The mechanisms that regulate induction of the antiapoptotic state and mitogenic signals in primary effusion lymphoma (PEL) are not well known. In efforts to identify novel approaches to block the proliferation of PEL cells, we found that curcumin (diferuloylmethane), a natural compound isolated from the plant Curcuma Ionga, inhibits cell proliferation and induces apoptosis in a dose dependent manner in several PEL cell lines. Such effects of curcumin appear to result from suppression of the constitutively active STAT3 through inhibition of Janus kinase 1 (JAK1). Our data also demonstrate that curcumin induces loss of mitochondrial membrane potential with subsequent release of cytochrome c and activation of caspase-3, followed by polyadenosin-5′-diphosphate-ribose polymerase (PARP) cleavage. Altogether, our findings suggest a novel function for curcumin, acting as a suppressor of JAK-1 and STAT3 activation in PEL cells, leading to inhibition of proliferation and induction of caspase-dependent apoptosis. Therefore, curcumin may have a future therapeutic role in PEL and possibly other malignancies with constitutive activation of STAT3.
Primary effusion lymphoma (PEL) is a subtype of non-Hodgkin's B-cell lymphoma, that mainly presents in patients with advanced AIDS, but is sometimes also found in human immunodeficiency virus (HIV)-negative individuals (Nador et al., 1996; Klepfish et al., 2001). PEL cells grow as a lymphomatous effusion in body cavities and are infected with Kaposi sarcoma-associated herpesvirus (KSVH/HHV8). Most cases show dual infection with Epstein–Barr virus (EBV/HHV4) (Drexler et al., 1998). Pleural and abdominal effusions from patients with AIDS–PEL contain a number of cytokines, which serve as autocrine growth factors (Jones et al., 1997; Aoki et al., 2000). For example, IL-10 has been reported to serve as autocrine growth factor for AIDS-related B-cell lymphoma (Masood et al., 1995). Recently, it has also been shown that PEL cells use viral IL-6 and IL-10 in an autocrine fashion for their survival and proliferation (Jones et al., 1997).
A number of constitutively activated signaling pathways play critical role in the survival and growth of PEL cells. These include JAK/STAT, NF-κB and PI3-kinase (Keller et al., 2000; Aoki et al., 2003; Uddin et al., 2005). The KSHV protein K1 has been shown to regulate a number of survival proteins. Studies have shown that transgenic mice with K1 are characterized by a constitutive activation of NF-κB and Oct-2 as well as activation of the Src-kinase Lyn (Prakash et al., 2002). Furthermore, K1 protein activates the PI3-kinase/AKT pathway in B lymphocytes and protects cells from FKHR- and FAS-mediated apoptosis (Tomlinson and Damania, 2004). A recent study by Cannon and Cesarman (2004) has demonstrated that vGPCR induces activation of the transcriptional factors AP1 and CREB in PEL cells.
Curcumin (diferuloylmethane) is a naturally occurring yellow pigment isolated from the rhizomes of the plant Curcuma longa, found in south Asia (Lodha and Bagga, 2000). Curcumin has antiproliferative and proapoptotic effects against diverse tumors in vitro (Chen et al., 1999; Li et al., 2004). In vivo, it has been found to suppress carcinogenesis of the skin, breast, colon, and liver in murine models (Limtrakul et al., 1997; Huang et al., 1998; Kawamori et al., 1999; Chuang et al., 2000). Recently, curcumin has been shown to cause apoptosis of multiple myeloma cells via inhibition of NF-kB and STAT3 activation (Bharti et al., 2003a, 2003b). Curcumin also suppresses the proliferation of human pancreatic cells via downregulation of NF-κB and IkB kinase and induction of apoptosis (Li et al., 2004). Curcumin has been also shown to down regulate the expression of various NF-κB-regulated genes, including Bcl2, COX2, MMP-9, TNF, cyclinD1, and adhesion molecules (Bush et al., 2001; Mukhopadhyay et al., 2001; Anto et al., 2002). In the current study, we investigated the antitumor activity of curcumin against human primary effusion lymphoma cell lines. We show for the first time that curcumin induces apoptosis of PEL cells. Curcumin inhibits the constitutive active STAT3, leading to the loss of mitochondrial membrane potential and subsequent release of cyrochrome c and activation of caspase-dependent apoptosis in PEL.
