- Email: [email protected]
Curcumin: Towards molecularly targeted chemoprevention of cancer
New Horizons in Translational Medicine 2 (2014) 20–26
Contents lists available at ScienceDirect
New Horizons in Translational Medicine journal homepage: www.elsevier.com/locate/nhtm
Research Articles
Curcumin: Towards molecularly targeted chemoprevention of cancer Ulrich Pfeffer a,n, Adriana Amaro a, Beatrice Bachmeier b, Giovanna Angelini a a b
Functional Genomics, IRCCS AOU San Martino – IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich, Munich, Germany
ar t ic l e i nf o
a b s t r a c t
Available online 27 August 2014
Everybody is at risk for cancer yet environmental factors, life style and diet as well as genetic factors influence the individual cancer risk. Targeted or personalized cancer prevention is based on the knowledge of the molecular characteristics of the tumor to be prevented, the molecular mechanisms of action of the compounds to be used and the genetic make-up of the person who opts for prevention medicine. Genetic factors are to a certain extent specific for cancer types or even subtypes as it has been shown for breast cancer. The growing knowledge of such genotype cancer risk associations will allow for the definition of personalized prevention strategies. Prevention in intermediate risk populations requires non-toxic, well tolerated and cheap compounds, such as Curcumin. Its main activity is the inhibition of nuclear factor kappa B (NFkB) activation. NFkB is involved in many cancers where it acts through the generation of chronic inflammation that can be contrasted with anti-inflammatory drugs such as Curcumin. Targeted prevention of cancer also increases the possibility to conduct serious clinical experimentation with target based patient selection.
Keywords: Inflammation Polyphenols Cancer risk SNP COX2
Focal points:
Bedside
Prevention might retard cancer development for years if specifically targeted. Growing knowledge of genetic determinants of cancer risk allows for the selection of individuals for targeted prevention. Benchside Genetic variants associated with the risk for specific cancer (sub-)types have been identified and additional research is needed in this promising field. The molecular mechanisms of cancer development and their relation with risk variants must be investigated and compounds that can interfere with these mechanisms must be identified. Industry A major effort in cancer prevention is needed and justified by a large potential market. The major challenge is the design of non-toxic compounds suitable for preventive treatments of healthy people who are at risk of developing cancer Community Active cancer prevention as opposed to early detection of cancer must become a focus of communication. Governments More effort in preventive cancer medicine is needed and justified by accumulating evidence for targeted prevention. Cancer prevention can add years of healthy life and can reduce cancer therapy associated costs. & 2014 European Society for Translational Medicine. Published by Elsevier Ltd. All rights reserved.
n
Correspondence to: Functional Genomics, IRCCS AOU San Martino – IST, Largo Rosanna Benzi 10, 16132 Genova, Italy. Tel.: þ 39 3283853547. E-mail address: [email protected] (U. Pfeffer).
http://dx.doi.org/10.1016/j.nhtm.2014.08.005 2307-5023/& 2014 European Society for Translational Medicine. Published by Elsevier Ltd. All rights reserved.
U. Pfeffer et al. / New Horizons in Translational Medicine 2 (2014) 20–26
1. Introduction Cancer is a disease of probability. Just like all biological processes, DNA replication is prone to errors, in this case, mutations. Mutations are not always repaired and repair sometimes introduces the wrong nucleotide. Most cells with DNA damage or mutations probably undergo apoptosis but with a certain probability, mutations are fixed and can determine increased proliferation and avoidance of apoptosis. Additional mutations eventually help the transformed cells to pass the hurdles of multistep carcinogenesis, many of which also need a contribution from the microenvironment [1,2]. All these steps, fortunately, occur with a low probability. Yet given the huge number of cells in the human organism and the length of a life cancer development becomes probable. Without afflicting the underlying probabilistic nature, life style (smoke, diet, physical activity, reproduction history), environmental (exposure to carcinogens) and genetic factors modify the cancer risk. Cancer risk increases with increasing age. If people do not die from other diseases before, their likelihood to develop and eventually die from cancer grows. Improving prevention of other (i.e. cardiovascular) diseases increases the lifetime cancer risk. Therefore, one in two or three persons in affluent countries will receive a cancer diagnosis at some point of her life. In other words: everybody is at risk. Everybody is eligible for cancer prevention measures.
