Curcumin for monoclonal gammopathies. What can we hope for, what should we fear?

Critical Reviews in Oncology/Hematology 84 (2012) 350–360

Curcumin for monoclonal gammopathies. What can we hope for, what should we fear? A.J.M. Vermorken a,∗ , J. Zhu a , W.J.M. Van de Ven a , E. Andrès b b

a Laboratory for Molecular Oncology, Department of Human Genetics, KU Leuven, Belgium Department of Internal Medicine, Diabetes and Metabolic Disorders, University Hospital of Strasbourg, Strasbourg, France

Accepted 25 April 2012

Contents 1.

2.

3. 4. 5.

6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Curcumin and health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Monoclonal gammopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Curcumin for monoclonal gammopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. The first results with curcumin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Reflecting on possible targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Curcumin does not influence the paraprotein level in all patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Can curcumin lower the risk for emergence of MGUS in some inflammatory diseases? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Curcumin might work on immune cells rather than on the bone marrow directly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Curcumin for prevention of progression of MGUS and SMM, reasons for concern? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Both curcumin and myeloma act on dendritic cells and induce immunosuppression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Increased susceptibility to infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Does curcumin suppress the immune response against (pre)malignant cells in MGUS? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. Could curcumin stimulate clonogenic growth of tumor cells? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5. Could curcumin induce a more malignant phenotype?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

351 351 351 352 352 352 352 353 353 354 354 354 356 356 356 356 357 357 357 357 359

Abstract Over the last decades there has been an increasing interest in a possible role of curcumin on cancer. Although curcumin is considered safe for healthy people, conclusive evidence on the safety and efficacy of curcumin for patients with monoclonal gammopathies is, so far, lacking. The present paper reviews the literature on molecular, cellular and clinical effects of curcumin in an attempt to identify, reasons for optimism but also for concern. The results of this critical evaluation can be useful for both patient- selection and monitoring in the context of clinical trials. Curcumin might be helpful for some but certainly not for all patients with monoclonal gammopathies. It is important to avoid

∗

Corresponding author at: KU Leuven, Herestraat 49 BOX, 602, BE-3000 Leuven, Belgium. Tel.: +32 16 3 46076; fax: +32 16 3 46073. E-mail addresses: [email protected] (A.J.M. Vermorken), [email protected] (J. Zhu), [email protected] (W.J.M. Van de Ven), [email protected] (E. Andrès). 1040-8428/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.critrevonc.2012.04.005

A.J.M. Vermorken et al. / Critical Reviews in Oncology/Hematology 84 (2012) 350–360

351

unnecessary detrimental side effects in some in order to safeguard curcumin for those that could benefit. Parameters for patient monitoring, that can be used as early warning signs and as indicators of a favorable development have therefore been suggested. © 2012 Elsevier Ireland Ltd. All rights reserved. Keywords: Monoclonal gammopathy; Multiple myeloma; Clinical trials; Immunosuppression; Dendritic cells; Curcumin; Inflammation; Clonogenic growth

1. Introduction 1.1. Curcumin and health During the last twenty years curcumin has been discovered by modern science, in particular molecular biology, as a substance with a potential role in the treatment of cancer. Almost 1700 papers were published, only 22 in the first decade and more than 500 in the year 2011 alone. About thirty papers were related to multiple myeloma. Besides this increasing interest in the scientific community there is an increasing exchange of information on internet forums among citizens about the spice and its alleged positive health effects. The substance is commercialized and widely available. In traditional medicine in India, turmeric, containing curcumin is known for its anti-inflammatory properties [1]. Curcumin (diferuloylmethane), is the main curcuminoid (>75%) in the Indian spice turmeric (see Fig. 1 for the structural formulas of the three main curcuminoids). Since it is extracted from a food component that has been used for centuries it is considered safe. Indeed the results of some clinical

Fig. 1. Structural formulas of the three main curcuminoids in turmeric.

trials indicated that even doses of up to 8 g per day of extracted curcumin provoked only minimal toxicity in healthy people. Food components might, however, be less safe for patients as thought by the general public. Legislation does not require companies producing supplements to show evidence of health benefits. Modern medicine has confirmed the anti-inflammatory effect of turmeric and curcumin, however, their bioavailability is different [2]. Chronic inflammation can predispose to cancer and non-toxic anti-inflammatory compounds could thus have a place in prevention and in delay of progression. The anti-inflammatory activity of curcumin comes, however, at a price: immunosuppression. The immune system also forms an important element in cancer prevention. Any decision to treat with curcumin must therefore take the balance between limiting inflammation and reducing immune competence in consideration. 1.2. Monoclonal gammopathies Monoclonal gammopathy of undetermined significance (MGUS) is a common plasma cell disorder with an unknown etiology and with a life-long increased risk of malignant progression. Prevalence of monoclonal gammopathy, without evidence of malignant disease, increases from below two percent in fifty to sixty year old people to above six percent over the age of eighty [3]. The main risk factors for progression of MGUS are size and type of the serum monoclonal protein and presence of an abnormal serum free light chain (FLC) ratio [4,5]. Diminished life expectancy of MGUS patients can, however, not be explained by progression to lymphoproliferative disorders alone. Other causes of death, both due to malignant and non-malignant diseases are also increased, especially in the first years after diagnosis [6]. When competing causes of death are taken into account, the risk of progression is around 0.5% per year [5]. MGUS is therefore monitored regularly (“watchful waiting”) in order to assure an early diagnosis of malignant progression [7]. In view of the relatively small overall risk for progression “watchful waiting” is prudent since intervention may pose the risk to disturb a possibly delicate balance keeping the gammopathy from progressing. The above mentioned risk factors allow distinguishing groups according to the risk for progression. Patients with an abnormal serum FLC ratio and a high serum monoclonal protein level (>15 g/L) have an almost 10 times higher risk for progression as compared to patients without these risk factors [4]. When monoclonal protein levels are 30 g/l or greater and the proportion of plasma cells in the bone marrow is above 10 percent but there is no associated organ damage, the diagnosis smoldering malignant myeloma

352

A.J.M. Vermorken et al. / Critical Reviews in Oncology/Hematology 84 (2012) 350–360

(SMM), a more advanced (pre)malignant condition, is made [8]. The overall risk of progression to a malignant condition is 10% per year for the first 5 years, it diminishes gradually thereafter [9]. Because myeloma is a devastating incurable condition while MGUS and SMM are often asymptomatic, patients with a high-risk MGUS and with SMM are candidates for preventive strategies. It is absolutely essential for a preventive approach that it does not itself increase the risk of progression.