Curcumin causes a dose-dependent growth inhibition of PEL Cells
We first sought to determine whether curcumin treatment leads to growth inhibition of PEL. BC1, BC3, BCBL1, BCP1 and HBL6 were cultured in the presence of 10, 20, 40 and 80 μ M curcumin for 24 h and MTT assays were performed. Figure 1a, shows that as the dose of curcumin increased from 10 to 80 μ M, cell growth inhibition significantly increased in a dose dependent manner in all the cell lines.
Effect of curcumin on cell cycle and apoptosis in PEL cells
To determine whether growth inhibition of curcumin was attributable to cell cycle arrest or apoptosis in PEL cells, all cell lines were treated with and without 40 μ M curcumin for 24 h. Cells were fixed and cell cycle fractions were determined by flow cytometry. As shown in Figure 1b, the sub-G1 population of cells was increased from 3 to 9% in the control to 51 to 54% in all cell lines treated with curcumin. This increase in sub-G1 populations was accompanied by loss of cells in G0/G1, S and G2/M phases. It has been reported that cells with these features are those dying of apoptosis (Zhang et al., 2002). In addition, to confirm the specificity of curcumin for PELs we tested the action of curcumin on Burkitt's lymphoma cell line LW878. As shown in Figure 1b, there was no increase of the sub-G population after curcumin treatment in this cell line.
To further confirm that this increase in the sub-G1 population is indeed apoptosis, PEL cells were treated with various doses of curcumin as indicated and apoptotic cells were analyzed by tunel assays. As shown in Figure 2, curcumin treatment resulted in apoptosis in a dose-dependent manner in all PEL cells tested. These results clearly implicate that curcumin suppresses growth of PEL cells via induction of apoptosis.
Curcumin inhibits constitutive activation/phosphorylation of STAT-3 in PEL cells
We next sought to determine whether curcumin inhibits the constitutive phosphorylation activation of STAT3 in PEL cells. BC1, BC3, BCBL1, BCP1 and HBL6 cells were treated for 24 h with various doses of curcumin as indicated in Figure 3a. Curcumin caused dephosphorylation of STAT3 in a dose-dependent manner in all cell lines. In addition, we also investigated the short-term effect of curcumin on dephosphorylation of STAT3. Our data shows that curcumin dephosphorylates STAT3 as early as 15 min (data not shown). We further investigated whether curcumin had any effect on the expression of STAT3 protein. To achieve this, cell lysates were immunoprecipitated using an anti-STAT3 antibody and immunoblotted with phospho and native STAT3 antibodies. As shown in Figure 3b, curcumin treatment resulted in abrogation of STAT3 phosphorylation/activation without affecting the STAT3 protein. We further tested the status of constitutive STAT3 in the Burkitt's lymphoma cell line LW878 by using phospho-STAT3 antibody. As shown in Figure 3c, constitutively activated STAT3 was not detected in LW878, although comparable level of STAT3 protein was found in this cell line. These results clearly demonstrate that curcumin induces apoptosis in PEL cells via inactivation of STAT3 phosphorylation and suppressing the STAT3 protection from apoptosis. On the other hand, cell that do not have constitutive STAT3 are refractory to curcumin-induced apoptosis.
Curcumin inhibits JAK1 tyrosine kinase in vitro and in vivo
It is known that the JAK1 tyrosine kinase, an enzyme essential for the receptor signaling of several cytokines and growth factors, functions upstream of STAT3 (Guschin et al., 1995; Rodig et al., 1998). Curcumin has been shown to inhibit phosphorylation of JAK1 and JAK2 in primary microglia (Kim et al., 2003). To determine whether JAK1 is the target of curcumin we sought to evaluate JAK1 tyrosine kinase activity in PEL cells treated with curcumin. As shown in Figure 4a, JAK1 was found to be constitutively activated (tyrosine phosphorylation at Y1022/1023) and curcumin treatment caused its dephosphorylation. These results suggest that curcumin induced STAT3 inactivation by inhibiting JAK1 kinase activity. To determine whether inhibition of JAK1 tyrosine kinase activity results from direct interaction of curcumin with JAK1 kinase, we used an in vitro immunocomplex kinase assay. Lysates from BC1 cells were immunoprecipitated with JAK1 antibody and in vitro kinases assays were performed using γ-[32P] ATP in the presence of different doses of curcumin. Direct incubation of JAK1 protein with curcumin resulted in a dose-dependent inhibition of JAK1 auto-phosphorylation (Figure 4b), suggesting that curcumin exerts direct interference with JAK1 protein kinase activity in PEL.
