curcumin and Multiple-Myeloma

Multiple Myeloma (MM) is the third most common and deadly hematological malignancy, which is characterized by a progressive monoclonal proliferation within the bone marrow. MM is cytogenetically heterogeneous with numerous genetic and epigenetic alterations, which lead to a wide spectrum of signaling pathways and cell cycle checkpoint aberrations. MM symptoms can be attributed to CRAB features (hyperCalcemia, Renal failure, Anemia, and Bone lesion), which profoundly affect both the Health-Related Quality of Life (HRQoL) and the life expectancy of patients. Despite all enhancement and improvement in therapeutic strategies, MM is almost incurable, and patients suffering from this disease eventually relapse. Curcumin is an active and non-toxic phenolic compound, isolated from the rhizome of Curcuma longa L. It has been widely studied and has a confirmed broad range of therapeutic properties, especially anti-cancer activity, and others, including anti-proliferation, anti-angiogenesis, antioxidant and anti-mutation activities. Curcumin induces apoptosis in cancerous cells and prevents Multidrug Resistance (MDR). Growing evidence concerning the therapeutic properties of curcumin caused a pharmacological impact on MM. It is confirmed that curcumin interferes with various signaling pathways and cell cycle checkpoints, and with oncogenes. In this paper, we summarized the anti- MM effects of curcumin.

Topics: Antineoplastic Agents, Phytogenic; Cell Cycle; Cell Proliferation; Cell Survival; Curcuma; Curcumin; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Multiple Myeloma

Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) represent useful models for studying multiple myeloma precursor disease, and for developing early intervention strategies. Administering a 4g dose of curcumin, we performed a randomised, double-blind placebo-controlled cross-over study, followed by an open-label extension study using an 8g dose to assess the effect of curcumin on FLC response and bone turnover in patients with MGUS and SMM. 36 patients (19 MGUS and 17 SMM) were randomised into two groups: one received 4g curcumin and the other 4g placebo, crossing over at 3 months. At completion of the 4g arm, all patients were given the option of entering an open-label, 8g dose extension study. Blood and urine samples were collected at specified intervals for specific marker analyses. Group values are expressed as mean ± 1 SD. Data from different time intervals within groups were compared using Student's paired t-test. 25 patients completed the 4g cross-over study and 18 the 8g extension study. Curcumin therapy decreased the free light-chain ratio (rFLC), reduced the difference between clonal and nonclonal light-chain (dFLC) and involved free light-chain (iFLC). uDPYD, a marker of bone resorption, decreased in the curcumin arm and increased on the placebo arm. Serum creatinine levels tended to diminish on curcumin therapy. These findings suggest that curcumin might have the potential to slow the disease process in patients with MGUS and SMM.

Topics: Aged; Aged, 80 and over; Amino Acids; Antineoplastic Agents, Phytogenic; Biomarkers; Bone Remodeling; Creatinine; Cross-Over Studies; Curcumin; Disease Progression; Double-Blind Method; Female; Humans; Immunoglobulin Light Chains; Male; Middle Aged; Monoclonal Gammopathy of Undetermined Significance; Multiple Myeloma; Myeloma Proteins; Parathyroid Hormone; Treatment Outcome; Vitamin D

Multiple myeloma (MM) is a hematological bone marrow malignancy that can be treated but is usually fatal. Medication resistance is the major cause of relapses due to cancer stem cells (CSCs). As a result, this study aimed to identify multiple myeloma cancer stem cells (MMCSCs) in the bone marrow of twelve MM patients with pathological complete response (pCR) after chemotherapy and to investigate the potential effect of Curcumin/Piperine (C/P) extract as an anti-MMCSCs treatment in twenty newly diagnosed patients.. This study included twenty bone marrow (BM) samples from newly diagnosed MM patients and twelve BM samples from pCR patients after a year of treatment. The MTT test was performed to assess the treatment's effective dosage. A flow cytometer was used to identify MMCSCs, cell cycle profile, extract's apoptotic activity, and proliferation marker in the selected samples. Also,  a colony formation test and stemness protein were investigated.. In newly diagnosed MM patients, the C/P extract suppressed MMCSCs by 64.71% for CD138-/CD19- and 38.31% for CD38++. In MM patients' samples obtained after one year of treatment, the MMCSCs inhibition percentage reached 44.71% (P < 0.008) for CD138-/CD19- and 36.94% (P < 0.221) for CD38++. According to cell cycle analyses, the number of cells treated with C/P extract was significantly reduced in the S and G0/G1 phases (87.38%: 35.15%, and 4.83%: 2.17% respectively), with a rapid increase in the G2/M phases (1.1%: 2.2%.). MMCSCs apoptosis was identified using a flow cytometer and Annexin-V. Multiple myeloma stem cell (MMCSC) proliferation was inhibited. Clonogenicity was suppressed by 60%, and stemness protein expression was reduced by 70%.. MMCSCs in the bone marrow of MM-pCR patients can be utilized as a prognostic tool to predict recurrent multiple myeloma incidence. Also, the therapeutic potential of C/P extract as a prospective anti-MM drug targeting MMCSCs.