2. Curcumin for monoclonal gammopathies 2.1. The first results with curcumin Curcumin has recently been (re)discovered by modern science as a therapeutic agent. It is currently used in human clinical trials for a variety of conditions, including psoriasis, Alzheimer’s disease and several types of cancer [10]. Doses of up to 8 g/day of extracted curcumin provoked only minimal toxicity in healthy volunteers [11]. The question whether curcumin is also safe for patients with monoclonal gammopathies remains, however, to be answered. Patients with MGUS are often without symptoms. Preventive strategies can therefore not use the effect of intervention on symptoms as early indicators of “success”. Because the annual risk for progression is relatively low, early endpoints are, however, needed. Preliminary studies performed so far [12,13] have used the above mentioned prognostic factor: size of the serum monoclonal protein peak, which is considered to be proportional to the size of the (pre)malignant clone, as well as the decrease in a urinary marker of bone turnover as indicators. MGUS is associated to osteoporosis [14] and excess of bone resorption was associated to earlier progression to malignancy [15]. These studies revealed that curcumin was able to decrease the paraprotein level in about half the patients having a high concentration (of > 20 g/L) [13]. About a quarter of the patients had a > 25% decrease in the urinary marker of bone turnover [13]. A very recent paper by the same group, a randomized double-blind placebocontrolled study, used one additional parameter: the FLC ratio [16]. In this study there was no influence on the average size of the monoclonal protein peak, although most patients had high paraprotein concentrations. On the other hand, curcumin was reported to modestly decrease the average FLC ratio. Even if the results in some individual patients are encouraging it has at this stage apparently not yet been possible to identify patient selection criteria that could lead to clinically significant effects in patient groups. It must be kept in mind that the methodology used by the above authors, in their work on curcumin for patients with MGUS, is not standard. Moreover, patient numbers were small and the duration of the studies short. The rather modest effect on the FLC ratio should therefore be interpreted with caution. It should be kept in mind that in multiple myeloma, so far, no significant activity of curcumin has been noted

in clinical trials in which the validated endpoints used for other myeloma drugs [17] were applied to adjudicate efficacy of therapy. More studies on larger numbers of patients and probably a more accurate definition of criteria for selection of patients that could potentially benefit will be necessary, before more definitive conclusions can be drawn. 2.2. Reflecting on possible targets The original idea leading to the use of curcumin for prevention of progression of MGUS [13] was based on its capacity to down-regulate interleukin-6 (IL-6) [1], a growth factor for both osteoclasts and myeloma cells [18] and to inhibit osteoclastogenesis. It was hoped that curcumin would inhibit effects of the abnormal plasma cells and normalize the increased activity of octeoclasts in patients with monoclonal gammopathies [18]. Serum levels of IL-6 are indeed increased in myeloma and correlate with stage and survival. Myeloma patients with osteolytic bone lesions have increased IL-6 levels. Inhibition of the IL-6 signaling pathway with specific antibodies led to in vitro and in vivo anti-multiple myeloma activity suggesting that it could contribute to control tumor burden and bone disease [19]. Curcumin has also been shown to inhibit osteoclastogenesis through the suppression of receptor activator of nuclear factor kappa-B ligand (RANKL) signaling [20], the expression of which is known to be increased in myeloma [21]. The mechanisms of action that could explain the effects on the paraprotein level, the FLC ratio and the bone turnover markers remain so far uncertain. Moreover, biological findings and even results in animal studies cannot always be extrapolated to the situation in patients. Empiric evidence from controlled studies using validated endpoints remains therefore necessary before therapy in the clinic is justified. Such data are, so far, lacking. It is therefore of the utmost importance to carefully analyze the effects on patients in trials and to report the outcome as soon as possible. This can both give indications as to the mechanism(s) involved but also allow identifying early warning signs of possible adverse effects in patients with (pre)malignant conditions. 2.3. Curcumin does not influence the paraprotein level in all patients An important early finding is that curcumin decreases the paraprotein load only in a limited group of patients with MGUS [13]. It cannot be excluded that this means that curcumin acts on some but not all cytogenetic subtypes of MGUS and SMM. A more probable explanation seems that curcumin does not act directly on the abnormal plasma cells. It could act indirectly on secondary mechanisms that play an increasingly important role in later stages of MGUS. As mentioned above, curcumin is known to downregulate IL-6, an inflammatory cytokine. IL-6 regulates differentiation

A.J.M. Vermorken et al. / Critical Reviews in Oncology/Hematology 84 (2012) 350–360

of dendritic cells (DCs), important antigen presenting cells [22]. In patients with multiple myeloma the serum IL-6 level is a marker of high tumor burden. In patients with MGUS serum IL-6 levels are not always increased but it can be increased in relation to inflammatory parameters [23]. This is the reason that IL-6 cannot be used to differentiate MGUS from myeloma. Increased C-reactive protein- (CRP) and erythrocyte sedimentation rate- (ESR) values (indicators of systemic inflammation) that can be increased in myeloma as well as MGUS are independent prognostic factors for survival in myeloma [24,25]. This is understandable since IL-6 may induce inflammation. The above data suggest that curcumin could be beneficial in patients with MGUS and SMM in which inflammation is present as witnessed by increased CRP and/or ESR. Indeed long-term curcumin treatment significantly reduces CRP levels [26] in agreement with its known anti-inflammatory activity. Regrettably, neither indicators of systemic inflammation nor IL-6 were measured in the earlier mentioned clinical studies on the effect of curcumin on MGUS and SMM [12,13,16].

3. Can curcumin lower the risk for emergence of MGUS in some inflammatory diseases? IL-6 is not the only growth factor for malignant plasma cells [27]. B-cell activating factor belonging to the TNF family (BAFF) and a proliferation-inducing ligand (APRIL) are two members of the TNF ligand superfamily that can protect myeloma cells from apoptosis induced by IL-6 deprivation [27]. BAFF levels are significantly increased in myeloma [28] and targeting BAFF is considered a therapeutic option in B-cell malignancies [29]. BAFF is also increased in inflamed target organs in autoimmune disease such as for example: rheumatoid arthritis and systemic lupus erythematosis (SLE) [30]. In SLE, BAFF levels are associated to CRP [30]. In osteoarthritis, in which autoimmunity is not supposed to play a role, both CRP and IL-6 are significant predictors of knee osteoarthritis [31]. BAFF has not yet been measured in osteoarthritic joint tissue but blood levels are increased in seronegative osteoarthritis [32] and the expression of furin, the pro-protein convertase responsible for the processing of pro-BAFF into the active form, is increased in osteoarthritic cartilage [33]. All three conditions mentioned have a slightly increased risk for developing MGUS [34,35]. Not all patients with monoclonal gammopathies have increased levels of CRP or ESR but these levels are indicators for prognosis. If indeed like in SLE the activity of the BAFF pathway would be correlated to CRP or ESR [30] in some or all patients with monoclonal gammopathies, curcumin could be helpful and CRP and ESR would be very useful indicators for success of intervention. Curcumin has also been shown to directly suppress BAFF expression in cultured cells, probably by interfering with NF-kB signaling [36] but it is doubtful

