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CCR Translation for the Article from The Potential Role of Curcumin in Patients with Monoclonal Gammopathy of Undefined Significance—Its Effect on Paraproteinemia and the Urinary N-Telopeptide of Type I Collagen Bone Turnover Marker

Purpose: To determine the effect of curcumin on plasma cells and osteoclasts in patients with MGUS.Experimental Design: Twenty-six patients with MGUS were recruited into the study and administered 4 grams/day oral curcumin. Blood and urine samples were collected at specified visits after initiating therapy. Full blood count, B2 microglobulin, serum paraprotein, and immunoglobulin electrophoresis (IEPG and EPG) were determined for all patients at each visit. Serum calcium, 25 hydroxyvitamin D3, and bone-specific alkaline phosphatase were determined at baseline only. Urine, as a morning second-void sample, was collected at each visit for urinary N-telopeptide of type I collagen.Results: Our results show that oral curcumin is able to decrease paraprotein load in a select group (i.e., those having a paraprotein level of >20 g/L) of patients with MGUS. Fifty percent (5 of 10) of these patients had a 12% to 30% reduction in their paraprotein levels, while on curcumin therapy. In addition, 27% of patients on curcumin had a >25% decrease in urinary N-telopeptide of type I collagen.Conclusion: Due to the possible progression of MGUS to multiple myeloma, the potential role of curcumin as a therapeutic intervention for MGUS patients warrants further investigation. (Clin Cancer Res 2009;15(18):5917–22)

Curcumin, when used in a combination regimen in multiple myeloma patients, has comparable progression‐free survival without the adverse effects of steroid‐based combination therapies that is curcumin may be a viable alternative to corticosteroids in combination with an immunomodulatory drug or proteasome inhibitor.

Myelodysplastic syndrome (MDS) evolves due to genomic instability, dysregulated signalling pathway and overproduction of inflammatory markers. Reactive oxygen species contribute to the inflammatory response, which causes gene damage, cellular remodelling and fibrosis. MDS can be a debilitating condition, and management options in patients with MDS aim to improve cytopenias, delay disease progression, and enhance quality of life. High serum ferritin levels, a source of iron for reactive oxygen species production, correlate with a higher risk of progression to acute myeloid leukaemia, and iron overload is compounded by blood transfusions given to improve anaemia. 6-shogaol is a natural phenolic compound formed when ginger is exposed to heat and/or acidic conditions, and it has been shown to possess anti-tumour activity against leukaemia cell lines and antioxidant effects. This narrative review assessed the potential benefits of this phytochemical in lower-risk MDS patients through examining the current evidence on the pharmacological and therapeutic properties of ginger and 6-shogaol.

Prebiotics are a class of functional foods which target beneficial microbial species of the gut to benefit host health. They consist of dietary fibres which, after ingestion, are degraded and fermented by microorganisms in the colon. Arabinoxylan (AX) is an important member of the prebiotic family. This non-digestible fibre is commonly found in cereal grains such as wheat and rice. Human in vivo studies have demonstrated that consumption of various species of AXs has profound effects on gut microorganisms. AX exists in different structures across cereal types. Structural differences of AXs impact their cleavage, degradation, and fermentation by gut microbiota. However, this structural diversity also makes it difficult to compare and contrast studies of different AXs. Nevertheless, common bacterial targets of prebiotics across all AX structures include Bifidobacterium spp. and Lactobacillus spp., which are both beneficial to human health. Existing research on AXs has primarily focused on wheat derived AX. As the structure of rice AXs varies significantly from that of wheat AXs, more research is needed on the effects of rice AXs on gut microbiota. This narrative review synthesises the current understandings of how prebiotic AX affects gut microbiota and its implications for human health.

Introduction Rice bran arabinoxylan compound (RBAC) is a nutraceutical for enhancing a depleted immune system during and after cancer treatment. This pilot feasibility trial aims to evaluate the effects of RBAC on cancer patients' quality of life during active treatment, compared to placebo, using a validated questionnaire. Other outcome measures include changes in inflammatory and nutritional status, cytokine profile, and gut microbiota. Methods/Design The study will recruit 50 participants from a regional cancer center in Australia. Patients aged 18–70, diagnosed with solid organ cancers stage II and above, and currently undergoing active systemic therapies, are eligible. Random allocation of participants into two groups is stratified based on metastatic status and treatment type. The dosage is either 3 g/day of RBAC or placebo in identical packaging. The participants, study coordinator, and treating oncologists are blinded to the interventions. Data collections are at baseline and at four follow-up sessions, which are six weeks apart (24 weeks). Statistical analysis will involve a protected p-value with multiple dependent values and analyzed by ANOVA with repeated measures on the occasion of testing and with both a full Bonferroni or Sidak corrections applied to protect against Type I errors. Any observed significance warrants further analysis with pairwise comparisons. Analysis of covariance will also be performed to assess any influence of the demographic data, cancer diagnosis, as well as changes in physical activity, dietary habits, and complementary medicine usage. Comparisons of gut microbiota will be based on the analysis of the fecal microbiome using 16S ribosomal ribonucleic acid amplicon sequencing. The proposed research timeline is from October 2018 to May 2022. Trial registration ANZCTR. Reg No: ACTRN12619000562178p.

