curcumin and Burkitt-Lymphoma

Curcumin, a bioactive compound from turmeric, eliminates cancer stem cells (CSCs) in some cancers. This study evaluates the effects of curcumin on CSC markers in Burkitt lymphoma and acute myeloid leukemia cells.. Cells were treated with increasing concentrations of curcumin, followed by an ALDEFLUOR assay, colony formation assay and western blot analysis for the CSC-associated proteins, Gli-1, Notch-1 and Cyclin D1.. Markers associated with CSCs were decreased in cells treated with curcumin. This included a decrease in the percentage of ALDH-positive cells, a decrease in colony formation and the downregulation of Gli-1, Notch-1 and Cyclin D1.. These results indicate that curcumin decreased CSC markers in lymphoma/leukemia cells, potentially through inhibiting self-renewal.

Topics: Antineoplastic Agents; Biological Products; Biomarkers; Biomarkers, Tumor; Burkitt Lymphoma; Cell Line, Tumor; Cell Proliferation; Curcumin; Humans; Leukemia, Myeloid, Acute; Neoplastic Stem Cells; Signal Transduction; Tumor Stem Cell Assay

Non-Hodgkin Lymphoma (NHL) is a type of hematological malignancy that affects two percent of the overall population in the United States. Tetraspanin CD9 is a cell surface protein that has been thoroughly demonstrated to be a molecular facilitator of cellular phenotype. CD9 expression varies in two human lymphoma cell lines, Raji and BJAB. In this report, we investigated the functional relationship between CD9 and cell proliferation regulated by histone deacetylase (HDAC) activity in these two cell lines. Introduction of CD9 expression in Raji cells resulted in significantly increased cell proliferation and HDAC activity compared to Mock transfected Raji cells. The increase in CD9-Raji cell proliferation was significantly inhibited by HDAC inhibitor (HDACi) treatment. Pretreatment of BJAB cells with HDAC inhibitors resulted in a significant decrease in endogenous CD9 mRNA and cell surface expression. BJAB cells also displayed decreased cell proliferation after HDACi treatment. These results suggest a significant relationship between CD9 expression and cell proliferation in human lymphoma cells that may be modulated by HDAC activity.

Topics: Burkitt Lymphoma; Cell Line, Tumor; Cell Proliferation; Curcumin; Epigenesis, Genetic; Gene Expression; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; Recombinant Proteins; RNA, Messenger; RNA, Neoplasm; Tetraspanin 29; Transfection

The phosphatidylinositol-3-kinase (PI3K) / protein kinase B (AKT) signal transduction pathway is commonly misregulated in lymphoma and associated with tumorigenesis and enhanced resistance to radiotherapy. Curcumin has been shown to inhibit the PI3K/AKT signal transduction pathway in several tumor models. In this study, we found that curcumin inhibits constitutive and radiation-induced expression of the PI3K/AKT pathway and its downstream regulator nuclear factor kappaB (NF-κB) in human Burkitt's lymphoma, a high-grade non-Hodgkin's lymphoma (NHL). We further demonstrated that the blockage of radiation-induced activation of the PI3K/AKT pathway and its downstream regulator NF-κB by either curcumin or specific PI3/AKT inhibitors (LY294002 for PI3K or SH-5 for AKT) enhance apoptosis in three human Burkitt's lymphoma cell lines (Namalwa, Ramos, and Raji) that were treated with ionizing radiation. However, no synergic effect on radiation-induced apoptosis was found in the cells co-pretreated with curcumin combined with LY294002 or curcumin combined with SH-5. The results from this study suggest that curcumin might play an important role in radiotherapy of high-grade NHL through inhibition of the PI3K/AKT-dependent NF-κB pathway.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Burkitt Lymphoma; Cell Line, Tumor; Chromones; Curcumin; Humans; Inositol Phosphates; Morpholines; NF-kappa B; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Radiation, Ionizing; Signal Transduction