353

whether the concentrations needed therefore are reached in other tissues than the intestine [12]. In this context it is noteworthy that IL-6 induces NF-kB activation, for example in intestinal epithelia [37]. Both NF-kB and IL-6 are involved in a positive feedback-loop that can be initiated by an inflammatory signal. It has been claimed that this can lead to an epigenetic switch from nontransformed to cancer cells [38]. The logical consequence of the above would be that relatively simple tests like CRP and ESR would be predictive for the functioning of NF-kB signaling and thus of inflammatory cytokines [39] produced in inflamed organs and thus for the risk of developing MGUS. Traditional methods for measuring CRP were developed for measuring the rather strong fluctuations as induced by bacterial infections. Recent techniques allow more refined determination, even within the previous reference ranges and moderately elevated levels of CRP could already be associated to colorectal cancer [40]. Interestingly BAFF and moderate CRP elevation could also be related to FLC levels. These are on average increased in autoimmune disease [40]. Abnormal FLC ratios were detected in patients with risk factors for progression only [40]. It is suggested that an abnormal ratio could be a more sensitive marker of clonality when this is still restricted to the site of inflammation [41]. Since curcumin is helpful in chronic inflammatory states like autoimmune disease [42] the above suggests that curcumin could have a preventive effect on the development of MGUS in chronic inflammatory conditions. However, this is not easy to prove and would need long term monitoring of large groups of patients. Trials about prevention of the emergence of MGUS with curcumin in a context of chronic immune stimulation and low grade inflammation could be useful and should undoubtedly include measuring ESR as well as CRP with high sensitivity. It is important to note that curcumin concentrations in the inflamed target organs are perhaps not of determining importance. Crucial for a favorable outcome is probably the influence of curcumin on circulating immune cells. These could be confronted to higher curcumin concentrations in the gut and migrate to target organs. Relatively low doses of curcumin would therefore probably be effective.

4. Curcumin might work on immune cells rather than on the bone marrow directly In the context of prevention of progression of high-risk MGUS and SMM the situation is probably quite different. Multiple myeloma cells adhere to bone marrow stromal cells [43]. While myeloma cells do not seem to produce IL-6, bone marrow stromal cells do [43]. When myeloma cells were adhered to the stromal cells, IL-6 secretion increased strongly [43]. BAFF secretion is also much higher in stromal cells than in myeloma cells, and tumor cell adhesion to stromal cells further augments BAFF secretion by 2- to 5fold [44]. Moreover, BAFF increases adhesion of myeloma

354

A.J.M. Vermorken et al. / Critical Reviews in Oncology/Hematology 84 (2012) 350–360

Table 1 Immunosuppression induced by curcumin has elements in common with that by multiple myeloma. Immunosuppression induced by curcumin

References

Immunosuppression induced by cancer and multiple myeloma

References

Curcumin suppresses a Th1-type immune response

[45]

[46,47]

Curcumin inhibits the maturation and modulates the cytokine pattern of DCs. IL-12 production is inhibited. Curcumin prevents DCs from inducing CD4+ T cell proliferation Curcumin-treated bone marrow derived DCs induced differentiation of naïve CD4+ T cells into regulatory T cells (Tregs) similar to those present in the intestine Curcumin treated DCs are not only immature, they are also maturation resistant. This means that curcumin treated DCs do not mature under inflammatory conditions Maturation resistant DCs can find application in the field of organ transplantation as a means to down-regulate anti-donor T cell responses but they are disadvantageous for protection against bacterial infections

[45]

A reduced Th1/Th2 ratio has been reported in myeloma. Inflammation driven by tumor specific Th1 cells is believed important for preventing B-cell cancer DCs fail to mature, as caused by immunosuppressive factors TGFbeta and IL-10 produced by many tumor types. This is suspected to form a critical mechanism to escape immune surveillance. Immature DCs induce immunosuppressive CD4 + T cells while mature DCs induce immunostimulatory CD4 + T cells Immature DCs can maintain peripheral T cell tolerance by the induction and stimulation of Treg populations

[50,51]

[48,49]

[49]

[51]

Tregs negatively modulate DC maturation thereby contributing to the immune tolerance of cancer

[48]

[51]

Tumor cells appear able to convert DCs into cells that secrete bioactive TGF-beta and stimulate proliferation of Tregs. These DCs secreting TGF beta were called regulatory DCs. They suppress the development of antitumor immune responses

[52]

Regulatory DCs, which accumulate in patients with different types of cancers, are involved in the generation of Tregs, in turn these latter cells, that expand during tumor progression, negatively modulate DC maturation thereby contributing to the immune tolerance of cancer Curcumin provokes Foxp3 expression in [51] DCs matured with inflammatory cytokines can also induce Tregs. These Tregs. Tregs express Foxp3 protein and exert suppression through cell-cell contact. Tregs induced by immature DCs secrete IL-10 as a suppressive factor Inflammatory cytokines in myeloma could lead to maturation of DCs and to the induction of Foxp3 expressing regulatory T cells Curcumin treated DCs are defective in both [45] Multiple myeloma reduces the percentage and numbers of both myeloid migration and endocytosis. and plasmacytoid DCs while the percentages of Tregs, both with and without expression of Foxp3 are strongly increased Warning: Multiple myeloma patients with higher percentages of regulatory T cells lived shorter suggesting a role in facilitation of disease progression and/or infectious complications. Higher percentages of regulatory T cells were correlated to death caused by infectious complications.

cells to bone marrow stromal cells in a dose-dependent manner [44]. High doses of curcumin are apparently necessary to impact on the paraprotein level in patients. Moreover, the effect is found in some but not all patients [13]. If curcumin concentrations in the bone marrow would be sufficient for a local effect one would expect a favorable effect in many patients. If, however, the effect of curcumin would be related to influence on immune cells elsewhere in the body, it is conceivable that patients with high levels of circulating IL-6, that can induce inflammation in other tissues, would benefit most. We have so far seen that there are reasons for being hopeful about the potential of curcumin to be beneficial for prevention of monoclonal gammopathies in patients with inflammatory conditions. The influence on inflammatory symptoms could form early indicators of success. For high risk MGUS and SMM high doses are needed to provoke an effect on the paraprotein load and this, even more, obliges to anticipate the possibility of side effects. It is therefore mandatory to discuss reasons for potential concern.