Introduction: Conventional cancer treatment, including surgery, chemotherapy, and radiotherapy, may not be sufficient to eradicate all malignant cells and prevent recurrence. Intensive treatment often leads to a depressed immune system, drug resistance, and toxicity, hampering the treatment outcomes. BioBran/MGN-3 Arabinoxylan is a standardized arabinoxylan concentrate which has been proposed as a plant-based immunomodulator that can restore the tumor-induced disturbance of the natural immune system, including natural killer cell activity to fight cancer, complementing conventional therapies. Objectives: To comprehensively review the available evidence on the effects and efficacies of MGN-3 as a complementary therapy for conventional cancer treatment. Methods: Systematic search of journal databases and gray literature for primary studies reporting the effects of MGN-3 on cancer and cancer treatment. Results: Thirty full-text articles and 2 conference abstracts were included in this review. MGN-3 has been shown to possess immunomodulating anticancer effects and can work synergistically with chemotherapeutic agents, in vitro. In murine models, MGN-3 has been shown to act against carcinogenic agents, and inhibit tumor growth, either by itself or in combination with other anticancer compounds. Fourteen successful MGN-3 treated clinical cases were found. Eleven clinical studies, including 5 nonrandomized, pre-post intervention studies and 6 randomized controlled trials (RCTs) were located. Reported effects include enhanced immunoprofile, reduced side effects, improved treatment outcomes; one RCT established significantly increased survival rates. There are no reports on adverse events on MGN-3. Most of the clinical trials are small studies with short duration. Conclusion: There is sufficient evidence suggesting MGN-3 to be an effective immunomodulator that can complement conventional cancer treatment. However, more well-designed RCTs on MGN-3 are needed to strengthen the evidence base.

Purpose: To determine the effect of curcumin (as Meriva) on absolute lymphocyte count (ALC), T cell populations and NK cells in patients with Rai stage 0/1 chronic lymphocytic leukemia (CLL) over a period of six months. Experimental Design: Twenty-one patients with significant lympho- cytosis (>20 × 10 9 lymphocytes/L) and stage 0/1 CLL were recruited into the study and received oral curcumin 2 grams/day. Blood samples were collected at baseline and at 2 monthly intervals for six months for full blood count, leukocyte surface antigens, liver function, serum biochemistry, immunoglobulins, CRP and ESR. A positive biologic response was defined as a reduction in the ALC of more than 20% from pre-treatment levels. Results: Four patients (20%) demonstrated more than 20% decrease in ALC, three of whom had lower ALC at the end of the study as compared to baseline. The decrease in ALC was accompanied by an increase in CD4, CD8 and NK cells. No de- monstrable response was seen in seventeen patients (80%) who exhibited stable, fluctuating or increasing ALC during the study. Conclusion: A subgroup of stage 0/1 CLL patients may be respon- sive to curcumin therapy. The beneficial response appears to be immunomodulated.

Background: Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal stem cell disorders characterized by dysplastic and ineffective hematopoiesis and peripheral cytopenias. Elevated serum ferritin (SF) is often observed in nontransfused, lower risk MDS. It has been reported that ineffective erythropoiesis enhances iron absorption in MDS through downregulation of hepcidin and its prohormones such that SF rises. Aim: To determine the effect of 6-shogaol, a dehydration derivative of ginger, known to have hepatoprotective and chemotherapeutic activity, on 6 early-stage, transfusion-independent patients with MDS, 3 of whom had raised levels of SF. Method: Six patients with MDS with low or intermediate-1 subtypes, as defined by the International Prognostic Scoring System (IPSS), were recruited into the study and were administered 1 gel capsule daily containing 20 mg ginger extract standardized for 20% 6-shogaol. Blood and urine samples were collected and various markers monitored at regular intervals. Results: 6-shogaol caused a decrease in SF levels in 3 of 6 patients with early MDS (50%) whose SF levels were elevated at the start of the study. Our findings suggest upregulation of hepcidin and its prohormones, possibly through an improvement in liver function. Discussion: In light of the encouraging results in this small, investigative study, we are planning a larger study to confirm the beneficial effect of 6-shogaol in patients with raised ferritin levels due to ineffective erythropoiesis.