Curcumin, a phenolic compound from the rhizomes of Curcuma longa, inhibits the growth of a variety of malignant cell types including lymphoma cells. We investigated the role of curcumin in modulating the response of Burkitt's lymphoma cells to ionizing radiation (IR) in vitro and explored the mechanisms that mediated this effect. We treated three Burkitt's lymphoma cell lines with vehicle, curcumin, IR, and curcumin in combination with IR. Cell viability, apoptosis, and cell cycle distribution were determined to ascertain the radiosensitization effect of curcumin. Nuclear factor-kappa B (NF-κB) activation was assessed by nuclear translocation of p65. Apoptosis-related proteins were monitored by western blot assay and real-time RT-PCR. Pretreatment of curcumin sensitized lymphoma cells to IR-induced apoptosis and increased G2/M phase arrest in the cell cycle distribution. Accordingly, the antiapoptotic Bcl-xL protein, cell cycle modulating protein CDC2, and cyclin B1 were downregulated by the curcumin treatment. IR activated NF-κB as evidenced by an increased nuclear p65 translocation and cytoplasmic IκBα expression. However, pretreatment with curcumin significantly decreased the nuclear translocation of p65 and cytoplasmic IκBα degradation. Survivin and hexokinase II, downstream effectors of NF-κB that mediate the antiapoptotic effect of NF-κB, were suppressed by the pretreatment of curcumin. These observations suggest that the activated NF-κB pathway plays a prosurvival role in Burkitt's lymphoma in response to IR. Curcumin blocks this pathway and has therapeutic potential for improving the antitumor effects of radiotherapy.

Topics: Apoptosis; Burkitt Lymphoma; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Curcumin; Cytoplasm; G2 Phase Cell Cycle Checkpoints; Gene Expression Regulation, Neoplastic; Humans; I-kappa B Proteins; Inhibitor of Apoptosis Proteins; M Phase Cell Cycle Checkpoints; NF-kappa B; Protein Transport; Survivin; X-Rays

Curcumin, a natural compound extracted from rhizomes of curcuma Curcuma species, has been shown to possess potent anti-inflammatory, anti-tumor and anti-oxidative properties. However, the mechanism of action of the compound remains poorly understood. In this report, we have analyzed the effects of curcumin on the cell proliferation of Burkitt's lymphoma Raji cells. The results demonstrated that curcumin could effectively inhibit the growth of Raji cells in a dose- and time-dependent manner. Further studies indicated that curcumin treatment resulted in apoptosis of cells. Biochemical analysis showed that the expression of Bax, Bid and cytochrome C were up-regulated, while the expression of oncogene c-Myc was down regulated after curcumin treatment. Furthermore, poly (ADP-ribose) polymerase (PARP) cleavage was induced by the compound. Interestingly, the antiapoptotic Bcl-2 expression was not significantly changed in Raji cells after curcumin treatment. These results suggested that the mechanism of action of curcumin was to induce mitochondrial damage and therefore led to Raji cell apoptosis. We further investigated the in vivo effects of curcumin on the growth of xenograft tumors in nude mice. The results showed that curcumin could effectively inhibit tumor growth in the xenograft mouse model. The overall results showed that curcumin could suppress the growth of Burkitt's lymphoma cells in both in vitro and in vitro systems.

Topics: Animals; Antineoplastic Agents; Apoptosis; Burkitt Lymphoma; Cell Growth Processes; Cell Line, Tumor; Curcumin; Female; Humans; Membrane Potential, Mitochondrial; Mice; Mice, Inbred BALB C; Mice, Nude; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

We provide evidence that curcumin, a natural compound isolated from rhizomes of plant Curcuma longa, induces apoptosis in several Burkitt's lymphoma cell lines expressing Bax protein (AS283A, KK124, and Pa682PB), whereas it has no effects in cell lines with no Bax expression (BML895 and CA46). Our data show that curcumin treatment results in down-regulation of constitutive activation of nuclear factor-kappaB (NF-kappaB) via generation of reactive oxygen species where it causes conformational changes in Bax protein leading to loss of mitochondrial membrane potential and release of cytochrome c to the cytosol. This leads to activation of caspase-9, caspase-3, and poly(ADP)-ribose polymerase cleavage leading to caspase-dependent apoptosis. In addition, curcumin treatment of Burkitt's lymphoma cell lines also causes up-regulation of DR5; however, this up-regulation does not result in apoptosis. Importantly, cotreatment with curcumin and TRAIL induces apoptosis in Bax-deficient cell lines. Taken together, our findings suggest that curcumin is able to induce apoptosis in Bax-positive cell lines, whereas combinations with TRAIL result in apoptosis in Bax-negative cell lines. These findings also raise the possibility that incorporation of curcumin in treatment regimens may provide a novel approach for the treatment of Burkitt's lymphomas and provide the molecular basis for such future translational efforts.