[53]

[54]

[55] [55,56]

[56]

5. Curcumin for prevention of progression of MGUS and SMM, reasons for concern? 5.1. Both curcumin and myeloma act on dendritic cells and induce immunosuppression Curcumin has immunosuppressive properties that resemble immunosuppression in patients with myeloma. In both cases DCs are involved. Table 1 summarizes the effects on DCs. The effects of curcumin on DCs lead to several reasons for concern in the context of treatment of monoclonal gammopathies with curcumin. 5.2. Increased susceptibility to infections Patients with MGUS, but less so than those with myeloma, have an increased risk of infection [57]. Peripheral blood DCs in patients with MGUS show significant abnormalities in the distribution, phenotype and pattern of secretion of inflammatory cytokines [58]. Abnormal DC maturation had previously

A.J.M. Vermorken et al. / Critical Reviews in Oncology/Hematology 84 (2012) 350–360

355

Table 2 Elements to consider before and during treatment of a patient with a monoclonal gammopathy with curcumin. Reasons for optimism

Reasons for concern

Parameters helpful in patient monitoring

Curcumin: Is a food component that has been used for centuries. Has also been used for centuries as an anti-inflammatory substance. Is rather insoluble which leads to low plasma values and thus low toxicity.

Curcumin: There is no need to provide evidence of safety or health benefits for food supplements.

General parameters associated with malignant progression: (list is not comprehensive). Bone marrow plasma cell infiltration. Free light chain ratio. Serum paraprotein level Bence Jones proteinuria Polyclonal serum Ig reduction Bone turnover markers ESR, CRP. Etc.

Provoked only minimal toxicity in healthy volunteers at doses of up to 8 g/day

Reduces the paraprotein load in some patients Reduces markers of bone turnover in some patients. Has anti-inflammatory properties.

Attempts to increase absorption and increase of the dose might also increase toxicity. Some food components, like e.g. piperine in pepper increase bioavailability. Is often regarded as efficient and safe, also in the scientific literature. However, proof for both efficiency and safety for patients with monoclonal gammopathies remain to be proven. Does it increase the paraprotein load in some patients? Does it increase markers of bone turnover in some patients? Reduces the expression of toll like receptors and thus induces immunesuppression.

Interferes with NF-␬B signaling which can reduce inflammation. Down-regulates interleukin-6 an inflammatory cytokine that inhibits the maturation of dendritic cells by activation of the STAT3 pathway. Inhibits the STAT3 pathway which is activated by IL-6 Might prevent maturation of dendritic cells by inflammatory cytokines and so reduce the induction of regulatory T cells.

Inhibits osteoclastogenesis.

Has anti-angiogenic properties.

Limits the Th1 cytokine response useful for cancer immunosurveillance. Could therefore reduce the T cell response against (pre)malignant cells present in MGUS but not in myeloma.

Paraprotein load and FLC ratio Markers of bone turnover and FLC ratio ESR, CRP, IL-6, FLC absolute values. Total Gammaglobulins, IgG, IgA, IgM and subclasses thereof. Determine absolute numbers of B-cells and percentages of switched memory B-cells. Th1 cytokines, IL-2 and IFN gamma. Th2 cytokines, IL-4, IL-5, IL-10. IL-6.

Renders dendritic cells maturation resistant.

ESR, CRP, IL-6

Leads to the induction of regulatory T cells which can reduce immune protection against infections and cancer. Could through induction of increased numbers of immature dendritic cells stimulate clonogenic growth of myeloma cells. (Bone marrow of myeloma patients has more iDCs as compared to MGUS patients). If the number of iDCs would be increased in the bone marrow by curcumin, myeloma cells could induce the transformation of immature dendritic cells into more osteoclasts. Could lead to resistance against anti-angiogenic therapy and thus induce a more malignant phenotype

Numbers of regulatory T cells

been found in myeloma and the effect had been ascribed to IL-6 although other factors are probably also involved. Indeed IL-6 is a potent inhibitor of DC maturation through activation of signal transducer and activator of transcription-3 (STAT3) [22]. Curcumin inhibits the STAT3 pathway [59]. Curcumin can thus on the one hand attenuate the inhibitory effect of IL-6 on DC maturation while it can on the other hand have an inhibitory effect itself. The risk of increased susceptibility to infections should be anticipated when treating MGUS patients with curcumin. This is particularly true for patients with a compromised immune system. We encountered a case in which a daily intake of turmeric for intestinal complaints repeatedly led to bronchitis. Analysis of patient’s immune competence revealed a familiar selective IgG1 deficiency [60]. Patients

Paraprotein level and FLC ratio

Markers of bone turnover

Paraprotein level, FLC ratio, markers of bone turnover

with common variable immunodeficiency (CVID), have toll like receptor (TLR)-mediated B-cell defects. In a milder form this is caused by impaired interferon-alpha production by plasmacytoid DCs [61]. This effect seems to be caused by a selected impairment of both plasmacytoid DCs and B cells to respond to TLR7 and TLR9 agonists. These are the predominant TLRs expressed in plasmacytoid DCs and B cells. The result is a loss of cell activation, proliferation, and cytokine production by B cells and plasmacytoid DCs [61]. Curcumin is known to inhibit the expression levels of TLR2, TLR4 and TLR9 and may thus further reduce immune competence in patients with immunodeficiency [62]. In this context it should be noted that one quarter of patients with MGUS have hypogammaglobulinemia [3]. Moreover, most patients with monoclonal gammopathies including those with MGUS have

356

A.J.M. Vermorken et al. / Critical Reviews in Oncology/Hematology 84 (2012) 350–360

significantly lower percentages of plasmacytoid DCs and in myeloma patients this is not improved by treatment [55]. 5.3. Does curcumin suppress the immune response against (pre)malignant cells in MGUS? As discussed earlier the immune system develops T cell responses to tumors, but this response can either improve immunosurveillance when it is brought about by mature DCs and their cytokine profile or induce tolerance by the induction of regulatory T cells by immature DCs [63]. A direct effect of plasmacytoid DCs on the tumor has recently also been demonstrated [64]. Patients with monoclonal gammopathies have lower percentages of these cells [55]. Nevertheless patients with MGUS develop a vigorous T cell response against the (pre)malignant cells. Patients with myeloma fail to do so [65]. It is to be feared that curcumin, since it induces maturation-arrested DCs that expand regulatory T cells in vitro and in vivo [51], could suppress the T cell response in MGUS. If this would be confirmed it would imply a risk for accelerated progression to malignancy. 5.4. Could curcumin stimulate clonogenic growth of tumor cells? Curcumin may also influence the close interaction between bone marrow stromal cells and malignant plasma cells. Both DCs and osteoclasts support the growth of normal plasmablasts, the precursors of plasmacells. Only osteoclasts, however, support growth of plasmacells [66]. DCs are known to penetrate tumor tissue and this has been correlated to a worse prognosis. While this has originally been ascribed to the induction of immune tolerance by DCs it has recently become clear that there is a more direct interaction with the tumor cells. Myeloma cells cultured in the presence of DCs have an altered phenotype and miss the plasma cell differentiation marker CD138 [67]. DCs enhance the clonogenic growth of myeloma cells [67]. This was particularly so for immature DCs [68]. While doing so these latter cells display osteoclast-like features and are able to resorb bone [69]. Bone marrow of myeloma patients contains more immature DCs as compared to that of MGUS patients. Cell to cell contact of myeloma cells with immature DCs led to their transformation into osteoclasts. Plasma cells of MGUS patients did not induce this transformation [69]. 5.5. Could curcumin induce a more malignant phenotype? Curcumin is also known to have anti-angiogenic properties in several systems [70,71]. Its mechanism of action includes the inhibition of the gene expression of vascular endothelial growth factor (VEGF) [72]. Anti-angiogenetic agents are already applied in modern treatment strategies for solid tumors and for myeloma [73]. Unfortunately, the period of clinical benefit that often follows anti-angiogenetic