2. Cancer prevention Cancer prevention as it is conceived here is not early detection. Mass screening as for example by mammography for breast cancer
21
or serum PSA levels for prostate cancer leads to early detection and, to a certain (highly discussed) extent, prevention of the development of aggressive and eventually life threatening disease. Cancer prevention as opposed to early detection aims at avoiding or retarding the development of cancer. The simplest measure of cancer prevention is the avoidance of carcinogens such as cigarette smoke, asbestos and chemical pollution in air, water, earth and food. This is mainly a public health issue and, except for smoking, cannot be modified by the intervention on the single person. The second simplest measure is to adopt a healthy life style in terms of diet, physical activity and appropriate timing of reproduction. This is what the physician will counsel her patients in the absence of specific genetic risk factors since in the low risk group no specific intervention and no side effects are tolerable. Often it is not possible to totally avoid carcinogen exposure; life style intervention does not work in each case and even in the absence of specific carcinogens and an unhealthy life style there is a cancer risk due to genetic factors. In these situations cancer prevention becomes important. An intermediate risk can be approached through targeted non-toxic prevention; interventions with side effects are limited to specific high risk situations (Fig. 1). A realistic aim of cancer prevention in intermediate- and highrisk populations could be the retardation of the onset of cancer development by several years while the complete avoidance appears to be out of sight. Yet a retardation of several years in the development of a cancer is likely to correspond to a similar extension of life and, most importantly, of healthy life. This must be compared to what is obtained by state-of-the-art pharmacological cancer therapies whose effects are often counted in months and rarely in years of survival, especially once the cancer is
Fig. 1. Targets of cancer prevention: population, cancer risk and side effects. The dimension of the population eligible for cancer prevention inversely correlates with the risk and tolerable side effects: For the general population facing a low risk of cancer, life style interventions are appropriate, the smaller but still numerous medium risk population could use non-toxic compounds such as Curcumin or other polyphenols as a prevention measure. Chemoprevention drugs with some toxicity can be proposed to the small high risk population with strong risk factors. The low risk population has no specific genetic risk factors and no accumulation of cancers in the family, intermediate risk is determined by cancer risk associated SNP and a weak familiarity, persons with cancer gene mutations and/or a clear accumulation of cancer cases in first line parents constituting a high risk population. Aspirin is only indicated for the high risk population since in the elderly, it has a relevant risk of inducing bleeding.
22
U. Pfeffer et al. / New Horizons in Translational Medicine 2 (2014) 20–26
metastatic. Moreover, even efficacious conventional therapy might come at the price of earlier senescence thus reducing the total life span [3] whereas prevention is likely to extend it. Prevention has therefore a potential to deliver a major advancement in the fight against cancer. This potential has so far been left mostly unexplored because the need to treat healthy people, not cancer patients, requires treatments that correspond to the following criteria: (i) absence of toxicity, (ii) low cost, (iii) suitability for long term treatments, and (iv) high compliance. These criteria are not matched by conventional drugs. On the other hand, evidence of cancer preventive effects of unconventional compounds derived from traditional or alternative medicine is often anecdotal and does not meet scientific criteria such as rigorous testing in controlled clinical trials. Evidence derived from preclinical studies has accumulated for at least some compounds yet in the absence of markers useful for the selection of risk populations and lack of surrogate efficacy markers make the translation into the clinical practice almost impossible. Moreover, the lack of economic interest due to the inability to obtain patents for these compounds prohibits the conduction of large, long term cohort studies needed to establish the efficacy. This applies particularly to primary prevention where the age corrected incidence of cancer is to be lowered. However, cancer prevention can also be applied after diagnosis and treatment of cancer where the progression of the diseases in terms of occurrence of secondary primaries and local and distant metastasis is to be prevented (adjuvant therapy). In some instances where the clinician opts for watchful waiting, cancer prevention could be applied to suppress progression of an existing cancer. Many drugs are available for adjuvant therapy and growth control of unresected primaries. Unconventional compounds may find an application for diseases without adequate adjuvant therapy as well as in certain low risk situations where the patient might opt against drugs with side effects.