Effect of curcumin on signaling pathways at the mitochondrial level in PEL cells
The apoptotic signaling cascade starts with activation of caspase-8 and truncation of BID that translocates to the mitochondrial membrane allowing activation of proapoptotic proteins and release of cytochrome c. Therefore, we sought to determine whether inhibition of JAK/STAT signaling involves the mitochondria. PEL cells were treated with various doses of curcumin for 24 h and cell lysates were separated on SDS–PAGE and immunoblotted antibodies against anticaspase-8 and anti-BID. Figure 5a, shows that curcumin treatment resulted in a significant reduction in the intensity of the full-length band of procaspase-8 indicating activation of caspase-8 and as well as truncation of BID. These effects were observed in all the PEL cell lines in a dose-dependent manner. These results suggesting that curcumin induced apoptosis in PEL cells may occur via the mitochondria.
Cytochrome c release from mitochondria in BC1, BC3, BCBL1, and HBL6 cells treated with curcumin was examined by Western blot analysis. Cells were treated in the presence and absence of 40 μ M curcumin for 24 h. Cytosolic-specific, mitochondria-free lysates were prepared as described in Materials and methods. As shown in Figure 5b, cytochrome c was released to the cytosol after curcumin treatment. These results suggests that curcumin treatment of PEL cells causes apoptosis via the intrinsic pathway following the release of cytochrome c. We further tested the effect of curcumin on mitochondrial membrane potential in these cells using the JC1 dye. BC1, BC3, BCBL1, BCP1, and HBL6 cells were treated with 40 μ M curcumin for 24 h. As shown in Figure 3c, curcumin treatment of these cells resulted in loss of mitochontrial membrane potential as measured by JC1-stained green florescence depicting apoptotic cells. These results further support our notion that curcumin induces apoptosis in PEL cells involve signaling at the mitochondrial level.
Curcumin induced signaling causes Caspase-3 activation and PARP cleavage in PEL cells
Since caspases are important mediators of apoptosis induced by various apoptotic stimuli (Desagher et al., 1999), we investigated whether curcumin treatment also caused their activation. BC1, BC3, BCBL1 and HBL6 cells were treated with 40 μ M curcumin for various time periods and immunoblotted with anticaspase-3, anticleaved caspase-3 and anti-PARP antibodies. As shown in Figure 6a, curcumin treatment of PEL cells induced caspase-3 cleavage at 12 h (BC1 and BC3) or 24 h (BCBL1 and HBL6). As expected with this result, PARP was also cleaved, a hallmark of cells undergoing apoptosis. Furthermore, pretreatment of PEL cells with 80 μ M of z-VAD-fmk (Figure 6b), a universal inhibitor of caspases, abrogated caspase and PARP activation and prevented cell death induced by curcumin (Figure 6c), clearly indicating that caspases play a critical role in curcumin induced apoptosis in PEL cells.
Modulation of IAP protein family in curcumin-induced apoptosis in PEL cells
We also examined whether curcumin induces cell death by modulating the expression of inhibitors of apoptosis protein (IAP) family members, which ultimately determine the cell's response to apoptotic stimuli. BC1, BC3, BCBL1 and HBL6 cells were treated with 40 μ M curcumin for 24 h and expression of cIAP1 and 2, XIAP and survivin was determined using Western blotting. As shown Figure 7, curcumin treatment caused a dose-dependent downregulation of cIAP 1, XIAP and survivin, while cIAP2 was not affected. These results indicate that IAP proteins may also be involved in curcumin-induced apoptosis. We also obtained similar results in another PEL cell line, BCP1 (data not shown).