Table 3 Memorandum. (1) If low doses of turmeric or curcumin improve a chronic inflammatory condition, this might, on the longer term, reduce the risk for emergence of MGUS. (2) Before starting therapy of a monoclonal gammopathy it is crucial to establish whether it is stable of evolving. (3) Indicators of (low-grade)-inflammation should be measured before and during treatment. (4) It is so far unknown whether curcumin could do any good in patients without inflammation. If such patients are entered into a trial, close monitoring is advised. (5) Any lack of coherence in the evolution of the different parameters for monitoring should be considered suspect. Interruption of treatment should be considered. (6) Risk of increased susceptibility to infections should be carefully monitored. (7) Patients with common variable immunodeficiency should probably not be treated with curcumin. (8) If a patient has even a mild hypogammaglobulinemia, it seems wise to determine cellular immunity before treating with curcumin. (9) It seems important to measure numbers and percentages of regulatory T cells before and during curcumin treatment. (10) Curcumin can inhibit osteoclastogenesis but it might also be able to induce the formation of osteoclasts. Increased bone turnover should be interpreted as a warning sign. Immediate interruption of treatment should be considered. (11) It should be realized that treatment with curcumin could pose the risk of inducing a more malignant phenotype.

treatment does usually only result in delay of progression due to the development of resistance to the therapy [74]. Unfortunately the relapsing tumors often appear more invasive than the original ones. So far no drug has yet resulted in enduring efficacy in terms long-term tumor shrinkage or survival [74].

6. Conclusions Curcumin is a pleiotropic substance with many targets of which only the most pertinent ones have been discussed in the present paper. This is why it often works like a doubleedged sword [75]. In its application to cancer there is a bright side that has received a lot of attention in the last decade. There is, unfortunately also a dark side [76]. In this respect there is, despite the fact that curcumin is derived from a food component, no fundamental difference with other treatments. Future research will establish more clearly the benefit-risk profile of curcumin. The preliminary data available so far suggest that curcumin, in those patients that respond, probably works indirectly on factors playing a role at later stages of disease. Inflammation is a known risk factor for the emergence and progression of cancer. In advanced cancer there is often inflammation. It is conceivable that curcumin could act on inflammation. Indicators of inflammation should therefore absolutely be monitored. Unfortunately this has not happened in the clinical studies published so far. Other parameters like FLC ratio, the paraprotein load, markers of bone turnover and others (Table 2) should be looked at together. Any lack

A.J.M. Vermorken et al. / Critical Reviews in Oncology/Hematology 84 (2012) 350–360

of coherence in their evolution should be considered suspect. Blind optimism could damage the chance to identify the criteria for selection of patients that could benefit. Since there is still a serious lack of knowledge, doctors and patients should be cautious. (Table 3). Whether curcumin will find an established place in the management of a subgroup of patients with monoclonal gammopathies will depend on results of controlled clinical trials with validated clinical endpoints. Only positive empiric evidence gathered in the course of such clinical studies will allow the validation of the vast quantity of biological findings published during the last decades. So far such convincing data are lacking and therapy in the clinic is therefore today not justified. The International Myeloma Working Group 2010 guidelines stipulate that patients diagnosed with MGUS and SMM should not be treated outside of clinical trials [8]. Curcumin is being tested in clinical trials for a variety of other indications [10]. It seems wise to exclude patients with monoclonal gammopathies from such trials. Patients should realize that higher doses of the food component turmeric, which contains curcumin, are also not without risk. Before markers, allowing to accurately predict which patients will progress to malignant disease, have been found, [77] and as long as adequate criteria for selection of patients that could benefit from curcumin have not been identified, “watchful waiting”, whatever frustrating it may be, may still be the wisest choice. This is particularly true for stable monoclonal gammopathies without inflammation. Conflict of interest The authors declare no conflict of interest. Professor E. Andrès is a member of the French Commission of Pharmacovigilance. However, the present paper is not associated with this commission (personal view). He has received several grants for lectures, studies or expertise from laboratories (AMGEN, ROCHE, CHUGAI, GSK, VIFOR, FERRING, SHERRING, GENZYME, ACTELION), but this present work is free of any such association. Reviewers Ramaswamy Narayanan, Ph.D., Professor and Associate Dean for Res&Ind Relations, Florida Atlantic University, Charles E. Schmidt College of Science, 777, Glades Road, Boca Raton, FL 33431, United States. S. Vincent Rajkumar, M.D., Professor of Medicine, Mayo Clinic, Division of Hematology, Rochester, MN 55905, United States. Acknowledgements This research was supported by ‘Geconcerteerde Onderzoeksactie’ (GOA-08/016), Project 324000 of K.U. Leuven

357

Research & Development, the ‘Fonds voor Wetenschappelijk Onderzoek Vlaanderen’ (FWO), the Foundation for Biochemical and Pharmaceutical Research and Education, the “Industrieel Onderzoeksfonds” (IOF-HB/06/040) of K.U. Leuven, and the Belgian Federation against Cancer. These funding bodies had no role in the study design, in the collection, analysis and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication.