Topics: Biomarkers; Curcumin; Humans; Multiple Myeloma; Neoplasm Recurrence, Local; Neoplastic Stem Cells; Prognosis

To evaluated the effect of curcumin on the bortezomib-resistant myeloma cells and the expression of Notch1 signaling pathway, in order to further explore its potential mechanism.. Curcumin, bortezomib, and curcumin combined bortezomib were added into RPMI 8266, U266, 5 nmol/L bortezomib-resistant RPMI 8266 (RPMI 8226-V5R), 5 nmol/L bortezomib-resistant U 266 (U266-V5R) and CD138+ plasma cells respectively. The cell proliferation was measured by MTT assay. the apoptotic rate was determined by flow cytometry, and the Western blot was used to detect the expression of apoptosis-related proteins. Then, the expression of Notch1 in cells was inhibited by notch1 inhibitor DAPT and RNA interference, the above-motioned experiments should be repeated.. Compared with single drug-treated groups, the treatment with 2 drugs could further inhibit cell proliferation, induce apoptosis and enhance the inhibition effect on notch1 signaling pathway (P<0.05), while the inhibiting Notch1 signaling pathway could reduce cell proliferation and increase the expression of cleaved caspase-3.. Curcumin can increase chemosensitivity of myeloma cells to bortezomib, this effect may be related to the inhibition of Notch1.. 姜黄素通过抑制Notch1信号通路增强多发性骨髓瘤对硼替佐米的化疗敏感性.. 探讨姜黄素对耐硼替佐米的骨髓瘤细胞的作用以及对Notch1信号通路表达的影响，进一步探索其潜在的作用机制。.. 分别将姜黄素、硼替佐米及姜黄素+硼替佐米作用于骨髓瘤细胞系RPMI8266、U266、耐5 nmol/L硼替佐米的RPMI 8266（RPMI8226-V5R）、耐5 nmol硼替佐米的U266（U266-V5R）及骨髓瘤CD138+浆细胞，应用MTT法检测细胞增殖活性，流式细胞术检测细胞凋亡，Western blot检测凋亡相关蛋白的表达；利用notch1抑制剂DAPT及RNA干扰技术抑制细胞内notch1表达，重复上述实验。.. 与单药组相比，联合作用组可进一步抑制细胞增殖，增加细胞凋亡，增强对Notch1信号通路的抑制作用（P＜0.05）；而抑制Notch1可以减少细胞的增殖，并增加凋亡相关蛋白Cleaved caspase-3的表达水平。.. 姜黄素能够增强骨髓瘤细胞对硼替佐米的敏感性，此作用可能与Notch1受抑制有关。.

Topics: Apoptosis; Bortezomib; Cell Line, Tumor; Cell Proliferation; Curcumin; Humans; Multiple Myeloma; Receptor, Notch1; Signal Transduction

Multiple myeloma is the second most prevalent hematologic malignancy and thought to be incurable. Therefore, it's urgent to find new drugs for treatment. Some experiments have shown that curcumin might have great potential in treating multiple myeloma, while the mechanism is still unknown. EZH2 and SUZ12 are the core proteins in PRC2 and their expressions are increased in various human cancers, including the poor prognostic multiple myeloma. Meanwhile, the regulation of miRNAs and EZH2 has been demonstrated in other cancer researches, like lung cancer, pancreatic cancer, leukemia and so on.. To reveal the mechanism behind the anti-tumor effect of cucurmin in multiple myeloma.. The effect of curcumin on the growth of MM cells was studied by MTT assay in the MM cell lines RPMI8226 and U266. Apoptosis was measured by Annexin V-FITC/PI double staining method. Western blotting, RT-PCR and luciferase activity assay were used to assess the expression of EZH2, SUZ12, miR-101 and downstream proteins such as E-cadherin, MMP9, c-Myc, cyclin D3, CDK4 and CDK6.. Curcumin could significantly inhibite the proliferation of MM cells in a time- and concentrationdependent manner. Curcumin induced apoptosis by inhibiting the expression of EZH2, and the apoptosis rates were 16.42% and 25.62% when the RPMI8226 cells incubated with 5 and 10 µmol/L of curcumin. For U266 cells, the apoptosis rates were 15.25% and 21.28%. The up-regulation of miR-101 led to the lower expression of EZH2. In adverse, the expression of EZH2 induced lower expression of miR-101. The down-stream proteins of miR-101 were regulated by curcumin and EZH2 at the same time.. Our experiments verified that the effect and mechanism of curcumin on multiple myeloma is via EZH2 - miR-101 regulatory feedback loop, which would lead us to a new way of investigating multiple myeloma and come up with new therapies in treating the disease.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Curcumin; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Enhancer of Zeste Homolog 2 Protein; Humans; MicroRNAs; Multiple Myeloma; RNA, Messenger; Structure-Activity Relationship

Multiple myeloma (MM) is a malignant B-cell neoplasm with accumulation of malignant plasma cells in bone marrow. Pharmacological therapy improves response frequency even if with various associated toxicities. Herein, we investigated if combination of curcumin with carfilzomib (CFZ) can induce a better cytotoxic effect on in vitro cultured U266 cells. Cell viability data showed that curcumin significantly ameliorates CFZ cytotoxic effect. Furthermore, curcumin alone did not affect proteasome at the tested dose, confirming the involvement of different mechanisms in the observed effects. U266 cells exposure to curcumin or CFZ increased reactive species (RS) levels, although their production did not appear further potentiated following drugs combination. Interestingly, NF-κB nuclear accumulation was reduced by treatment with CFZ or curcumin, and was more deeply decreased in cells treated with CFZ-curcumin combinations, very likely due to the different mechanisms through which they target NF-κB. Our results confirmed the induction of p53/p21 axis and G0/G1 cell cycle arrest in anticancer activities of both drugs, an effect more pronounced for the CFZ-curcumin tested combinations. Furthermore, curcumin addition enhanced CFZ proapoptotic effect. These findings evidence that curcumin can ameliorate CFZ efficacy, and lead us to hypothesize that this effect might be useful to optimize CFZ therapy in MM patients.