PEL is a very aggressive type of cancer, which frequently becomes resistant to conventional chemotherapeutic agents. As a result of the relative lack of efficacy of chemotherapy in the treatment of this malignancy, there is a need for the development of new therapeutic targets and clinical trials with novel agents. PEL cells produce a variety of inflammatory cytokines and growth factors, in an autocrine fashion, including viral IL6, IL10 and VEGF, providing them cytoprotection against apoptosis (Jones et al., 1997). It is now postulated that the mechanisms of lymphomagenesis involve deregulation of several signaling pathways that may act either independently or crosstalk with each other. Constitutive activation of various signaling pathways is a common finding in hematological malignancies, while some of these pathways are implicated in the promotion of cell growth and the generation of antiapoptotic signals (Pene et al., 2002; Benekli et al., 2003; Cheong et al., 2003). Various signaling cascades are triggered by the activation of nonreceptor tyrosine kinases of the Janus family JAK kinases. It is now well established that major targets for the kinase activities of JAK are transcription factors of the STAT-family of proteins, including STAT3 (Guschin et al., 1995; Rodig et al., 1998). There is also clear-cut evidence that aberrant activation of STAT3 is often associated with cell survival, proliferation and transformation of a wide variety of human tumors (Bromberg et al., 1999; Buettner et al., 2002). Therefore, identifying ways and means to block STAT3 activation may prove to be a novel and attractive approach for the treatment of specific malignancies in which there is constitutive activation of STAT3. Curcumin has well-documented proapoptotic properties in a variety of cell types, including cells of hematopoietic origin (Bharti et al., 2003a, 2004). Previous studies have demonstrated that this agent inhibits NF-κB activity, resulting in apoptosis of various cancer cell types (Mukhopadhyay et al., 2001; Bharti et al., 2003a). On the other hand, curcumin did not induce apoptosis in normal lymphocytes (Syng-Ai et al., 2004), suggesting that this agent may prove to be very useful in the treatment of lymphomas and possibly lymphoid leukemias. However, the effect of curcumin on PEL cells is still unclear. In this study, we demonstrate that curcumin is able to suppress the growth of PEL cells and induce apoptosis. Our findings provide the first evidence for a novel function of curcumin, which involves rapid inactivation of JAK1, followed by dephosphorylation of STAT3 and subsequent activation of the mitochondrial apoptotic pathway. Our data demonstrates that constitutive STAT3 plays a critical role in curcumin-induced apoptosis. Cells that do not have constitutively active STAT3 are resistant to curcumin-induced cell death. Taken together with the results of a recent study (Barton et al., 2004), in which it was demonstrated that inhibition of STAT3 expression results in mitochondrial-dependent induction of apoptosis, our data provide a mechanism by which curcumin induces apoptosis in lymphoma cells, involving sequential involvement of JAK1, STAT3 and mitochondrial changes. It is also possible that this pathway is specific for malignant lymphoid cells, as targeting of STAT3 expression in prostate carcinoma cell lines overexpressing STAT3 does not result in apoptosis (Barton et al., 2004). Our data is also consistent with previous observations that STAT3 plays key roles in proliferation and survival of PEL cells (Aoki et al., 2003). Our finding that curcumin induces truncation of the proapoptotic BID and translocation of cytochrome c from the mitochondria to the cytosol provides a link between the mitochondria and curcumin-induced apoptosis in PEL cells. We also show that curcumin causes decreased expression of cIAPI, XIAP and survivin but not cIAP2. IAPs have been reported to inhibit apoptosis by directly inhibiting effector caspases, caspase-3 and caspase-7 (Deveraux and Reed, 1999). Furthermore, cIAP1 is also able to inhibit cytochrome c-induced activation of caspase-9 (Deveraux et al., 1998).
Numerous studies indicate that IL-10 is a potent growth factor for a variety of malignant cells, including PEL. This cytokine has been shown to activate the transcriptional factors STAT1 and STAT3 through engagement of JAK kinases. (Sredni et al., 2004). Recently, it has been reported that the immunomodulator AS101 inhibits mesangial cell proliferation by inhibiting IL-10. The mechanisms of AS101-dependent inhibition of cell proliferation appear to reflect dephosphorylation of STAT3 resulting from inhibition of IL-10 production (Kalechman et al., 2004). Consistent with this, inhibition of IL10 by neutralizing IL10 antibody abolishes the phosphorylation of STAT3 and proliferation of these cells. We have some preliminary data that is consistent with the results of these studies, and provide the first evidence that curcumin inhibits IL-10 production in PEL cells (data not shown). Such suppressive effects of curcumin on IL-10 secretion may account for the induction of JAK1-inactivation, STAT3-dephosphorylation and induction of apoptosis in PEL. However, at this point there is no direct evidence whether curcumin inhibit directly IL-10 secretion in PEL, which in turn inhibit JAK-STAT signaling and further studies are required to confirm this issue. These findings may also help us to understand the mechanisms of action of curcumin against other malignant cell types as well. It is possible that a similar mechanism may apply in other malignant cell types, but this needs to be directly addressed in future studies. Independently of the precise mechanisms involved, our findings have important clinical–translational implications, as they raise the possibility that curcumin may be useful against PEL in vivo. Future investigations aimed at determining the efficacy of curcumin and possibly other inhibitors of the JAK/STAT pathway in PEL are warranted and lead to the development of new effective therapies for the treatment of these lymphomas.