References [1] Aggarwal BB, Kumar K, Aggarwal MS, Shishodia S. Curcumin derived from turmeric (Curcuma longa): a spice for all seasons. In: Bagchi D, Preuss HG, editors. Phytopharmaceuticals in cancer chemoprevention. Boca Raton: CRC Press; 2004. p. 349–87. [2] Martin RC, Aiyer HS, Malik D, Li Y. Effect on pro-inflammatory and antioxidant genes and bioavailable distribution of whole turmeric vs curcumin: similar root but different effects. Food and Chemical Toxicology 2011;50(2):227–31. [3] Kyle RA, Therneau TM, Rajkumar SV, et al. Prevalence of monoclonal gammopathy of undetermined significance. New England Journal of Medicine 2006;354(13):1362–9. [4] Rajkumar SV, Kyle RA, Therneau TM, et al. Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood 2005;106(3):812–7. [5] Kyle RA, Rajkumar SV. Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. Current Hematologic Malignancy Reports 2010;5(2):62–9. [6] Gregersen H, Ibsen J, Mellemkjoer L, Dahlerup J, Olsen J, Sorensen HT. Mortality and causes of death in patients with monoclonal gammopathy of undetermined significance. British Journal of Haematology 2001;112(2):353–7. [7] Kyle RA, Rajkumar SV. Monoclonal gammopathy of undetermined significance. British Journal of Haematology 2006;134(6):573–89. [8] Kyle RA, Durie BG, Rajkumar SV, et al. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management. Leukemia 2010;24(6):1121–7. [9] Kyle RA, Buadi F, Rajkumar SV. Management of monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Oncology (Williston Park) 2011;25(7):578–86. [10] Hatcher H, Planalp R, Cho J, Torti FM, Torti SV. Curcumin: from ancient medicine to current clinical trials. Cellular and Molecular Life Sciences 2008;65(11):1631–52. [11] Sharma RA, Euden SA, Platton SL, et al. Phase I clinical trial of oral curcumin: biomarkers of systemic activity and compliance. Clinical Cancer Research 2004;10(20):6847–54. [12] Golombick T, Diamond T. The potential role of curcumin (diferuloylmethane) in plasma cell dyscrasias/paraproteinemia. Biologics 2008;2(1):161–3. [13] Golombick T, Diamond TH, Badmaev V, Manoharan A, Ramakrishna R. 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. Clinical Cancer Research 2009;15(18):5917–22. [14] Bida JP, Kyle RA, Therneau TM, et al. Disease associations with monoclonal gammopathy of undetermined significance: a population-based study of 17,398 patients. Mayo Clinic Proceedings 2009;84(8):685–93. [15] Bataille R, Chappard D, Basle MF. Quantifiable excess of bone resorption in monoclonal gammopathy is an early symptom of

358

[16]

[17]

[18]

[19]

[20]

[21] [22]

[23]

[24]

[25]

[26]

[27]

[28]

[29]

[30]

[31]

[32]

[33]

A.J.M. Vermorken et al. / Critical Reviews in Oncology/Hematology 84 (2012) 350–360 malignancy: a prospective study of 87 bone biopsies. Blood 1996;87(11):4762–9. Golombick T, Diamond TH, Manoharan A, Ramakrishna R. Monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and curcumin: A randomized, double-blind placebocontrolled cross-over 4 g study and an open-label 8 g extension study. American Journal of Hematology 2012;87(5):455–60. Rajkumar SV, Harousseau JL, Durie B, et al. International Myeloma Workshop Consensus Panel 1.Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood 2011;117(18):4691–5. Treon SP, Anderson KC. Interleukin-6 in multiple myeloma and related plasma cell dyscrasias. Current Opinion in Hematology 1998;5(1):42–8. Fulciniti M, Hideshima T, Vermot-Desroches C, et al. A high-affinity fully human anti-IL-6 mAb, 1339, for the treatment of multiple myeloma. Clinical Cancer Research 2009;15(23):7144–52. Oh S, Kyung TW, Choi HS. Curcumin inhibits osteoclastogenesis by decreasing receptor activator of nuclear factor-kappaB ligand (RANKL) in bone marrow stromal cells. Molecules and Cells 2008;26(5):486–9. Abe M. Myeloma bone disease and RANKL signaling. Clinical Calcium 2011;21(8):1167–74. Park SJ, Nakagawa T, Kitamura H, et al. IL-6 regulates in vivo dendritic cell differentiation through STAT3 activation. Journal of Immunology 2004;173(6):3844–54. DuVillard L, Guiguet M, Casasnovas RO, et al. Diagnostic value of serum IL-6 level in monoclonal gammopathies. British Journal of Haematology 1995;89(2):243–9. Alexandrakis MG, Passam FH, Ganotakis ES, et al. The clinical and prognostic significance of erythrocyte sedimentation rate (ESR), serum interleukin-6 (IL-6) and acute phase protein levels in multiple myeloma. Clinical and Laboratory Haematology 2003;25(1):41–6. Cesana C, Klersy C, Barbarano L, et al. Prognostic factors for malignant transformation in monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. Journal of Clinical Oncology 2002;20(6):1625–34. Shin SK, Ha TY, McGregor RA, Choi MS. Long-term curcumin administration protects against atherosclerosis via hepatic regulation of lipoprotein cholesterol metabolism. Molecular Nutrition & Food Research 2011;55(12):1829–40. Moreaux J, Legouffe E, Jourdan E, et al. BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone. Blood 2004;103(8):3148–57. Ju S, Wang Y, Ni H, et al. Correlation of expression levels of BLyS and its receptors with multiple myeloma. Clinical Biochemistry 2009;42(4–5):387–99. Shivakumar L, Ansell S. Targeting B-lymphocyte stimulator/B-cell activating factor and a proliferation-inducing ligand in hematologic malignancies. Clinical Lymphoma Myeloma 2006;7(2):106–8. Eilertsen GO, Van Ghelue M, Strand H, Nossent JC. Increased levels of BAFF in patients with systemic lupus erythematosus are associated with acute-phase reactants, independent of BAFF genetics: a case-control study. Rheumatology 2011;50(12):2197–205. Livshits G, Zhai G, Hart DJ, et al. Interleukin-6 is a significant predictor of radiographic knee osteoarthritis: the Chingford study. Arthritis and Rheumatism 2009;60(7):2037–45. Morel J, Roubille C, Planelles L, et al. Serum levels of tumour necrosis factor family members a proliferation-inducing ligand (APRIL) and B lymphocyte stimulator (BLyS) are inversely correlated in systemic lupus erythematosus. Annals of the Rheumatic Diseases 2009;68(6):997–1002. Moldovan F, Pelletier JP, Mineau F, Dupuis M, Cloutier JM, MartelPelletier J. Modulation of collagenase 3 in human osteoarthritic cartilage by activation of extracellular transforming growth factor beta: role of furin convertase. Arthritis and Rheumatism 2000;43(9): 2100–9.

