Curcumin for monoclonal gammopathies what can we hope for, what should we fear

Curcumin for monoclonal gammopathies what can we hope for, what should we fear Curcumin for monoclonal gammopathies what can we hope for, what should we fear Curcumin for monoclonal gammopathies what can we hope for, what should we fear Curcumin for monoclonal gammopathies what can we hope for, what should we fear Curcumin for monoclonal gammopathies what can we hope for, what should we fear

Curcumin for monoclonal gammopathies What can we hope for, what

should we fear?

aLaboratory for Molecular Oncology, Department of Human Genetics, KU Leuven, Belgium

bDepartment of Internal Medicine, Diabetes and Metabolic Disorders, University Hospital of Strasbourg, Strasbourg, France

Accepted 25 April 2012

Contents

1 Introduction 351

1.1 Curcumin and health 351

1.2 Monoclonal gammopathies 351

2 Curcumin for monoclonal gammopathies 352

2.1 The first results with curcumin 352

2.2 Reflecting on possible targets 352

2.3 Curcumin does not influence the paraprotein level in all patients 352

3 Can curcumin lower the risk for emergence of MGUS in some inflammatory diseases? 353

4 Curcumin might work on immune cells rather than on the bone marrow directly 353

5 Curcumin for prevention of progression of MGUS and SMM, reasons for concern? 354

5.1 Both curcumin and myeloma act on dendritic cells and induce immunosuppression 354

5.2 Increased susceptibility to infections 354

5.3 Does curcumin suppress the immune response against (pre)malignant cells in MGUS? 356

5.4 Could curcumin stimulate clonogenic growth of tumor cells? 356

5.5 Could curcumin induce a more malignant phenotype? 356

6 Conclusions 356

Conflict of interest 357

Reviewers 357

Acknowledgements 357

References 357

Biographies 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:fons.vermorken@med.kuleuven.be (A.J.M Vermorken), jingjing.zhu@med.kuleuven.be (J Zhu), wim.vandeven@med.kuleuven.be

(W.J.M Van de Ven), emmanuel.andres@chru-strasbourg.fr (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

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

sub-stance 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

cur-cumin is known for its anti-inflammatory properties [1]

Curcumin (diferuloylmethane), is the main curcuminoid

(>75%) in the Indian spice turmeric (seeFig 1for the

struc-tural formulas of the three main curcuminoids) Since it is

extracted from a food component that has been used for

cen-turies 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 peo-ple Food components might, however, be less safe for patients as thought by the general public Legislation does not require companies producing supplements to show evi-dence 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 com-pounds 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 pro-gression Prevalence of monoclonal gammopathy, without evidence of malignant disease, increases from below two per-cent in fifty to sixty year old people to above six perper-cent 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 lympho-proliferative 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 com-peting 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

(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

candi-dates 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

sci-ence as a therapeutic agent It is currently used in human

clinical trials for a variety of conditions, including

psoria-sis, 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

Preven-tive 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

con-sidered 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

placebo-controlled 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

encour-aging 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 pre-vention 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 suggest-ing that it could contribute to control tumor burden and bone disease[19] Curcumin has also been shown to inhibit osteo-clastogenesis 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 find-ings 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 ana-lyze 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 cur-cumin 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

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

sur-vival 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

lev-els [26] in agreement with its known anti-inflammatory

activity Regrettably, neither indicators of systemic

inflam-mation 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

fam-ily (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

arthri-tis 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

osteoarthri-tis[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,

proba-bly by interfering with NF-kB signaling[36]but it is doubtful

whether the concentrations needed therefore are reached in other tissues than the intestine[12] In this context it is note-worthy 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 inflam-matory 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 rela-tively 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 fluctu-ations 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 clon-ality 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 cur-cumin 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 per-haps 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 Rel-atively 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 stro-mal cells than in myeloma cells, and tumor cell adhesion to stromal cells further augments BAFF secretion by 2- to 5-fold[44] Moreover, BAFF increases adhesion of myeloma

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] 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

[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

[45] 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

[48,49]

Curcumin-treated bone marrow derived DCs

induced differentiation of nạve CD4+ T

cells into regulatory T cells (Tregs) similar

to those present in the intestine

[50,51] Immature DCs can maintain peripheral T cell tolerance by the induction

and stimulation of Treg populations

[49]

Curcumin treated DCs are not only

immature, they are also maturation

resistant This means that curcumin

treated DCs do not mature under

inflammatory conditions

[51] Tregs negatively modulate DC maturation thereby contributing to the

immune tolerance of cancer

[48]

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

[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

[53]

Curcumin provokes Foxp3 expression in

Tregs.