Materials and methods
The human PEL (BC1, BC3, BCBL1, BCP1 and HBL6) and Burkitt's (BrgIgA) cell lines were cultured in RPMI 1640 medium supplemented with 10% (v/v) fetal bovine serum (FBS), 100 U/ml penicillin, 100 U/ml streptomycin at 37°C in an humidified atmosphere containing 5% CO2.
Reagents and antibodies
Curcumin was purchased from Sigma Chemical Co (St Louis, MO, USA) and Phospho JAK1 and anti-BID antibodies were purchased from Cell Signaling Technologies (Beverly, MA, USA). Phospho-STAT3 antibody was purchased from Santa Cruz Biotechnology Inc. (Santa Cruz, CA, USA). Anti-Jak1 antibody was purchased from Upstate Biotechnology Inc. (Lake Placid, NY, USA). Anti-β actin was purchased from Abcam (Cambridge, England). Anticytochrome c, and anticaspase-3 were purchased from BD (San Diego, CA, USA). The anti-PARP antibody was obtained from Zymed Lab (San Francisco, CA, USA).
The antiproliferative effects of curcumin against different primary effusion lymphoma cell lines were determined by the MTT dye uptake method as described earlier (Uddin et al., 2004a). Briefly, 104 cells were incubated in triplicate in a 96-well plate in the presence or absence of indicated test doses of curcumin in a final volume of 0.20 ml for 24 h at 37°C. Thereafter, 25 μl MTT solution (5 mg/ml in water) was added to each well. After 2–4 h incubation at 37°C, 0.1 ml extraction buffer (20% SDS) was added, incubation was continued overnight at 37°C, and then the optical density (OD) at 590 nm was measured. Cell viability was calculated as OD of the experiment samples/OD of the control (untreated) × 100.
PEL cell lines were treated with curcumin as described in the legends. Cells were harvested and the percentage of apoptosis was determined by flow cytometry after tunel assays (MBL, Watertown, MA, USA).
Cell lysis and immunoblotting
Cells were treated with curcumin as described in the legends and lysed as previously described (Uddin et al., 2004a). Briefly, cell pellets were resuspended in phosphorylation lysis buffer (0.5–1.0% TritonX-100, 150 mM NaCl, 1 mM EDTA, 200 μ M sodium orthovanadate, 10 mM sodium pyrophosphate, 100 mM sodium fluoride, 1.5 mM magnesium chloride, 1 mmol/l phenylmethylsulfonyl-flouride, 10 μg/ml aprotonin). Protein concentrations were assessed by Bradford assay before loading the samples. Equal amount of proteins were separated by SDS–PAGE and transferred to polyvinylidene difluoride membrane (Immobilion, Millipore, etc.). Immunoblotting was performed with different antibodies and visualized by an enhanced chemiluminescence (ECL, Amersham, IL, USA) method.
The in vitro kinase assays were performed as described earlier (Uddin et al., 1997). Briefly, the endogenous JAK1 proteins from PEL cells were immunoprecipitated using anti-JAK l antibody and sepharose beads. After washing several times with lysis buffer, sepharose beads were resuspended in kinase buffer and incubated with γ-[32P] ATP in the presence of different concentration of curcumin at room temperature for 30 min. Reaction was stopped by adding 5 × protein loading buffer and phosphorylated proteins were resolved on SDS–PAGE and visualized by exposure to X-ray film.