3. The concept of targeted cancer prevention Targeted or personalized cancer prevention is based on the knowledge of the molecular characteristics of the tumor to be
prevented, the molecular mechanisms of action of the compounds to be used and the genetic make-up of the person who opts for prevention medicine (Fig. 2). Recent advances in the molecular characterization of human tumors have revealed a wealth of knowledge on specific molecular characteristics [4]. Breast cancer, for instance, can now be classified in probably four large molecular classes, the estrogen receptor ERα positive subtypes luminal A and B that greatly differ with respect to their proliferative potential and the associated risk of distant relapse, the HER2 subtype carrying an amplification of the epidermal growth factor 2 (ERRB2) encoding gene on chromosome 17q12, and the triple negative subtype characterized by the lack of expression of ERα, the progesterone receptor and ERRB2 [5]. Each of these subtypes can be considered a specific disease with particular molecular characteristics. On the other hand, genome wide association studies deliver an ever growing number of genetic variations that are associated with the cancer risk. So far, most studies have considered only single nucleotide polymorphisms (SNPs) but more recently, the presence of deletions, insertions, amplifications, and inversions involving hundreds of basepairs has shown to be frequent in the general population and most likely contribute to the cancer risk [6,7]. The growing knowledge of functional aspects of the genome even outside protein encoding regions will lead to a further identification of molecular factors that may be associated with the cancer risk of each individual. Yet most importantly, genetic factors do not necessarily increase the general cancer risk but can contribute to the risk for a specific cancer type or even a specific subtype as it has been shown for breast cancer [8–11]. Hence it is possible, to a certain extent, to weight the additional risk for a specific subtype of cancer conferred by the person's genotype. If this subtype deploys molecular targets for prevention the triangle of targeted prevention (Fig. 2) can be completed. Again, breast cancer sets the stage since hardly any other cancer is better characterized than ERα positive breast cancers. ERα has been explored as a target not only for the prevention of distant metastases in the adjuvant setting but also for primary prevention [12]. However, this is limited by considerable side effects of the anti-estrogens or aromatase inhibitors used. The actual use of tamoxifen for cancer
Fig. 2. The concept of targeted prevention. Targeting of cancer prevention requires the personal risk assessment based on the knowledge of the genetic background of each individual. If a risk for a specific cancer type or subtype is present the knowledge of the molecular characteristics of this cancer (sub-)type allows for the selection of specific molecular targets. These targets must be matched by compounds with known molecular mechanisms of action that affect these targets.