[34] Ali YM, Urowitz MB, Ibanez D, Gladman DD. Monoclonal gammopathy in systemic lupus erythematosus. Lupus 2007;16(6):426–9. [35] Lindqvist EK, Goldin LR, Landgren O, et al. Personal and family history of immune-related conditions increase the risk of plasma cell disorders: a population-based study. Blood 2011;118(24):6284–91. [36] Huang G, Yang Y, Xu Z, et al. Downregulation of B lymphocyte stimulator expression by curcumin in B lymphocyte via suppressing nuclear translocation of NF-kappaB. European Journal of Pharmacology 2011;650(1):451–7. [37] Wang L, Walia B, Evans J, Gewirtz AT, Merlin D, Sitaraman SV. IL-6 induces NF-kappa B activation in the intestinal epithelia. Journal of Immunology 2003;171(6):3194–201. [38] Iliopoulos D, Jaeger SA, Hirsch HA, Bulyk ML, Struhl K. STAT3 activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the epigenetic switch linking inflammation to cancer. Molecular Cell 2010;39(4):493–506. [39] Yde P, Mengel B, Jensen MH, Krishna S, Trusina A. Modeling the NF-kappaB mediated inflammatory response predicts cytokine waves in tissue. BMC Systems Biology 2011;5:115. [40] Hutchison CA, Landgren O. Polyclonal immunoglobulin free light chains as a potential biomarker of immune stimulation and inflammation. Clinical Chemistry 2011;57(10):1387–9. [41] Gottenberg JE, Aucouturier F, Goetz J, et al. Serum immunoglobulin free light chain assessment in rheumatoid arthritis and primary Sjogren’s syndrome. Annals of the Rheumatic Diseases 2007;66(1):23–7. [42] Srivastava RM, Singh S, Dubey SK, Misra K, Khar A. Immunomodulatory and therapeutic activity of curcumin. International Immunopharmacology 2011;11(3):331–41. [43] Gupta D, Treon SP, Shima Y, et al. Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: therapeutic applications. Leukemia 2001;15(12):1950–61. [44] Tai YT, Li XF, Breitkreutz I, et al. Role of B-cell-activating factor in adhesion and growth of human multiple myeloma cells in the bone marrow microenvironment. Cancer Research 2006;66(13):6675–82. [45] Shirley SA, Montpetit AJ, Lockey RF, Mohapatra SS. Curcumin prevents human dendritic cell response to immune stimulants. Biochemical and Biophysical Research Communications 2008;374(3):431–6. [46] Haabeth OA, Lorvik KB, Hammarstrom C, et al. Inflammation driven by tumour-specific Th1 cells protects against B-cell cancer. Nature Communications 2011;2:240. [47] Sharma A, Khan R, Joshi S, Kumar L, Sharma M. Dysregulation in T helper 1/T helper 2 cytokine ratios in patients with multiple myeloma. Leukemia and Lymphoma 2010;51(5):920–7. [48] Cools N, Van Tendeloo VF, Smits EL, et al. Immunosuppression induced by immature dendritic cells is mediated by TGF-beta/IL10 double-positive CD4+ regulatory T cells. Journal of Cellular and Molecular Medicine 2008;12(2):690–700. [49] Pinzon-Charry A, Maxwell T, Lopez JA. Dendritic cell dysfunction in cancer: a mechanism for immunosuppression. Immunology and Cell Biology 2005;83(5):451–61. [50] Cong Y, Wang L, Konrad A, Schoeb T, Elson CO. Curcumin induces the tolerogenic dendritic cell that promotes differentiation of intestine-protective regulatory T cells. European Journal of Immunology 2009;39(11):3134–46. [51] Rogers NM, Kireta S, Coates PT. Curcumin induces maturationarrested dendritic cells that expand regulatory T cells in vitro and in vivo. Clinical and Experimental Immunology 2010;162(3):460–73. [52] Shurin GV, Ouellette CE, Shurin MR. Regulatory dendritic cells in the tumor immunoenvironment. Cancer Immunology, Immunotherapy 2012;61(2):223–30. [53] Janikashvili N, Bonnotte B, Katsanis E, Larmonier N. The dendritic cell-regulatory T lymphocyte crosstalk contributes to tumor-induced tolerance. Clinical and Developmental Immunology 2011;2011:430394. [54] Banerjee DK, Dhodapkar MV, Matayeva E, Steinman RM, Dhodapkar KM. Expansion of FOXP3high regulatory T cells by human dendritic

A.J.M. Vermorken et al. / Critical Reviews in Oncology/Hematology 84 (2012) 350–360

[55]

[56]

[57]

[58]

[59]

[60]

[61]

[62]

[63] [64]

[65]

[66]

[67]

[68]

[69]

[70]

[71]

[72]

cells (DCs) in vitro and after injection of cytokine-matured DCs in myeloma patients. Blood 2006;108(8):2655–61. Brimnes MK, Vangsted AJ, Knudsen LM, et al. Increased level of both CD4 + FOXP3 + regulatory T cells and CD14 + HLA-DR/low myeloidderived suppressor cells and decreased level of dendritic cells in patients with multiple myeloma. Scandinavian Journal of Immunology 2010;72(6):540–7. Giannopoulos K, Kaminska W, Hus I, Dmoszynska A. The frequency of T regulatory cells modulates the survival of multiple myeloma patients: detailed characterisation of immune status in multiple myeloma. British Journal of Cancer 2012;106(3):546–52. Kristinsson SY, Tang M, Pfeiffer RM, et al. Monoclonal gammopathy of undetermined significance and risk of infections: a population-based study. Haematologica 2011:054015. Martin-Ayuso M, Almeida J, Perez-Andres M, et al. Peripheral blood dendritic cell subsets from patients with monoclonal gammopathies show an abnormal distribution and are functionally impaired. Oncologist 2008;13(1):82–92. Bharti AC, Donato N, Aggarwal BB. Curcumin (diferuloylmethane) inhibits constitutive and IL-6-inducible STAT3 phosphorylation in human multiple myeloma cells. Journal of Immunology 2003;171(7):3863–71. Vermorken AJM, Zhu J, Van de Ven WJM, Cui Y, Fryns JP. Curcumin for the prevention of progression in monoclonal gammopathy of undetermined significance: a word of caution. Experimental and Therapeutic Medicine 2010;1(2):265–9. Yu JE, Zhang L, Radigan L, Sanchez-Ramon S, Cunningham-Rundles C. TLR-mediated B cell defects and IFN-alpha in common variable immunodeficiency. Journal of Clinical Immunology 2012;32(1): 50–60. Tu CT, Han B, Yao QY, Zhang YA, Liu HC, Zhang SC. Curcumin attenuates Concanavalin A-induced liver injury in mice by inhibition of Toll-like receptor (TLR) 2, TLR4 and TLR9 expression. International Immunopharmacology 2012;12(1):151–7. Gerloni M, Zanetti M. CD4 T cells in tumor immunity. Springer Seminars in Immunopathology 2005;27(1):37–48. Drobits B, Holcmann M, Amberg N, et al. Imiquimod clears tumors in mice independent of adaptive immunity by converting pDCs into tumor-killing effector cells. Journal of Clinical Investigation 2012;122(2):575–85. Dhodapkar MV, Krasovsky J, Osman K, Geller MD. Vigorous premalignancy-specific effector T cell response in the bone marrow of patients with monoclonal gammopathy. Journal of Experimental Medicine 2003;198(11):1753–7. Geffroy-Luseau A, Jego G, Bataille R, Campion L, Pellat-Deceunynck C. Osteoclasts support the survival of human plasma cells in vitro. International Immunology 2008;20(6):775–82. Kukreja A, Hutchinson A, Dhodapkar K, et al. Enhancement of clonogenicity of human multiple myeloma by dendritic cells. Journal of Experimental Medicine 2006;203(8):1859–65. Tucci M, Stucci S, Strippoli S, Dammacco F, Silvestris F. Dendritic cells and malignant plasma cells: an alliance in multiple myeloma tumor progression? Oncologist 2011;16(7):1040–8. Tucci M, Ciavarella S, Strippoli S, Brunetti O, Dammacco F, Silvestris F. Immature dendritic cells from patients with multiple myeloma are prone to osteoclast differentiation in vitro. Experimental Hematology 2011;39(7):773–83. Binion DG, Otterson MF, Rafiee P. Curcumin inhibits VEGFmediated angiogenesis in human intestinal microvascular endothelial cells through COX-2 and MAPK inhibition. Gut 2008;57(11): 1509–17. Yoysungnoen P, Wirachwong P, Changtam C, Suksamrarn A, Patumraj S. Anti-cancer and anti-angiogenic effects of curcumin and tetrahydrocurcumin on implanted hepatocellular carcinoma in nude mice. World Journal of Gastroenterology 2008;14(13):2003–9. Gururaj AE, Belakavadi M, Venkatesh DA, Marme D, Salimath BP. Molecular mechanisms of anti-angiogenic effect of

