenesis as well as activation of early stress activated genes and glycolytic pathway. Curcumin treatment resulted in activation of antioxidant enzyme super oxide dismutase and down regulation of ROS level as well as activity of ROS producing enzyme NADPH:oxidase, expression of stress activated genes HIF-1α, cMyc and LDH activity towards normal level. Further, it lead to significant inhibition of angiogenesis, observed via MMPs activity, PKCα and VEGF level, as well as by matrigel plug assay. Thus findings of this study conclude that the long term effect of curcumin shows anticarcinogenic potential via induction of antioxidant defense system and inhibition of angiogenesis via down regulation of stress activated genes and glycolytic pathway in liver of lymphoma bearing mice.

Topics: Angiogenesis Inhibitors; Animals; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Antioxidants; Biotransformation; Collagen; Curcumin; Disease Progression; Down-Regulation; Drug Combinations; Drug Screening Assays, Antitumor; Gene Expression Regulation, Neoplastic; Glycolysis; Laminin; Liver; Lymphoma, T-Cell; Male; Mice; Mice, Inbred AKR; Neoplasm Proteins; Neovascularization, Pathologic; Oxidative Stress; Proteoglycans; Random Allocation

Curcumin is known to exert its anticancer effect either by scavenging or by generating reactive oxygen species (ROS). In this study, we report that curcumin-mediated rapid generation of ROS induces apoptosis by modulating different cell survival and cell death pathways in HuT-78 cells. Curcumin induces the activation of caspase-8, -2, and -9, alteration of mitochondrial membrane potential, release of cytochrome c, and activation of caspase-3 and concomitant PARP cleavage, but the addition of caspase inhibitors only partially blocked the curcumin-mediated apoptosis. Curcumin also downregulates the expression of antiapoptotic proteins c-FLIP, Bcl-xL, cellular inhibitor of apoptosis protein, and X-linked IAP in a ROS-dependent manner. Curcumin disrupts the integrity of IKK and beclin-1 by degrading Hsp90. Degradation of IKK leads to the inhibition of constitutive NF-κB. Degradation of beclin-1 by curcumin leads to the accumulation of autophagy-specific marker, microtubule-associated protein-I light chain 3 (LC3), LC3-I. Our findings indicate that HuT-78 cells are vulnerable to oxidative stress induced by curcumin and as a result eventually undergo cell death.

Topics: Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Caspases; Cell Line, Tumor; Cell Survival; Curcumin; Cytochromes c; Down-Regulation; Enzyme Activation; HSP90 Heat-Shock Proteins; Humans; I-kappa B Kinase; Lymphoma, T-Cell; Molecular Targeted Therapy; NF-kappa B; Oxidative Stress; Protein Stability; Reactive Oxygen Species

Using a murine model of a T cell lymphoma, in the present study, we report that tumor growth retarding action of curcumin involves modulation of some crucial parameters of tumor microenvironment regulating tumor progression. Curcumin-administration to tumor-bearing host caused an altered pH regulation in tumor cells associated with alteration in expression of cell survival and apoptosis regulatory proteins and genes. Nevertheless, an alteration was also observed in biophysical parameters of tumor microenvironment responsible for modulation of tumor growth pertaining to hypoxia, tumor acidosis, and glucose metabolism. The study thus sheds new light with respect to the antineoplastic action of curcumin against a tumor-bearing host with progressively growing tumor of hematological origin. This will help in optimizing application of the drug and anticancer research and therapy.

Topics: Animals; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; ATP Binding Cassette Transporter, Subfamily B; Cell Growth Processes; Curcumin; Female; Glucose Transport Proteins, Facilitative; HSP70 Heat-Shock Proteins; Hypoxia-Inducible Factor 1, alpha Subunit; Lymphoma, T-Cell; Male; Mice; Mice, Inbred BALB C; Proto-Oncogene Proteins c-bcl-2; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Specific Pathogen-Free Organisms; Survival Analysis; Tumor Microenvironment; Tumor Suppressor Proteins; Vascular Endothelial Growth Factor A

Curcumin inhibits cell growth and induces apoptosis in a number of tumor cell lines and animal models. Human clinical trials indicated no dose-limiting toxicity when administered at doses up to 8 g per day. The purpose of this study was to address the antitumor effect of curcumin on cutaneous T-cell lymphoma (CTCL) cell lines and peripheral blood mononuclear cells (PBMCs) from patients with CTCL compared with healthy donors' controls. Curcumin at 5-20 microM for 24 and 48 hours induced apoptosis in a time- and dose-dependent manner in three CTCL cell lines (namely MJ, Hut78, and HH). Curcumin at 5-20 microM for 48 hours also caused more apoptosis in patients' PBMCs compared with healthy donors' PBMCs (P<0.05). Curcumin decreased protein and mRNA expression levels of signal transducer and activator of transcription (STAT)-3, bcl-2, and survivin in three cell lines and in patients' PBMCs. Curcumin inhibited STAT-3 and IkappaB-alpha phosphorylation, as well as suppressed DNA binding of nuclear factor (NF)-kappaB in these cells. Caspase-3 was activated and poly (ADP-Ribose) polymerase was cleaved after curcumin treatment. These data suggest that curcumin selectively induces apoptosis in association with the downregulation of STAT-3 and NF-kappaB signaling pathways in CTCL cells. Our findings provide a mechanistic rationale for the potential use of curcumin as a therapeutic agent for patients with CTCL.