[51] DCs matured with inflammatory cytokines can also induce Tregs These

Tregs express Foxp3 protein and exert suppression through cell-cell contact Tregs induced by immature DCs secrete IL-10 as a suppressive factor

[54]

Inflammatory cytokines in myeloma could lead to maturation of DCs and

to the induction of Foxp3 expressing regulatory T cells

[55]

Curcumin treated DCs are defective in both

migration and endocytosis.

[45] Multiple myeloma reduces the percentage and numbers of both myeloid

and plasmacytoid DCs while the percentages of Tregs, both with and without expression of Foxp3 are strongly increased

[55,56]

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.

[56]

cells to bone marrow stromal cells in a dose-dependent

man-ner[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

con-ceivable 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

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 resem-ble immunosuppression in patients with myeloma In both cases DCs are involved.Table 1summarizes the effects on DCs The effects of curcumin on DCs lead to several rea-sons 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 inflamma-tory cytokines[58] Abnormal DC maturation had previously

Table 2

Elements to consider before and during treatment of a patient with a monoclonal gammopathy with curcumin.

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.

Is a food component that has been used for

centuries Has also been used for centuries as

an anti-inflammatory substance.

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

Is rather insoluble which leads to low plasma

values and thus low toxicity.

Attempts to increase absorption and increase of the dose might also increase toxicity Some food components, like e.g piperine in pepper increase bioavailability.

Provoked only minimal toxicity in healthy

volunteers at doses of up to 8 g/day

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.

Reduces the paraprotein load in some patients Does it increase the paraprotein load in some

patients?

Paraprotein load and FLC ratio Reduces markers of bone turnover in some

patients.

Does it increase markers of bone turnover in some patients?

Markers of bone turnover and FLC ratio

Reduces the expression of toll like receptors and thus induces immunesuppression.

Total Gammaglobulins, IgG, IgA, IgM and subclasses thereof.

Determine absolute numbers of B-cells and percentages of switched memory B-cells 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.

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.

Th1 cytokines, IL-2 and IFN gamma.

Th2 cytokines, IL-4, IL-5, IL-10.

IL-6.

Inhibits the STAT3 pathway which is activated

by IL-6

Renders dendritic cells maturation resistant ESR, CRP, IL-6 Might prevent maturation of dendritic cells by

inflammatory cytokines and so reduce the

induction of regulatory T cells.

Leads to the induction of regulatory T cells which can reduce immune protection against infections and cancer.

Numbers of regulatory T cells

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).

Paraprotein level and FLC ratio

Inhibits osteoclastogenesis 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.

Markers of bone turnover

Has anti-angiogenic properties Could lead to resistance against anti-angiogenic

therapy and thus induce a more malignant phenotype

Paraprotein level, FLC ratio, markers of bone turnover

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

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 predom-inant 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

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

differ-entiation 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

transforma-tion 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

prop-erties 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] Unfortu-nately 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 double-edged 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 cur-cumin, in those patients that respond, probably works indirectly on factors playing a role at later stages of dis-ease 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

of coherence in their evolution should be considered suspect.

Blind optimism could damage the chance to identify the

cri-teria 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

gam-mopathies will depend on results of controlled clinical trials

with validated clinical endpoints Only positive empiric

evi-dence gathered in the course of such clinical studies will allow

the validation of the vast quantity of biological findings

pub-lished 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]

Cur-cumin is being tested in clinical trials for a variety of other

indications[10] It seems wise to exclude patients with

mono-clonal 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

mon-oclonal gammopathies without inflammation

Conflict of interest

The authors declare no conflict of interest

Professor E Andrès is a member of the French

Commis-sion 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

Onder-zoeksactie’ (GOA-08/016), Project 324000 of K.U Leuven

Research & Development, the ‘Fonds voor Wetenschap-pelijk 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 collec-tion, analysis and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication

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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 Transforma-tion in Nijmegen from 1978 onwards In that funcTransforma-tion 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 coordina-tion 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

Bio-science 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 Inter-national 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 nanopar-ticles 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