Topics: Active Transport, Cell Nucleus; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Survival; Curcumin; Humans; Multiple Myeloma; Neoplasm Proteins; NF-kappa B p50 Subunit; Oligopeptides; Osmolar Concentration; Oxidative Stress; Proteasome Inhibitors; Reactive Oxygen Species; Resting Phase, Cell Cycle; Signal Transduction; Tumor Suppressor Protein p53

Myeloma is a haematological malignancy which typically follows a relapsing-remitting course. While treatment can control the myeloma and improve quality of life for given periods of time, remissions generally become progressively shorter with subsequent relapses, and patients ultimately enter a final refractory phase. To help control symptoms and enhance quality of life, some patients use complementary therapies as an adjunct to their conventional therapy. Here, we describe a myeloma patient who started a daily dietary supplement of curcumin when approaching her third relapse. In the absence of further antimyeloma treatment, the patient plateaued and has remained stable for the last 5 years with good quality of life.

Topics: Curcumin; Female; Humans; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Treatment Outcome

Hypothesis Prior studies on patients with early B-cell lymphoid malignancies suggest that early intervention with curcumin may lead to delay in progressive disease and prolonged survival. These patients are characterized by increased susceptibility to infections. Rice bran arabinoxylan (Ribraxx) has been shown to have immunostimulatory, anti-inflammatory, and proapoptotic effects. We postulated that addition of Ribraxx to curcumin therapy may be of benefit. Study design Monoclonal gammopathy of undetermined significance (MGUS)/smoldering multiple myeloma (SMM) or stage 0/1 chronic lymphocytic leukemia (CLL) patients who had been on oral curcumin therapy for a period of 6 months or more were administered both curcumin (as Curcuforte) and Ribraxx. Methods Ten MGUS/SMM patients and 10 patients with stage 0/1 CLL were administered 6 g of curcumin and 2 g Ribraxx daily. Blood samples were collected at baseline and at 2-month intervals for a period of 6 months, and various markers were monitored. MGUS/SMM patients included full blood count (FBC); paraprotein; free light chains/ratio; C-reactive protein (CRP)and erythrocyte sedimentation rate (ESR); B2 microglobulin and immunological markers. Markers monitored for stage 0/1 CLL were FBC, CRP and ESR, and immunological markers. Results Of 10 MGUS/SMM patients,5 (50%) were neutropenic at baseline, and the Curcuforte/Ribraxx combination therapy showed an increased neutrophil count, varying between 10% and 90% among 8 of the 10 (80%) MGUS/SMM patients. An additional benefit of the combination therapy was the potent effect in reducing the raised ESR in 4 (44%) of the MGUS/SMM patients. Conclusion Addition of Ribraxx to curcumin therapy may be of benefit to patients with early-stage B-cell lymphoid malignancies.

Topics: Aged; Aged, 80 and over; Biomarkers, Tumor; C-Reactive Protein; Curcumin; Disease Progression; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocytes; Male; Middle Aged; Monoclonal Gammopathy of Undetermined Significance; Multiple Myeloma; Myeloma Proteins; Oryza; Xylans

Multiple myeloma (MM), a plasma cell malignancy, remains incurable despite the development of new therapies. Curcumin anti-tumor effects were previously characterized in multiple myeloma, however only few MM cell lines were included in these studies. Since myeloma is a heterogeneous disease it is important to address the impact of myeloma molecular heterogeneity in curcumin cell death induction. In the present study, a large panel of human myeloma cell lines (HMCLs) (n = 29), representing the main molecular MM subgroups, was screened for curcumin sensitivity. We observed that curcumin cell death induction was heterogeneous, of note 16 HMCLs were highly sensitive to curcumin (LD50 < 20.5 μM), 6 HMCLs exhibited intermediate LD50 values (20.5 μM ≤ LD50 < 32.2 μM) and only 7 HMCLs were weakly sensitive (35 < LD50 < 56 μM). Cell lines harboring the t(11;14) translocation were less sensitive (median LD50 32.9 μM) than non-t(11;14) (median LD50 17.9 μM), which included poor prognosis t(4;14) and t(14;16) cells. Interestingly, curcumin sensitivity was not dependent on TP53 status. For the first time we showed that primary myeloma cells were also sensitive, even those displaying del(17p), another poor prognosis factor. We also unravel the contribution of anti-apoptotic Bcl-2 family molecules in curcumin response. We found that down-regulation of Mcl-1, an essential MM survival factor, was associated with curcumin-induced cell death and its knockdown sensitized myeloma cells to curcumin, highlighting Mcl-1 as an important target for curcumin-induced apoptosis. Altogether, these results support clinical trials including curcumin in association with standard therapy.

Topics: Antineoplastic Agents; Caspase 3; Cell Death; Cell Line, Tumor; Curcumin; Drug Resistance, Neoplasm; Humans; Multiple Myeloma; Myeloid Cell Leukemia Sequence 1 Protein; Plasma Cells; Prognosis

Multiple myeloma (MM) is a hematological malignancy characterized by the aberrant accumulation of clonal plasma cells in the bone marrow. Despite recent advancement in anti-myeloma treatment, MM remains an incurable disease. This study showed higher intrinsic oxidative stress and higher Trx1 and TrxR1 protein levels in MM cells compared to normal cells. Drug-induced Trx1 (PX-12) and TrxR1 (Auranofin) inhibition disrupted redox homeostasis resulting in ROS-induced apoptosis in MM cells and a reduction in clonogenic activity. Knockdown of either Trx1 or TrxR1 reduced MM cell viability. Trx1 inhibition by PX-12 sensitized MM cells to undergo apoptosis in response to the NF-κβ inhibitors, BAY 11-7082 and curcumin. PX-12 treatment decreased the expression of the NF-κβ subunit p65 in MM cells. Bortezomib-resistant MM cells contained higher Trx1 protein levels compared to the parental cells and PX-12 treatment resulted in apoptosis. Thus, increased Trx1 enhances MM cell growth and survival and exerts resistance to NF-κβ inhibitors. Therefore inhibiting the thioredoxin system may be an effective therapeutic strategy to treat newly diagnosed as well as relapsed/refractory MM.