U. Pfeffer et al. / New Horizons in Translational Medicine 2 (2014) 20–26
prevention remains therefore low [13]. Other chemoprevention drugs, such as the anti-osteoporosis drug bisphosphonate and cholesterol lowering statins also have a profile of side effects, so that their use must be limited to the original indications or cancer prevention in high risk populations [14]. In a near future, patient selection based on genetic risk factors for ERα positive breast cancer will become feasible and other weak dietary estrogens that compete with endogenous estrogens for binding to the receptor might be used. We have recently shown that Curcumin also shows weak estrogenic activity on gene transcription [15]. A paramount example of targeted prevention of cancer progression is acetyl-salicylic acid, Aspirin, a non-steroidal anti-inflammatory drug in use since more than hundred years. Recent evidence derived from clinical studies in colon cancer shows that Aspirin can drastically reduce the progression rate of colon cancers that carry a mutation in the PIK3CA gene encoding the catalytic subunit of the phosphatidylinositol-4,5-bisphosphate 3-kinase. The mutation leads to enhanced activation of the prostaglandin-endoperoxide synthase 2 also known as cyclooxygenase 2 (PTGS, COX2), one of the targets of Aspirin. This effect leads to a highly significant difference in disease free and overall survival (Fig. 3) [16]. If the PIK3CA mutation is associated with a specific subtype of colon cancer and a related risk profile, Aspirin could become interesting also for primary prevention. Another example of targeted prevention is “angioprevention”, cancer prevention obtained through the suppression of angiogenesis in a prevention setting [17,18]. The biguanide drug, metformin, that activates the main metabolic switch AMP-kinase (AMPK) [14,19] and probably other key metabolism regulators such as hexokinase [20], in use as a first line treatment of type 2 diabetes, has also been proposed for cancer prevention, eventually in combination with Aspirin [19]. Targeting for prevention is also needed because, against widely held beliefs, up-take of preventive compounds with the diet has most likely no or weak effects on cancer development and survival as recently shown for resveratrol, a compound contained in red wine [21]. Efficacious prevention strategies require the intake of non-toxic compounds at pharmacological doses and their prescription should therefore be based on a measurable risk.
4. Curcumin for targeted prevention How does this apply to Curcumin? Curcumin is a polyphenol extracted from turmeric (Curcuma longa) and is used as a spice (the yellow component of curry) and for the treatment of inflammation related diseases in traditional Indian and Chinese medicine. There is ample evidence for the anti-tumoral activities of Curcumin derived from in vitro and in vivo studies summarized in recent reviews [22–24]. Curcumin inactivates NFkB through the stabilization of IkB that blocks the translocation of the transcription factor complex into the nucleus and thus abolishes its effects on the transcription of anti-apoptotic, pro-inflammatory and pro-metastatic genes. Curcumin stabilizes IkB through the inhibition of the kinase IkK [25]. In the absence of Curcumin, the active IkK phosphorylates IkB directing the latter towards degradation in the proteasome. Curcumin acts like synthetic inhibitors such as SC-514 by blocking phosphorylation of IkB and activation of NFkB. SC-514 and Curcumin do not show additive or synergistic effects when used in combination [26]. Curcumin also acts through the induction of miR181b that also affects NFkB signaling [27]. IkKα and IkKβ form the catalytic subunits of the IkK complex that contains IkKγ (nemo) as a regulatory subunit. The complex controls NFkB activity through the phosphorylation of IkBα. Phosphorylated IkBα is ubiquitinylated and rapidly degraded by the proteasome. Free of IkBα, the NFkB subunit p65 can translocate into the nucleus
23
and activate the transcriptional inflammation and anti-apoptosis program (for a review see [28]). NFkB is a major regulator of inflammation and controls the transcription of inflammatory cytokines [29]. Curcumin interrupts a positive feedback loop of the NFkB induced cytokines CXCL-1 and -2 that enhance NFkB signaling and stimulate the expression of anti-apoptotic and prometastatic genes [26,30]. Several additional cellular signaling pathways have been described to be affected by Curcumin such as the metabolic sensor mTOR (mammalian target of rapamycin) [31], peroxisome proliferator-activated receptor gamma (PPARγ) [32], AMPK [33], SRC [34] and STAT3 [35]. The analysis of IkK deficient cells with constitutively inactive NFkB shows that at least some of these additional activities are NFkB independent [35] but the contribution of the effects on these signaling molecules to the anti-tumoral effect has not systematically been studied. The potential of Curcumin to inhibit the activation of NFkB indicates its use for the prevention of cancer subtypes that depend on the stimulatory effects of inflammatory cytokines for their growth and/or survival. Inflammatory breast cancer is a rare, aggressively growing form of breast cancer with a 5-year survival rate of less than 5% [36] and no specific risk factors