Assay for cytochrome c release
Release of cytochrome c from mitochondria was assayed as described earlier (Uddin et al., 2004b). Briefly, cells were treated with and without curcumin as described in figure legends, harvested and resuspended in 5 volumes of a hypotonic buffer (20 mM Hepes-KOH (pH 7.5), 10 mM KCl, 1.5 mM MgCl2, 1 mM EDTA, 1 mM EGTA, 1 mM DTT, 20 μg/ml leopeptin, 10μg/ml aprotonin, 250 mM sucrose) and incubated for 15 min on ice. Cells were homogenized by 15–20 passages through a 22-gauge needle, 1.5 in long. The lysates were centrifuged at 1000 g for 5 min at 4°C to pellet nuclei and unbroken cells. Supernatants were collected and centrifuged at 12 000 g for 15 min. The resulting mitochondrial pellets were suspended in lysis buffer. Supernatants were transferred to new tubes and centrifuged again at 12 000 g for 15 min and resulting supernatants representing cytosolic fractions were separated. In all, 20–25 μg of proteins from cytosolic fraction of each sample were analyzed by immunoblotting using an anticytochrome c antibody.
Measurement of mitochondrial potential using the JC-1 (5, 5′, 6, 6′-teterachloro-1, 1′, 3,3′-tetraethylbenzimidazolylcarbocyanine iodide) assay kit
In all, 1 × 106 cells were treated with curcumin for 24 h. Cells were washed twice with phosphate buffer saline (PBS) and suspended in mitochondrial incubation buffer. JC1 was added to a final concentration of 10 μ M and cells were incubated at 37°C in dark for 15 min. Cells were washed twice with PBS and resuspended in 500 μl of mitochondrial incubation buffer and mitochondrial membrane potential (% of green and red aggregates) was determined by flow cytometry as described previously (Uddin et al., 2004b).
Anto RJ, Mukhopadhyay A, Denning K and Aggarwal BB . (2002). Carcinogenesis, 23, 143–150.
Aoki Y, Feldman GM and Tosato G . (2003). Blood, 101, 1535–1542.
Aoki, Y, Yorchoan R, Braun J, Iwamoto A and Tosato G . (2000). Blood, 96, 1599–1601.
Barton BE, Murphy TF, Shu P and Huang HF . (2004). Mol. Cancer Ther., 3, 1183–1191.
Benekli M, Baer MR, Baumann H and Wetzler M . (2003). Blood, 101, 2940–2954.
Bharti AC, Donato N, Singh S and Aggarwal BB . (2003a). Blood, 101, 1053–1062.
Bharti AC, Donato N and Aggarwal BB . (2003b). J. Immunol., 171, 3863–3871.
Bharti AC, Shishodia S, Reuben JM, Weber D, Alexanian R, Raj-Vadhan S, Estrov Z, Talpaz M and Aggarwal BB . (2004). Blood, 103, 3175–3184.
Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C and Darnell Jr JE . (1999). Cell, 98, 295–303.
Buettner R, Mora LB and Jove R . (2002). Clin. Cancer Res., 8, 945–954.
Bush JA, Cheung Jr KJ and Li G . (2001). Exp. Cell Res., 271, 305–314.
Cannon ML and Cesarman E . (2004). Oncogene, 23, 514–523.
Chen H, Zhang ZS, Zhang YL and Zhou DY . (1999). Anticancer Res., 19, 3675–3680.
Cheong JW, Eom JI, Maeng HY, Lee ST, Hahn JS, Ko YW and Min YH . (2003). Leuk. Res., 27, 1159–1162.
Chuang SE, Kuo ML, Hsu CH, Chen CR, Lin JK, Lai GM, Hsieh CY and Cheng AL . (2000). Carcinogenesis, 21, 331–335.
Desagher S, Osen-Sand A, Nichols A, Eskes R, Montessuit S, Lauper S, Maundrell K, Antonsson B and Martinou JC . (1999). J. Cell Biol., 144, 891–901.
Deveraux QL and Reed JC . (1999). Genes Dev., 13, 239–252.
Deveraux QL, Roy N, Stennicke HR, Van Arsdale T, Zhou Q, Srinivasula SM, Alnemri ES, Salvesen GS and Reed JC . (1998). EMBO J., 17, 2215–2223.
Drexler HG, Uphoff CC, Gaidano G and Carbone A . (1998). Leukemia, 12, 1507–1517.
Guschin D, Rogers N, Briscoe J, Witthuhn B, Watling D, Horn F, Pellegrini S, Yasukawa K, Heinrich P and Stark GR . (1995). EMBO J., 14, 1421–1429.