Topics: Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Burkitt Lymphoma; Caspase 3; Caspase 9; Cell Line, Tumor; Curcumin; Cytochromes c; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; I-kappa B Kinase; I-kappa B Proteins; Membrane Potential, Mitochondrial; NF-kappa B; NF-KappaB Inhibitor alpha; Phosphorylation; Poly(ADP-ribose) Polymerases; Protein Structure, Quaternary; Reactive Oxygen Species; Receptors, TNF-Related Apoptosis-Inducing Ligand; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand; Up-Regulation

Histone deacetylase (HDAC1) has a high expression in many cancer cells and curcumin can inhibit the growth of cancer cells. This paper was designed to investigate the expression of HDAC1 of Raji cells and the effect of curcumin on their proliferation and apoptosis. Raji cells were treated with 3.125-50 micromol/L curcumin for 8-48 h and the growth inhibition rates of Raji cells were measured by MTT. The expression of HDAC1 on Raji cells were examined by mRNA, Western blot at 24 h various concertrations (1.6-50 micromol/L). Curcumin could selectively inhibit the proliferation of Raji cells in a dose- and time-dependent manner, with the inhibition rate being 52.47 %-82.18 % (P<0.01). The up-regulation of HDAC1 expression was observed within 24 h after the treatment with curcumin as shown by RT-PCR and Western blot. With the increase of concentration, the expression was down-regulated in a dose- dependent manner. It is concluded that the expression of HDAC1 plays an important role in the proliferation and apoptosis of Raji cells and curcumin can inhibit the growth of Raji cells at various concentrations and promote the apoptosis of Raji cells.

Topics: Antineoplastic Agents, Phytogenic; Blotting, Western; Burkitt Lymphoma; Cell Proliferation; Curcumin; Drugs, Chinese Herbal; Gene Expression Regulation, Neoplastic; Histone Deacetylase 1; Histone Deacetylases; Humans; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

To study the anticancer activities of curcumin on human Burkitt's lymphoma and their molecular mechanism.. The effect of curcumin on the growth of CA46 cells and apoptosis were studied through Trypan blue exclusion, MTT assay, cell cycle, DNA fragmentation analysis and detection of TdT-mediated dUTP nick end labeling (TUNEL). The effect of curcumin on the expression of c-myc, bcl-2, mutant-type p53 and Fas protein and mRNA was studied by flow cytometry (FCM) and reverse transcription-polymerase chain reaction (RT-PCR).. 1. Curcumin inhibited proliferation of CA46 cells in a time- and dose-dependent manner, 2. CA46 cells treated with curcumin showed G(0)/G(1) or G(2)/M phase increase and S phase decrease, 3. CA46 cells apoptosis induced by curcumin was confirmed by DNA fragmentation and TUNEL and 4. The expression of c-myc, bcl-2, mutant-type p53 protein and mRNA was decreased sharply in CA46 cells treated with curcumin, while Fas protein and mRNA was increased.. Curcumin is able to inhibit the proliferation of CA46 cells and induce the cell apoptosis by down-regulating the expression of c-myc, bcl-2, mutant-type p53 and up-regulating the expression of Fas.

Topics: Antineoplastic Agents; Apoptosis; Burkitt Lymphoma; Cell Cycle; Cell Division; Curcumin; fas Receptor; Gene Expression Regulation; Humans; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-myc; Tumor Cells, Cultured; Tumor Suppressor Protein p53