are known. Hence, a role for Curcumin in primary or secondary prevention of IBC appears unlikely. NFkB is, however, also involved in non-IBC, triple negative breast cancer where its constitutive activation is linked to the proliferative potential [37]. Inhibition of NFkB by Curcumin in the triple negative breast cancer cell line MDA-MB-231 leads to reduced expression of inflammatory cytokines and pro-metastatic genes that translate into reduced formation of metastases in a murine model of hematogeneous metastasis [30,38]. Polymorphisms in the genes encoding NFkB and IkK have been found to be associated with breast cancer risk [39]. These findings make a major point for Curcumin as a targeted prevention of breast cancer. Inflammation also plays a major role in the etiology of prostate cancer [40,41] and the frequent conditions of benign prostatic hyperplasia and proliferative inflammatory atrophy enhance the prostate cancer risk. Similar to what we observed for breast cancer, the metastatization of prostate cancer is also tamed by Curcumin through its action on NFkB and the inflammatory cytokines CXCL-1 and -2 [26]. Pre-neoplastic inflammation related conditions are often diagnosed and can be approached by the addition of Curcumin to existing therapies. Moreover, early stage, highly differentiated prostate cancers are not necessarily removed by surgery and during watchful waiting, Curcumin might find an application. The recent identification of a rare polymorphism in the butyrophilin-like 2 gene (BTNL2), a putative negative regulator of T-cell proliferation [42], that is associated with prostate cancer risk for sporadic and familiar forms of the cancer [43] opens a door to the identification of high risk subjects who should adopt primary prevention protocols. Inflammation certainly contributes to colon carcinogenesis and inflammatory bowel disease is a risk factor. Orally administered Curcumin reaches the highest concentrations in the colorectum [44] and the NFkB regulated COX2 gene, a recognized prevention target, is frequently overexpressed in colon cancer [45]. Chemoprevention with Curcumin has therefore been proposed [46]. Interestingly, polymorphisms in genes of the NFkB pathway have shown to be associated with colon cancer risk [47] eventually allowing for selection of subjects at intermediate risk for primary prevention.
5. Present limitations of molecularly targeted cancer prevention Targeted cancer prevention as outlined here has a great potential. The identification of an elevated risk for a specific cancer
24
U. Pfeffer et al. / New Horizons in Translational Medicine 2 (2014) 20–26
Fig. 3. Mortality among patients with colorectal cancer, according to regular use or nonuse of Aspirin after diagnosis and PIK3CA mutation status. Panels A and B show colorectal cancer-specific mortality among patients with (a-c) mutant-PIK3CA tumors and those with (b-d) wild-type PIK3CA tumors, respectively, and Panels C and D show overall mortality in the respective subgroups of patients (reproduced from Ref. [16] with permission).
subtype with particular molecular characteristics is an important pre-requisite for the formulation of appropriate targeting strategies. The evidence cited here shows that this is in principle feasible but suffers from the general limitations of the identification of complex genotype–phenotype associations. The best example for these limitations is the genome wide association study that identified twenty loci that are associated with adult height in humans: a perfect linear correlation between the number of loci and the height was found yet these loci only explain 6 cm of height [48]. Similarly, cancer risk associations only identify a minor part of the actual risk. The missing part of the genetically determined risk is probably due to non-SNP variations such as copy number variations that can be identified by CNV microarrays or next generation sequencing or to rare or even private variations that can be identified by personal genome sequencing. The translation of these findings into targeted prevention studies relies on the understanding of the biological function of the variations identified. Although this requires considerable effort, in a near future the three pillars (Fig. 2) of targeted prevention will be known for many cancers.
6. Conclusions The advancement of our understanding of the mechanisms of carcinogenesis and the molecular characteristics and driving forces of cancer subtypes makes it possible to identify compounds that can be used to contrast tumor development in its very early phases before diagnosis. Preventive treatments need, however, the definition of the specific risk of each person. There is evidence that specific genetic variants confer an increased risk for specific tumor subtypes yet only a minor part of the genetically determined risk is presently known. Targeted prevention of cancer will become a reality through
matching well characterized compounds with specific tumor subtypes for which the person is susceptible inasmuch she carries specific risk associated genetic variants. Curcumin, an inhibitor of NFkB signaling, could be one of those compounds to be used for the prevention of inflammation associated cancers once the genetic basis of inflammation associated development of cancer is consolidated.