Topics: Apoptosis; Auranofin; Bortezomib; Caspase 3; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Disulfides; Drug Resistance, Neoplasm; Humans; Imidazoles; Leukocytes, Mononuclear; Multiple Myeloma; Nitriles; Oxidative Stress; Reactive Oxygen Species; Sulfones; Thioredoxin Reductase 1; Thioredoxins; Transcription Factor RelA

In our efforts to develop effective treatment agents for human multiple myeloma (MM), a series of hybrid molecules based on the structures of thalidomide (1) and curcumin (2) were designed, synthesized, and biologically characterized in human multiple myeloma MM1S, RPMI8226, U266 cells, and human lung cancer A549 cells. The biological results showed that two hybrid compounds, 5 and 7, exhibited significantly improved lethal effects towards all three human MM cell models compared to 1 or 2 alone, as well as the combination of 1 and 2. Furthermore, mechanistic studies in U266 cells demonstrated that 5 and 7 can induce the production of reactive oxygen species (ROS) and cause G1/S arrest, thus leading to apoptosis and cell death. Additionally, they exhibited inhibitory effects on NFκB activation in A549 cells. Collectively, the results obtained from these hybrid compounds strongly encourage their further optimization as new leads to develop effective treatment agents for human MM.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Curcumin; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Multiple Myeloma; Reactive Oxygen Species; Structure-Activity Relationship; Thalidomide

The proteasome plays a vital role in the degradation of proteins involved in several pathways including the cell cycle, cellular proliferation and apoptosis and is a validated target in cancer treatment. Bortezomib (Velcade®, PS-341) is the first US FDA approved proteasome inhibitor anticancer drug used in the treatment of refractory multiple myeloma. In spite of its improved efficacy compared to alternative therapies, about 60% of patients do not respond to bortezomib due to the emergence of resistance. We hypothesized that novel small molecules could enhance the proteasome-inhibitory and anticancer activities of bortezomib in resistant multiple myeloma cells in vitro and in vivo. The dietary polyphenol curcumin has been shown to exert anti-cancer activity in several cancer cell lines, but the effects of curcumin in solid tumors have been modest primarily due to poor water solubility and poor bioavailability in tissues remote from the gastrointestinal tract. Here we show that the water-soluble analog of curcumin #12, but not curcumin, in combination with bortezomib could enhance the proteasome-inhibitory effect in multiple myeloma cells. Furthermore, the sensitivity of the myeloma cells to cytotoxic killing in the presence of otherwise sublethal concentrations of bortezomib was enhanced by incubation with the curcumin analog #12. These findings justify further investigation into those combinations that may yield potential therapeutic benefit.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Boronic Acids; Bortezomib; Cell Line, Tumor; Cell Proliferation; Curcumin; Drug Synergism; Humans; Immunoblotting; Multiple Myeloma; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Pyrazines

Topics: Antineoplastic Agents, Phytogenic; Curcumin; Female; Humans; Male; Monoclonal Gammopathy of Undetermined Significance; Multiple Myeloma

Combined curcumin and PS-341 treatment has been reported to enhance cytotoxicity and minimize adverse effects through ERK and p38MAPK mechanisms in human multiple myeloma cells. However, whether JNK plays similar role in this process remains unclear. In the present study, we found combined treatment altered NF-κB p65 expressions and distributions in multiple myeloma H929 cells. Western blot analysis showed combined treatment inactivated NF-κB while activated JNK signaling. Pre-treatment with JNK inhibitor SP600125 could attenuate NF-κB inactivation and restored H929 cells' survival. These results suggested that curcumin might enhance the cytotoxicity of PS-341 by interacting with NF-κB, at least in part, through JNK mechanism.

Topics: Anthracenes; Antineoplastic Agents; Apoptosis; Boronic Acids; Bortezomib; Cell Line, Tumor; Curcumin; Drug Synergism; Extracellular Signal-Regulated MAP Kinases; Humans; JNK Mitogen-Activated Protein Kinases; MAP Kinase Signaling System; Multiple Myeloma; p38 Mitogen-Activated Protein Kinases; Pyrazines; Transcription Factor RelA

Topics: Antineoplastic Agents, Phytogenic; Curcumin; Female; Humans; Male; Monoclonal Gammopathy of Undetermined Significance; Multiple Myeloma