Huang MT, Lou YR, Xie JG, Ma W, Lu YP, Yen P, Zhu BT, Newmark H and Ho CT . (1998). Carcinogenesis, 19, 1697–1700.
Jones KD, Aoki Y, Chang Y, Moore PS, Yarchoan R and Tosato G . (1997). Blood, 94, 2871–2879.
Kalechman Y, Gafter U, Weinstein T, Chagnac A, Freidkin I, Tobar A, Albeck M and Sredni B . (2004). J. Biol. Chem., 279, 24724–24732.
Kawamori T, Lubet R, Steele VE, Kelloff GJ, Kaskey RB, Rao CV and Reddy BS . (1999). Cancer Res., 59, 597–601.
Keller SA, Schattner EJ and Cesarman E . (2000). Blood, 96, 2537–2542.
Kim HY, Park EJ, Joe EH and Jou I . (2003). J. Immunol., 171, 6072–6079.
Klepfish A, Sarid R, Shtalrid M, Shvidel L, Berrebi A and Schattner A . (2001). Leuk. Lymphoma, 41, 439–443.
Li L, Aggarwal BB, Shishodia S, Abbruzzese J and Kurzrock R . (2004). Cancer, 101, 2351–2362.
Limtrakul P, Lipigorngoson S, Namwong O, Apisariyakul A and Dunn FW . (1997). Cancer Lett., 116, 197–203.
Lodha R and Bagga A . (2000). Ann. Acad. Med. Singapore, 29, 37–41.
Masood R, Zhang Y, Bond MW, Scadden DT, Moudgil T, Law RE, Kaplan MH, Jung B, Espina BM, Lunardi-Iskandar Y, Levin A and Jill PS . (1995). Blood, 85, 3423–3430.
Mukhopadhyay A, Bueso-Ramos C, Chatterjee D, Pantazis P and Aggarwal BB . (2001). Oncogene, 20, 7597–7609.
Nador PG, Cesarman E, Chadburn A, Dawson DB, Ansari MQ, Sald J and Knowles DM . (1996). Blood, 88, 645–656.
Prakash O, Tang ZY, Peng X, Coleman R, Gill J, Farr G and Samaniego F . (2002). J. Natl. Cancer Inst., 94, 926–935.
Pene F, Claessens YE, Muller O, Viguie F, Mayeux P, Dreyfus F, Lacombe C and Bouscary D . (2002). Oncogene, 21, 6587–6597.
Rodig SJ, Meraz MA, White JM, Lampe PA, Riley JK, Arthur CD, King KL, Sheehan KC, Yin L, Pennica D, Johnson Jr EM and Schreiber RD . (1998). Cell, 93, 373–383.
Sredni B, Weil M, Khomenok G, Lebenthal I, Teitz S, Mardor Y, Ram Z, Orenstein A, Kershenovich A, Michowiz S, Cohen YI, Rappaport ZH, Freidkin I, Albeck M, Longo DL and Kalechman Y . (2004). Cancer Res., 64, 1843–1852.
Syng-Ai C, Kumari AL and Khar A . (2004). Mol. Cancer Ther., 3, 1101–1108.
Tomlinson CC and Damania B . (2004). J. Virol., 78, 1918–1927.
Uddin S, Fish EN, Sher DA, Gardziola C, White MF and Platanias LC . (1997). J. Immunol., 158, 2390–2397.
Uddin S, Ah-Kang J, Ulaszek J, Mahmud D and Wickrema A . (2004a). Proc. Natl. Acad. Sci. USA, 101, 147–152.
Uddin S, Hussain A, Al-Hussein K, Platanias LC and Bhatia KG . (2004b). Biochem. Biophys. Res. Commun., 320, 932–938.
Uddin S, Hussain RA, Al-Husein KA, Manogaran PS, Wickrema A, Gutierrez MI and Bhatia KG . (2005). Clin. Cancer. Res., 11, 3102–3108.
Zhang C, Hazarika P, Ni X, Weidner DA and Duvic M . (2002). Clin. Cancer Res., 8, 1234–1240.
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Uddin, S., Hussain, A., Manogaran, P. et al. Curcumin suppresses growth and induces apoptosis in primary effusion lymphoma. Oncogene 24, 7022–7030 (2005). https://doi.org/10.1038/sj.onc.1208864
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