Acknowledgments This work was made possible by an institutional “5xmille” grant to UP. AA is recipient of a fellowship PO CRO Fondo Sociale Europeo Regione Liguria 2007–2013 Asse IV “Capitale Umano”. We thank Renata Scarzello for secretarial assistance. Executive summary
Targeted prevention of cancer consists in the match of well
characterized compounds with the molecular mechanisms involved in specific cancer (sub-)types in the presence of specific genetic risk factors. Single nucleotide polymorphisms have been shown to be associated with the risk for specific cancer subtypes, i.e. estrogen receptor α (ER) positive breast cancer. Curcumin has strong anti-inflammatory effects mediated by the inhibition of nuclear factor kappa B (NFkB). NFkB is involved in the development of several cancers including breast and prostate cancer. In the presence of a genetically determined risk for inflammation associated cancer, Curcumin could be the preventive compound of choice.
U. Pfeffer et al. / New Horizons in Translational Medicine 2 (2014) 20–26
Inflammation associated polymorphisms that increase the prostate cancer risk have recently been identified.
References [1] D. Hanahan, R.A. Weinberg, The hallmarks of cancer, Cell 100 (2000) 57–70. [2] D. Hanahan, R.A. Weinberg, Hallmarks of cancer: the next generation, Cell 144 (2011) 646–674. [3] H.K. Sanoff, A.M. Deal, J. Krishnamurthy, C. Torrice, P. Dillon, J. Sorrentino, et al., Effect of cytotoxic chemotherapy on markers of molecular age in patients with breast cancer, J. Natl. Cancer Inst. 106 (2014) dju057. [4] Cancer Genomics: Molecular Classification, Prognosis and Response Prediction, in: U. Pfeffer (Ed.), Springer Science and Business Media, Dordrecht, 2013. [5] D.C. Koboldt, R.S. Fulton, M.D. McLellan, H. Schmidt, J. Kalicki-Veizer, J. F. McMichael, L.L. Fulton, D.J. Dooling, L. Ding, E.R. Mardis, R.K. Wilson, A. Ally, M. Balasundaram, Y.S. Butterfield, R. Carlsen, C. Carter, A. Chu, E. Chuah, H.J. Chun, R.J. Coope, N. Dhalla, R. Guin, C. Hirst, M. Hirst, R. A. Holt, D. Lee, H.I. Li, M. Mayo, R.A. Moore, A.J. Mungall, E. Pleasance, A. Robertson, J.E. Schein, A. Shafiei, P. Sipahimalani, J.R. Slobodan, D. Stoll, A. Tam, N. Thiessen, R.J. Varhol, N. Wye, T. Zeng, Y. Zhao, I. Birol, S.J. Jones, M. A. Marra, A.D. Cherniack, G. Saksena, R.C. Onofrio, N.H. Pho, S.L. Carter, S. E. Schumacher, B. Tabak, B. Hernandez, J. Gentry, H. Nguyen, A. Crenshaw, K. Ardlie, R. Beroukhim, W. Winckler, G. Getz, S.B. Gabriel, M. Meyerson, L. Chin, P.J. Park, R. Kucherlapati, K.A. Hoadley, J. Auman, C. Fan, Y.J. Turman, Y. Shi, L. Li, M.D. Topal, X. He, H.H. Chao, A. Prat, G.O. Silva, M.D. Iglesia, W. Zhao, J. Usary, J.S. Berg, M. Adams, J. Booker, J. Wu, A. Gulabani, T. Bodenheimer, A.P. Hoyle, J.V. Simons, M.G. Soloway, L.E. Mose, S. R. Jefferys, S. Balu, J.S. Parker, D. Hayes, C.M. Perou, S. Malik, S. Mahurkar, H. Shen, D.J. Weisenberger, T. Triche