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.

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.

Multiple myeloma (MM), smoldering myeloma (SMM), and monoclonal gammopathy of undetermined significance (MGUS) represent a spectrum of plasma cell dyscrasias (PCDs). Immunoglobulin light chain amyloidosis (AL) falls within the spectrum of these diseases and has a mortality rate of more than 80% within 2 years of diagnosis. Curcumin, derived from turmeric, has been shown to have a clinical benefit in some patients with PCDs. In addition to a clinical benefit in these patients, curcumin has been found to have a strong affinity for fibrillar amyloid proteins. We thus administered curcumin to a patient with laryngeal amyloidosis and smoldering myeloma and found that the patient has shown a lack of progression of his disease for a period of five years. This is in keeping with our previous findings of clinical benefits of curcumin in patients with plasma cell dyscrasias. We recommend further evaluation of curcumin in patients with primary AL amyloidosis.

Myeloma is a progressive neoplastic disease characterized by plasma cell dyscrasia, progressive bone loss, and pathological fractures. We conducted a prospective, single center study on myeloma patients to determine the impact of osteoporosis on disease activity and survival. Data collected on 108 patients followed for 13 years included clinical demographics, markers of myeloma activity, skeletal radiography, and bone densitometry. There were 56 men and 52 women with mean age of 69 years. Of these, 78% presented with stage I/II disease, 11% underwent stem cell or bone marrow transplants, 78% received adjuvant intravenous bisphosphonates, and 80% died during the course of the study (median survival of 47.3 months). There were 66% with osteoporosis, 54% with fractures, and 56% with lytic bone lesions. Femoral neck dual energy X-ray absorptiometry (DXA) and lumbar spine quantitative computed tomography (QCT) were major independent predictors of patient survival. Kaplan-Meier survival estimates demonstrated that patients presenting with a lumbar spine QCT T-score ≤ -3.5, died on average 18 months earlier than those with a lumbar spine QCT T-score > -3.5. These data suggest that the severity of osteoporosis, as defined by initial BMD T-score values, significantly impact on patient survival.

Background: Curcumin, the active component of the Curcuma longa plant, has been shown to potentiate the effect of the immunomodulatory drugs (IMiDs) thalidomide and Bortezomib against human myeloma cell lines and a nude mice model. Its effect on the other IMid, lenalidomide, has not been evaluated. This study aims to investigate the mechanism of action of curcumin and its potential ability to positively interact with lenalidomide. Method: we designed an in-vitro study to investigate the cytotoxic and chemo-sensitising effects of curcumin alone and in combination with lenalidomide on the human myeloma H929 cell line. Results: Incubation of H929 cells with curcumin (30mM) or lenalidomide (2.5 mM) for 3 days resulted in 26.35% (±1.06) and 30.81%(±2.98) apoptotic cells respectively. When 30 mM curcumin was combined with 2.5 mM lenalidomide, 50.4% (±3.37) apoptotic cells were detected by flow cytometry and the increase was significant compared to either curcumin alone or lenalidomide alone (anova p = 0.0026). Furthermore, gene analysis studies show that curcumin enhances the cytotoxic effect of lenalidomide via suppression of the cereblon and multi-drug resistant genes. Conclusion: Curcumin exerts a cytotoxic effect additive to that of lenalidomide on H929 myeloma cells, and it also enhances the chemo-sensitizing effects of this agent.

Introduction: Smoldering Multiple Myeloma (SMM) is an asymptomatic plasma cell disorder which has an overall risk of progression to multiple myeloma of 10% per year. The cornerstone of managing SMM is a “watch and wait” strategy. Curcumin has been shown to improve disease status in some patients with MGUS and SMM and has been added to the mainstream treatment of myeloma patients. We report here for the first time on long term use of oral curcumin in 2 SMM patients. Patients: Two male Caucasian patients over the age of 40 presented to their general practitioners with fatigue/shoulder pain. Blood tests revealed paraproteinemia and a diagnosis of SMM was made based on IMWG guidelines. Both were entered into a 9 month clinical trial of oral curcumin in patients with plasma cell dyscrasias. Thereafter, they elected to continue on the same regimen of oral curcumin, for a period of 2 years. Results/Discussion: Both patients showed continued improvement in a number of markers of disease activity including serum free light chains, paraprotein and % plasma cells in the bone marrow. These results suggest that patients with smoldering myeloma may benefit from daily ingestion of curcumin and long term use does not result in toxicity.