Acquired chemotherapy resistance is a major contributor to treatment failure in oncology. For example, the efficacy of the common anticancer agent doxorubicin (DOX) is limited by the emergence of multidrug resistance (MDR) phenotype in cancer cells. While dose escalation of DOX can circumvent such resistance to a degree, this is precluded by the appearance of cardiotoxicity, a particularly debilitating condition in children. In vitro studies have established the ability of the natural phytochemical curcumin to overcome MDR; however, its widespread clinical application is restricted by poor solubility and low bioavailability. Building upon our recently developed polymer nanoparticle of curcumin (NanoCurc or NC) that significantly enhances the systemic bioavailability of curcumin, we synthesized a doxorubicin-curcumin composite nanoparticle formulation called NanoDoxCurc (NDC) for overcoming DOX resistance. Compared to DOX alone, NDC inhibited the MDR phenotype and caused striking growth inhibition both in vitro and in vivo in several models of DOX-resistant cancers (multiple myeloma, acute leukemia, prostate and ovarian cancers, respectively). Notably, NDC-treated mice also demonstrated complete absence of cardiac toxicity, as assessed by echocardiography, or any bone marrow suppression, even at cumulative dosages where free DOX and pegylated liposomal DOX (Doxil®) resulted in demonstrable attenuation of cardiac function and hematological toxicities. This improvement in safety profile was achieved through a reduction of DOX-induced intracellular oxidative stress, as indicated by total glutathione levels and glutathione peroxidase activity in cardiac tissue. A composite DOX-curcumin nanoparticle that overcomes both MDR-based DOX chemoresistance and DOX-induced cardiotoxicity holds promise for providing lasting and safe anticancer therapy.

Topics: Animals; Antibiotics, Antineoplastic; Cardiomyopathies; Cell Line, Tumor; Curcumin; Doxorubicin; Drug Resistance, Neoplasm; Glutathione; Humans; Male; Mice; Mice, Nude; Multiple Myeloma; Nanoparticles; Prostatic Neoplasms; Random Allocation; Xenograft Model Antitumor Assays

Topics: Antineoplastic Agents, Phytogenic; Curcumin; Female; Humans; Male; Monoclonal Gammopathy of Undetermined Significance; Multiple Myeloma

The present study was carried out to investigate the synergistic apoptotic potential of arabinoxylan rice bran (MGN-3/Biobran) and curcumin (turmeric) on human multiple myeloma (MM) cell line U266 , in vitro. U266 cells were cultured with MGN-3 (50 or 100μg/ml) and curcumin (2.5-10μM) for 3 days. The effects of MGN-3 and curcumin on the growth and survival of the U266 cells were determined by trypan blue, MTT assay, flow cytometry analysis of cancer cell cycle, and apoptosis. Expression of proapoptotic Bax, and antiapoptotic Bcl2 was determined by Western blot analysis. Treatment with MGN-3 alone or curcumin alone caused a dose-dependent inhibition in the proliferation of U266 cells. However, a synergistic effect was noticed post-treatment with both agents that maximized at 100μg/ml MGN-3 plus 10μM curcumin. This synergy was characterized by an 87% decrease in cell number and a 2.6 fold increase in the percentage of apoptotic U266 cells. Cell cycle analysis showed a 53% decrease in the percentage of cells in the G0-G1 phase treated with MGN-3 and curcumin (from 36% to 17%). Analysis of the expression of the pro and antiapoptotic molecules Bax and Bcl-2 revealed synergistic effects of these agents, as the expression of Bcl-2 was decreased and Bax was increased. This resulted in a cellular microenvironment favorable for apoptosis. We conclude that MGN-3 and curcumin synergize in the induction of U266 cell apoptosis. This data may establish the foundation for in vivo studies that could have therapeutic implications.

Topics: Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Survival; Curcumin; Drug Synergism; Humans; Multiple Myeloma; Xylans

This study was aimed to investigate the effect of curcumin in combination with bortezomib on the proliferation and apoptosis of human MM cell line H929 in vitro, and to explore its mechanisms. MTT assay was applied to detect the inhibitory effects of curcumin and bortezomib either alone or combined at different concentrations on H929 cells, and flow cytometry was employed to assay the apoptosis rate. In addition, RT-PCR was used to analyze the mRNA expression of gene BCL-2, BAX, cyclin D1. Immunofluorescence technique was performed to study the location changes of NF-κB P65 in different groups. The results showed that both curcumin and bortezomib inhibited the proliferation of MM cell line H929 in dose-dependent manner, and combination of these two drugs displayed synergistical effect. A much higher apoptosis rate was determined by flow cytometry in combinative groups than that in single or control group. And RT-PCR showed, as compared with curcumin or bortezomib group, there was mRNA expression decrease of BCL-2, cyclin D1 but increase of BAX in combined group. The expression of NF-κB P65 in nucleus was downregulated in either the curcumin or bortezomib group, however, distribution of NF-κB P65 in cytoplasm was observed in combined group. It is concluded that the combination of curcumin and bortezomib is much more effective for the inhibiting proliferation and promoting apoptosis of H929 cell line, which may function by inhibiting the transcription of NF-κB and apoptosis-related genes.

Topics: Apoptosis; bcl-2-Associated X Protein; Boronic Acids; Bortezomib; Cell Line, Tumor; Cell Proliferation; Curcumin; Cyclin D1; Drug Therapy, Combination; Humans; Multiple Myeloma; NF-kappa B; Proto-Oncogene Proteins c-bcl-2; Pyrazines; Transcription Factor RelA

Multiple myeloma remains an incurable malignancy despite of the recent approval of new molecular-targeted agents. The complex molecular mechanism, composed of various signal networks, including nuclear factor-κB (NF-κB), phosphoinositide 3-kinase (PI3K)/AKT, Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3), and interferon regulatory factor 4 (IRF4) pathways, is a major reason for treatment failure. Curcumin can regulate these molecules, but its low bioavailability prevents its clinical application.. Growth-suppressive abilities of newly synthesized analogs, GO-Y030 and GO-Y078 were analyzed. Molecular-targeted abilities of the analogs for NF-κB, PI3K/AKT, JAK/STAT3, IRF4 pathways, as well as inhibition of interleukin-6 (IL-6) production, were also examined.. GO-Y030 and GO-Y078 were 7 to 12-fold more potent growth suppressors for myeloma cells, and 6- to 15-fold stronger inhibitors of NF-κB, PI3K/AKT, JAK/STAT3, and IRF4 pathways than curcumin. GO-Y78 also 14-fold more potently inhibited IL-6 production.. GO-Y030 and GO-Y078 are potential therapeutic candidates with enhanced abilities for multiple myeloma.