Topics: Antineoplastic Agents; Apoptosis; Autophagy; Caspase 3; Cell Division; Cell Line, Tumor; Curcumin; Humans; I-kappa B Proteins; Inhibitor of Apoptosis Proteins; Leukocytes, Mononuclear; Lymphoma, T-Cell; Microtubule-Associated Proteins; NF-kappa B; NF-KappaB Inhibitor alpha; Phosphorylation; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-bcl-2; RNA, Messenger; Signal Transduction; Skin Neoplasms; STAT3 Transcription Factor; Survivin

Biopsies from patients with cutaneous T-cell lymphoma (CTCL) exhibit stage-dependent increase in angiogenesis. However, the molecular mechanisms responsible for the increased angiogenesis are unknown. Here we show that malignant CTCL T cells spontaneously produce the potent angiogenic protein, vascular endothelial growth factor (VEGF). Dermal infiltrates of CTCL lesions show frequent and intense staining with anti-VEGF antibody, indicating a steady, high production of VEGF in vivo. Moreover, the VEGF production is associated with constitutive activity of Janus kinase 3 (Jak3) and the c-Jun N-terminal kinases (JNKs). Sp600125, an inhibitor of JNK activity and activator protein-1 (AP-1) binding to the VEGF promoter, downregulates the VEGF production without affecting Jak3 activity. Similarly, inhibitors of Jak3 inhibit the VEGF production without affecting JNK activity. Downregulation of Stat3 with small interfering RNA has no effect, whereas curcumin, an inhibitor of both Jak3 and the JNKs, almost completely blocks the VEGF production. In conclusion, we provide evidence of VEGF production in CTCL, which is promoted by aberrant activation of Jak3 and the JNKs. Inhibition of VEGF-inducing pathways or neutralization of VEGF itself could represent novel therapeutic modalities in CTCL.

Topics: Cell Line, Tumor; Curcumin; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Janus Kinase 3; JNK Mitogen-Activated Protein Kinases; Lymphoma, T-Cell; Neovascularization, Pathologic; Protein-Tyrosine Kinases; RNA, Messenger; Skin Neoplasms; Sp1 Transcription Factor; Sp3 Transcription Factor; STAT3 Transcription Factor; Transcription Factor AP-1; Transcription Factor AP-2; Transfection; Vascular Endothelial Growth Factor A

Natural killer/T-cell lymphoma (NKTL) is a highly aggressive disease. Despite the use of various treatment regimens, the prognosis of NKTL is poor, and new treatment strategies need to be determined. Because of the significant survival potential, nuclear factor (NF)-kappaB has become one of the major targets for drug development. In this study, we explored the effect and action mechanism of NF-kappaB inhibitors, BAY 11-7082 and curcumin, on NKTL cell lines (NKL, NK-92 and HANK1). Electrophoretic mobility shift assay showed that NF-kappaB was constitutively active in HANK1, a chemoresistant cell line. BAY 11-7082 and curcumin suppressed NF-kappaB activation in a time- and dose-dependent manner, which finally resulted in cell death. BAY 11-7082- and curcumin-induced cell death was associated with downregulation of Bcl-xL, cyclin D1, XIAP and c-FLIP, followed by caspase-8, poly(ADP-ribose) polymerase cleavage and activation. Given that the chemoresistant NK-92 cells respond to NF-kappaB inhibitors but not to conventional drugs, BAY 11-7082 and curcumin could be potentially useful for achieving improved outcome in chemotherapy-refractory NKTL.

Topics: bcl-X Protein; CASP8 and FADD-Like Apoptosis Regulating Protein; Caspase 8; Caspases; Cell Line, Tumor; Curcumin; Cyclin D1; Dose-Response Relationship, Drug; Down-Regulation; Drug Resistance, Neoplasm; Electrophoretic Mobility Shift Assay; Enzyme Inhibitors; Humans; Intracellular Signaling Peptides and Proteins; Killer Cells, Natural; Lymphoma, T-Cell; NF-kappa B; Nitriles; Poly(ADP-ribose) Polymerases; Proteins; Proto-Oncogene Proteins c-bcl-2; Sulfones; Time Factors; X-Linked Inhibitor of Apoptosis Protein