Purpose: To determine the effect of curcumin on plasma cells and osteoclasts in patients with MGUS. Experimental Design: Twenty-six patients with MGUS were recruited into the study and administered 4 grams/day oral curcumin. Blood and urine samples were collected at specified visits after initiating therapy. Full blood count, B2 microglobulin, serum paraprotein, and immunoglobulin electrophoresis (IEPG and EPG) were determined for all patients at each visit. Serum calcium, 25 hydroxyvitamin D3, and bone-specific alkaline phosphatase were determined at baseline only. Urine, as a morning second-void sample, was collected at each visit for urinary N-telopeptide of type I collagen. Results: Our results show that oral curcumin is able to decrease paraprotein load in a select group (i.e., those having a paraprotein level of >20 g/L) of patients with MGUS. Fifty percent (5 of 10) of these patients had a 12% to 30% reduction in their paraprotein levels, while on curcumin therapy. In addition, 27% of patients on curcumin had a >25% decrease in urinary N-telopeptide of type I collagen. Conclusion: Due to the possible progression of MGUS to multiple myeloma, the potential role of curcumin as a therapeutic intervention for MGUS patients warrants further investigation. (Clin Cancer Res 2009;15(18):5917–22)

Terry Golombick, Terry DiamondDepartment of Endocrinology, St George Hospital, Kogarah, AustraliaAbstract: Plasma cell dyscrasias, most commonly associated with paraproteinemia, are a diverse group of diseases. Monoclonal gammopathy of undefined significance (MGUS) can precede multiple myeloma, a progressive neoplastic disease. MGUS occurs in association with a variety of other diseases and currently no treatment is recommended but rather “watchful waiting”. Given that the size of the M-protein is a risk factor for disease progression, early intervention with the aim of reducing the paraprotein load would provide an innovative therapeutic tool. Preliminary results from our pilot study show a drop of between 5% and 30% serum paraprotein in patients taking curcumin compared with patients on placebo. Curcumin is a diferuloylmethane present in extracts of the rhizome of the Curcuma longa plant. As a natural product, this has exciting potential in the treatment of plasma cell dyscrasias.Keywords: plasma cell dyscrasias, MGUS, myeloma, curcumin, paraproteinemia

Intraperitoneal treatment with interferon (IFN) for malignant ascites due to advanced ovarian carcinoma refractory to chemotherapy gave an objective response rate of 36% (7/19 patients treated). In vitro studies demonstrated that cytotoxicity of peripheral blood monocytes/macrophages was stimulated by IFN. However, peritoneal exudate cells obtained after intraperitoneal treatment with interferon were not stimulated to kill autologous tumour cells. Clinical response was therefore most probably due to a direct inhibitory effect of IFN on growth of malignant cells rather than due to an immune modulatory effect. Using a newly established ovarian cancer cell line (UWOV1), synergy between the growth inhibitory/antitumour effects of IFN and cisplatin was demonstrated at clinically achievable concentrations of each agent. IFN plus cisplatin proved to be more effective than intraperitoneal cisplatin alone in control of peritoneal carcinomatosis. The response rate was 5/7 (77%) for combined modality therapy vs. 2/9 (22%) for intraperitoneal chemotherapy alone. Both in vitro and in vivo studies suggest a role for interperitoneal therapy for control of refractory ascites in ovarian cancer.

The establishment, growth, and characterization of two new continuously growing human ovarian cancer cell lines (UWOV1 and UWOV2) as, well as a subline (UWOV2, Sf) grown in chemically defined, serum-free medium are described. The cell lines were derived from ascitic tumors of two patients suffering from cystadenocarcinomas of the ovary. Both UWOV1 and UWOV2 lines grow in anchorage-dependent fashion as monolayers, whereas UWOV2 (Sf) forms multilayered domelike structures. Cytogenetic studies revealed nonrandom abnormalities involving chromosomes 1 and 11 in all three cell lines. Secretion of soluble collagen was detected in all three cell lines. In addition, UWOV2 (Sf) produces and secretes large amounts of extracellular matrix material with an ordered fibrillar structure which may function as an attachment factor for the serum-free cells. These cell lines seem to be useful for further studies of the biology of human ovarian cancer.

A rapid and simple method for determination of cellular uptake of adriamycin is described. The method is based on the principle that active uptake is proportional to alterations of drug distribution, measured as a fraction of time, between suspending medium and cells, the volume of each having been accurately determined. Cellular drug uptake can be calculated by the use of a simple distribution formula. This method represents a compromise between indirect measurement of the loss of drug from suspending medium and direct measurement of drug uptake following cell separation, washing, and lysis. This method should be applicable to the measurement of cellular uptake of a wide range of drugs.