Topics: Apoptosis; Benzene Derivatives; Blotting, Western; Cell Cycle; Cell Proliferation; Curcumin; Flow Cytometry; Humans; Interferon Regulatory Factors; Interleukin-6; Janus Kinase 1; Ketones; Multiple Myeloma; NF-kappa B; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Tumor Cells, Cultured

Most patients with multiple myeloma (MM) will relapse eventually due to the acquired multidrug resistance (MDR). The objective of this study was to explore the reversal effect of curcumin on the MDR of human MM cell line, MOLP-2/R, and analyze the role of Fanconi anemia (FA)/BRCA pathway in this process. MOLP-2/R was selected by stepwise exposure of parental MOLP-2 cells to increasing concentrations of melphalan. The MTT assay was used to detect the reversal ratio of curcumin. The FANCD2 monoubiquitination expression was detected by western blotting to explore the role of FA/BRCA pathway. Cell cycle, apoptosis, and intracellular drug concentration were analyzed by flow cytometry. The results indicated that combination of melphalan with curcumin had stronger effects on the proliferation inhibition, inducement of apoptosis, G2/M phase arrest, and enhancement of intracellular drug concentration than melphalan alone in MOLP-2/R cells. These effects were accompanied with inhibition of FA/BRCA pathway by down regulation of FANCD2 protein monoubiquitination in a dose-dependent manner. In conclusion, curcumin reversed multidrug resistance of MOLP-2/R through inhibition of FA/BRCA pathway. The possible mechanisms include (1) reduction of DNA damage repair and stimulation of apoptosis of tumor cells through inhibition of FA/BRCA pathway, which is important for DNA repair, and (2) achievement of high concentration in target cells. Curcumin may be a safe reversal agent of multidrug resistance with low-dose DNA cross-linking agents.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Curcumin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Fanconi Anemia Complementation Group D2 Protein; Humans; Multiple Myeloma; Signal Transduction; Ubiquitination

Curcumin (diferuloylmethane), a yellow pigment in turmeric, has been shown to inhibit the activation of nuclear factor-kappaB (NF-kappaB), a transcription factor closely linked to chemoresistance in multiple myeloma cells. Whether curcumin can overcome chemoresistance and enhance the activity of thalidomide and bortezomib, used to treat patients with multiple myeloma, was investigated in vitro and in xenograft model in nude mice. Our results show that curcumin inhibited the proliferation of human multiple myeloma cells regardless of their sensitivity to dexamethasone, doxorubicin, or melphalan. Curcumin also potentiated the apoptotic effects of thalidomide and bortezomib by down-regulating the constitutive activation of NF-kappaB and Akt, and this correlated with the suppression of NF-kappaB-regulated gene products, including cyclin D1, Bcl-xL, Bcl-2, TRAF1, cIAP-1, XIAP, survivin, and vascular endothelial growth factor. Furthermore, in a nude mice model, we found that curcumin potentiated the antitumor effects of bortezomib (P<0.001, vehicle versus bortezomib+curcumin; P<0.001, bortezomib versus bortezomib+curcumin), and this correlated with suppression of Ki-67 (P<0.001 versus control), CD31 (P<0.001 versus vehicle), and vascular endothelial growth factor (P<0.001 versus vehicle) expression. Collectively, our results suggest that curcumin overcomes chemoresistance and sensitizes multiple myeloma cells to thalidomide and bortezomib by down-regulating NF-kappaB and NF-kappaB-regulated gene products.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Boronic Acids; Bortezomib; Cell Proliferation; Curcumin; Disease Models, Animal; Drug Resistance, Neoplasm; Drug Synergism; Humans; Immunoenzyme Techniques; Male; Mice; Mice, Nude; Multiple Myeloma; NF-kappa B; Proto-Oncogene Proteins c-akt; Pyrazines; Signal Transduction; Thalidomide; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

To investigate the reverse effect of mutidrug resistance of curcumin combined with melphalan on the mutidrug-resistant human multiple myeloma cell line MOLP-2/R and the relation with FA/BRCA pathway.. The inhibitory effects of the drugs on the growth of MOLP-2/R cells were determined by MTT assay. Cell cycle analysis, intracellular drug concentration and apoptosis were assayed by flow cytometry. The expression of FANCD2 monoubiquitination was determined by Western blot analysis.. Co-administration of curcumin and melphalan had an synergistic inhibitory effects on the proliferation, IC50 of melphalan with 10 micromol/L curcumin reduced from 45.5 micromol/L to 19 micromol/L in MOLP-2/R cells. The apoptosis percentage of MOLP-2/R cells was significantly increased from (23.3 +/- 0.6)% to (52.6% +/- 0.8)% by the treatment of melphalan 20 micromol/L plus curcumin 10 micromol/L with the increased percentage of cells in the G2/M phase (from 9.1% to 18.5%) and enhanced intracellular drug concentration of MOLP-2/ R cells (from 15.2 +/- 0.3 to 21.4 +/- 0.8 ). The effects were accompanied with inhibition of FA/BRCA pathway by down regulation of FANCD2 protein monoubiquitination.. Curcumin combined with melphalan results in synergistic effects and reverses multiple drug resistance of MOLP-2/R cells effectively. The inhibition of FA/BRCA pathway may be the mechanism.