[73]

[74]

[75]

[76]

[77]

359

curcumin. Biochemical and Biophysical Research Communications 2002;297(4):934–42. Fan F, Schimming A, Jaeger D, Podar K. Targeting the tumor microenvironment: focus on angiogenesis. Journal of Oncology 2012;2012:281261. Paez-Ribes M, Allen E, Hudock J, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 2009;15(3):220–31. Marathe SA, Dasgupta I, Gnanadhas DP, Chakravortty D. Multifaceted roles of curcumin: two sides of a coin! Expert Opinion on Biological Therapy 2011;11(11):1485–99. Burgos-Moron E, Calderon-Montano JM, Salvador J, Robles A, LopezLazaro M. The dark side of curcumin. International Journal of Cancer 2010;126(7):1771–5. Waxman AJ, Kuehl M, Balakumaran A, Weiss B, Landgren O. Smoldering (asymptomatic) multiple myeloma: revisiting the clinical dilemma and looking into the future. Clinical Lymphoma Myeloma and Leukemia 2010;10(4):248–57.

Biographies Professor Alphons Vermorken in 1977, received his PhD degree in Molecular Biology, with the greatest distinction, at the University of Nijmegen, the Netherlands. In 1988 he obtained a postdoctoral degree in toxicology. He was awarded the Nijmegen, Faculty of Sciences price for research in 1973, the Shell price in 1977 and the “Young Investigators Award” during the International Congress of Pediatric Laboratory Medicine in Jerusalem, Israel in 1980. He was head of the Research Unit for Cellular Differentiation and Transformation in Nijmegen from 1978 onwards. In that function he was recruited as advisor to three pharmaceutical companies. In 1986, he was nominated Professor on Steroid Biochemistry at the University of Montpellier in France. In 1989, he was nominated Professor at the University of Leuven, Belgium. Between 1987 and 2005 he was involved in the coordination of Health Research, at the European level, as a civil servant at the European Commission in Brussels, Belgium. In 2005 he again joined the University of Leuven where he was nominated Professor of Molecular Oncology. In 2009, he was also nominated visiting Professor at the Northwest University, Xi’an, China. Jingjing Zhu M.Sc. did two bachelor’s degrees, on Bioscience and Technology and on Foreign-oriented English translation. She subsequently completed her master’s degree in Biochemistry and Molecular Biology at the Northwest University in Xi’an, China, in June 2009. During her master’s study, she participated in the 5th Annual Congress of International Drug Discovery Science and Technology in 2007 in Xi’an and she followed a three months training period at the University of Leuven in Belgium. She studied the Japanese language. After her study on the expression and purification of GST fusion proteins using magnetic nanoparticles at the Northwest University, she joined the Laboratory for Molecular Oncology at the University of Leuven in Belgium where she follows a PhD program on biomedical

360

A.J.M. Vermorken et al. / Critical Reviews in Oncology/Hematology 84 (2012) 350–360

research on Cancer. Her subject deals with physiological mechanisms in the regulation of the proprotein convertase furin. Professor Wim J.M. Van de Ven Upon completion of his PhD in viral oncology at the University of Nijmegen, The Netherlands, Dr. Van de Ven joined in 1979 the National Cancer Institute of the United States, where he participated as a post-doc in basic cancer research. In 1983, he joined the faculty of the Biochemistry Department of the University of Nijmegen. This led to the discovery and cloning of the FUR gene and his pioneering work led to the identification of the function of furin as the first and long elusive mammalian proprotein convertase. The furin enzyme was then used in developing a precursor protein processing technology for application for the enhanced production of relevant protein-based biopharmaceuticals. Furin pro-protein processing technology has been patent protected by the University of Leuven, covering countries of major markets. In 1987, he joined the Medical School of the University of Leuven in Belgium, where he is a full professor in Molecular Genetics and Biotechnology. At the Department of Human Genetics, he focused his research on genes involved in benign tumor formation. This led to the discovery of two novel gene families, i.e. the HMGA and the PLAG gene family, respectively, and both of these are involved in multiple tumor types (Nature Genetics 10, 436-444,1995; Nature Genetics 15, 170-174, 1997). Subsequently, he generated a versatile

PLAG1 transgenic mouse strain that is instrumental in specifically mimicking various human tumor types. In 2009, he was invited as visiting professor at the Northwest University in Xi’an, P.R. China. Professor Emmanuel Andrès In 1996, received his MD degree in Internal Medicine, at the University of Strasbourg, France. He worked as an associated professor in the University Hospital of Strasbourg, France. In 1998 he worked as PhD in Molecular Biology in the Laboratory of Professor Hoffmann (2011, Nobel Prize of Medicine) in the field of cationic antimicrobial peptides and pathogens – host relations. In 2002, he was nominated Professor at the University of Strasbourg, France. He also was in the head of an Internal Medicine Department (of > 60 beads) in the University hospital of Strasbourg, France. He was awarded the French Society of Hematology, price for research in the field of anemia related to cobalamin or folate deficiencies in 2004. Achievements include development of research in: all type of anemia, neutropenia and thrombocytopenia, particularly drug-induced neutropenia and agranulocytosis or thrombocytopenia; haematopoietic growth factors; and cobalamin deficiencies. His recent works also include research and development on human sounds analysis, electronic stethoscope, e-auscultation, and e-medicine. In that function he was recruited as advisor to several pharmaceutical companies or start-up. In 2007, he was nominated in the French National Commission of Pharmacovigilence.