Topics: Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Curcumin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Fanconi Anemia Complementation Group D2 Protein; Humans; Multiple Myeloma

Growth of multiple myeloma cells is controlled by various factors derived from host bone marrow microenvironments. Interaction between multiple myeloma cells and bone marrow stromal cells (BMSCs) plays an important role in the expression of adhesive molecules and secretion of growth factors involved in multiple myeloma (MM) cell growth, survival, and resistance to anticancer drugs. Recently, the possibility of developing novel anti-cancer therapeutic strategies targeting both MM cells and MM cell-BMSC interactions has been discussed. Here we present data showing that curcumin, a major constituent of turmeric compounds extracted from the rhizomes of the plant Curcuma longa, effectively reduced the growth of MM cells and BMSCs. Upon treatment with curcumin, IL-6/sIL-6R-induced STAT3 and Erk phosphorylation was dramatically reduced in the co-cultured cells. In addition, curcumin inhibited the production of pro-inflammatory cytokines and VEGF, factors that are associated with the progression of multiple myeloma, from both MM cells and BMSCs. In a combination treatment with curcumin and bortezomib, IL-6/sIL-6R-induced STAT3 and Erk phosphorylation was effectively inhibited. Moreover, this combination treatment synergistically inhibited the growth of MM cells co-cultured with BMSCs as compared to controls. Taken together, these results indicate that curcumin potentiates the therapeutic efficacy of bortezomib in MM suggesting this combination therapy to be of value in the clinical management of MM.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Boronic Acids; Bortezomib; Cell Line, Tumor; Cell Proliferation; Coculture Techniques; Curcumin; Cytokines; Drug Synergism; Humans; Inflammation Mediators; Multiple Myeloma; Pyrazines; Stromal Cells

To explore the mechanisms of suppression growth and induction apoptosis of curcumin on human multiple myeloma cell line RPMI8226, the suppressive effect of curcumin on RPMI8226 was examined by MTT assay; the induction apoptosis and cell cycle arrest of curcumin on RPMI8226 were determined by flow cytometry (FCM); the changes of survivin, Bcl-2, Bax mRNA levels were detected by RT-PCR. The results showed that curcumin obviously suppressed the proliferation of RPMI8226 in both time- and dose-dependent manners, and the IC(50) were 12.15 micromol/L, 4.9 micromol/L for 24 and 48 hours respectively. FCM indicated that the apoptosis ratio rose from 10.6% of untreated cells up to 36.9% of treated cells (p < 0.05), and curcumin arrested cell cycle of RPMI8226 at G(2)/M phase. RT-PCR showed that RPMI8226 cells expressed survivin, Bcl-2 strongly and Bax slightly; while RPMI8226 cells were treated with curcumin 10 micromol/L for 24 hours, the expressions of survivin, Bcl-2 mRNA were apparently down-regulated, and the expression of Bax mRNA was markedly up-regulated. It is concluded that curcumin can suppress the proliferation of human multiple myeloma cell line RPMI8226, and induce their apoptosis. The mechanism of antitumous effect of curcumin may be related to down-regulation of survivin, Bcl-2 mRNA and up-regulation of Bax mRNA.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Curcumin; Humans; Inhibitor of Apoptosis Proteins; Microtubule-Associated Proteins; Multiple Myeloma; Proto-Oncogene Proteins c-bcl-2; RNA, Messenger; Survivin

In order to explore the probability of curcumin treating multiple myeloma (MM) via the inhibition of angiogenesis, the expressions of brain derived neurotrophic factor (BDNF) and its specific receptor in human MM cells and endothelial cells were detected by reverse transcriptase-polymerase chain reaction (RT-PCR). The angiogenic activity was evaluated by endothelial cell migration assay and tubule formation assay in vitro. The results showed that exogenous BDNF significantly induced endothelial cell tubule formation and endothelial cell migration, these two effects were inhibited by curcumin. Furthermore, BDNF was detected in the MM cell and TrkB was detected in the endothelial cell and curcumin depressed the mRNA expression of BDNF and TrkB in the dose- and time-dependent manners. It is concluded that BDNF is a novel angiogenesis protein. Curcumin interrupts the interaction between multiple myeloma cells and endothelial cells by reducing TrkB expression in endothelial cells and inhibiting BDNF production in multiple myeloma cells, eventually, resulting in inhibition of angiogenesis. This is probably one part of the mechanism of the curcumin treating MM via the inhibition of angiogenesis.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Brain-Derived Neurotrophic Factor; Cell Line, Tumor; Curcumin; Endothelial Cells; Humans; Multiple Myeloma; Neovascularization, Pathologic; RNA, Messenger

Chemoresistance is a major problem in the treatment of patients with multiple myeloma (MM). Because of the central role of the nuclear transcription factors nuclear factor-kappaB (NF-kappaB) and signal transducer and activator of transcription 3 (STAT3) in chemoresistance, cell survival, and proliferation, we investigated whether MM cells derived from patients express activated NF-kappaB and STAT3 and if their suppression induces apoptosis. We assayed CD138+ cells from the bone marrow of 22 MM patients and checked for the activated forms of NF-kappaB and STAT3 by immunocytochemistry. We found that MM cells from all the patients expressed the activated forms of NF-kappaB and STAT3 but to a variable degree (NF-kappaB: low, 3 of 22; moderate, 5 of 22; or high, 14 of 22; STAT3: none, 1 of 22; low, 3 of 22; moderate, 5 of 22; or high, 14 of 22). Constitutive activation of NF-kappaB was in some cases also independently confirmed by electrophoretic mobility gel shift assay. In contrast to MM patients, activated forms of NF-kappaB and STAT3 were absent in cells from healthy individuals. Suppression of NF-kappaB and STAT3 activation in MM cells by ex vivo treatment with curcumin (diferuloylmethane) resulted in a decrease in adhesion to bone marrow stromal cells, cytokine secretion, and in the viability of cells. When compared with curcumin, dexamethasone was less effective in suppression of NF-kappaB activation and induction of apoptosis in myeloma cells. Overall, our results indicate that fresh cells from MM patients express constitutively active NF-kappaB and STAT3, and suppression of these transcription factors inhibits the survival of the cells.

Topics: Adult; Aged; Apoptosis; Bone Marrow Cells; Cell Adhesion; Cell Survival; Curcumin; Dexamethasone; DNA-Binding Proteins; Drug Resistance, Neoplasm; Female; Humans; Immunohistochemistry; In Vitro Techniques; Interleukin-6; Male; Membrane Glycoproteins; Middle Aged; Multiple Myeloma; NF-kappa B; Proteoglycans; STAT3 Transcription Factor; Syndecan-1; Syndecans; Trans-Activators; Transcription Factor RelA

Because of the central role of the transcription factor nuclear factor-kappaB (NF-kappaB) in cell survival and proliferation in human multiple myeloma (MM), we explored the possibility of using it as a target for MM treatment by using curcumin (diferuloylmethane), an agent known to have very little or no toxicity in humans. We found that NF-kappaB was constitutively active in all human MM cell lines examined and that curcumin, a chemopreventive agent, down-regulated NF-kappaB in all cell lines as indicated by electrophoretic mobility gel shift assay and prevented the nuclear retention of p65 as shown by immunocytochemistry. All MM cell lines showed consitutively active IkappaB kinase (IKK) and IkappaBalpha phosphorylation. Curcumin suppressed the constitutive IkappaBalpha phosphorylation through the inhibition of IKK activity. Curcumin also down-regulated the expression of NF-kappaB-regulated gene products, including IkappaBalpha, Bcl-2, Bcl-x(L), cyclin D1, and interleukin-6. This led to the suppression of proliferation and arrest of cells at the G(1)/S phase of the cell cycle. Suppression of NF-kappaB complex by IKKgamma/NF-kappaB essential modulator-binding domain peptide also suppressed the proliferation of MM cells. Curcumin also activated caspase-7 and caspase-9 and induced polyadenosine-5'-diphosphate-ribose polymerase (PARP) cleavage. Curcumin-induced down-regulation of NF-kappaB, a factor that has been implicated in chemoresistance, also induced chemosensitivity to vincristine and melphalan. Overall, our results indicate that curcumin down-regulates NF-kappaB in human MM cells, leading to the suppression of proliferation and induction of apoptosis, thus providing the molecular basis for the treatment of MM patients with this pharmacologically safe agent.

Topics: Antineoplastic Agents; Apoptosis; Cell Division; Curcumin; Down-Regulation; Drug Synergism; G1 Phase; Humans; I-kappa B Kinase; Multiple Myeloma; NF-kappa B; Phosphorylation; Protein Serine-Threonine Kinases; Tumor Cells, Cultured

Numerous reports suggest that IL-6 promotes survival and proliferation of multiple myeloma (MM) cells through the phosphorylation of a cell signaling protein, STAT3. Thus, agents that suppress STAT3 phosphorylation have potential for the treatment of MM. In the present report, we demonstrate that curcumin (diferuloylmethane), a pharmacologically safe agent in humans, inhibited IL-6-induced STAT3 phosphorylation and consequent STAT3 nuclear translocation. Curcumin had no effect on STAT5 phosphorylation, but inhibited the IFN-alpha-induced STAT1 phosphorylation. The constitutive phosphorylation of STAT3 found in certain MM cells was also abrogated by treatment with curcumin. Curcumin-induced inhibition of STAT3 phosphorylation was reversible. Compared with AG490, a well-characterized Janus kinase 2 inhibitor, curcumin was a more rapid (30 min vs 8 h) and more potent (10 micro M vs 100 micro M) inhibitor of STAT3 phosphorylation. In a similar manner, the dose of curcumin completely suppressed proliferation of MM cells; the same dose of AG490 had no effect. In contrast, a cell-permeable STAT3 inhibitor peptide that can inhibit the STAT3 phosphorylation mediated by Src blocked the constitutive phosphorylation of STAT3 and also suppressed the growth of myeloma cells. TNF-alpha and lymphotoxin also induced the proliferation of MM cells, but through a mechanism independent of STAT3 phosphorylation. In addition, dexamethasone-resistant MM cells were found to be sensitive to curcumin. Overall, our results demonstrated that curcumin was a potent inhibitor of STAT3 phosphorylation, and this plays a role in the suppression of MM proliferation.

Topics: Active Transport, Cell Nucleus; Cell Line; Cell Line, Tumor; Cell Membrane Permeability; Cell Nucleus; Curcumin; DNA-Binding Proteins; Growth Inhibitors; Humans; Interferon-alpha; Interleukin-6; Milk Proteins; Multiple Myeloma; Oligopeptides; Phosphorylation; Signal Transduction; STAT1 Transcription Factor; STAT3 Transcription Factor; STAT5 Transcription Factor; Trans-Activators; Tyrphostins