Jr, P.H. Lai, M.S. Bootwalla, D.T. Maglinte, B.P. Berman, D.J. Van Den Berg, S.B. Baylin, P.W. Laird, C.J. Creighton, L. A. Donehower, G. Getz, M. Noble, D. Voet, G. Saksena, N. Gehlenborg, D. DiCara, J. Zhang, H. Zhang, C.J. Wu, S.Y. Liu, M.S. Lawrence, L. Zou, A. Sivachenko, P. Lin, P. Stojanov, R. Jing, J. Cho, R. Sinha, R.W. Park, M. D. Nazaire, J. Robinson, H. Thorvaldsdottir, J. Mesirov, P.J. Park, L. Chin, S. Reynolds, R.B. Kreisberg, B. Bernard, R. Bressler, T. Erkkila, J. Lin, V. Thorsson, W. Zhang, I. Shmulevich, G. Ciriello, N. Weinhold, N. Schultz, J. Gao, E. Cerami, B. Gross, A. Jacobsen, R. Sinha, B. Aksoy, Y. Antipin, B. Reva, R. Shen, B.S. Taylor, M. Ladanyi, C. Sander, P. Anur, P.T. Spellman, Y. Lu, W. Liu, R.R. Verhaak, G.B. Mills, R. Akbani, N. Zhang, B.M. Broom, T.D. Casasent, C. Wakefield, A.K. Unruh, K. Baggerly, K. Coombes, J.N. Weinstein, D. Haussler, C.C. Benz, J.M. Stuart, S.C. Benz, J. Zhu, C.C. Szeto, G.K. Scott, C. Yau, E.O. Paull, D. Carlin, C. Wong, A. Sokolov, J. Thusberg, S. Mooney, S. Ng, T.C. Goldstein, K. Ellrott, M. Grifford, C. Wilks, S. Ma, B. Craft, C. Yan, Y. Hu, D. Meerzaman, J. M. Gastier-Foster, J. Bowen, N.C. Ramirez, A.D. Black, R.E. Pyatt, P. White, E. J. Zmuda, J. Frick, T.M. Lichtenberg, R. Brookens, M.M. George, M.A. Gerken, H. A. Harper, K.M. Leraas, L.J. Wise, T.R. Tabler, C. McAllister, T. Barr, M. HartKothari, K. Tarvin, C. Saller, G. Sandusky, C. Mitchell, M.V. Iacocca, J. Brown, B. Rabeno, C. Czerwinski, N. Petrelli, O. Dolzhansky, M. Abramov, O. Voronina, O. Potapova, J.R. Marks, W.M. Suchorska, D. Murawa, W. Kycler, M. Ibbs, K. Korski, A. Spychała, P. Murawa, J.J. Brzeziński, H. Perz, R. Łaźniak, M. Teresiak, H. Tatka, E. Leporowska, M. Bogusz-Czerniewicz, J. Malicki, A. Mackiewicz, M. Wiznerowicz, X.V. Le, B. Kohl, V.T. Nguyen, R. Thorp, V. B. Nguyen, H. Sussman, D.P. Bui, R. Hajek, P.H. Nguyen, V.T. Tran, Q.T. Huynh, K. Z. Khan, R. Penny, D. Mallery, E. Curley, C. Shelton, P. Yena, J.N. Ingle, F.J. Couch, W.L. Lingle, T.A. King, A.M. Gonzalez-Angulo, G.B. Mills, M.D. Dyer, S. Liu, X. Meng, M. Patangan, F. Waldman, H. Stöppler, W. Rathmell, L. Thorne, M. Huang, L. Boice, A. Hill, C. Morrison, C. Gaudioso, W. Bshara, K. Daily, S. C. Egea, M. Pegram, C. Gomez-Fernandez, R. Dhir, R. Bhargava, A. Brufsky, C. D. Shriver, J.A. Hooke, J.L. Campbell, R.J. Mural, H. Hu, S. Somiari, C. Larson, B. Deyarmin, L. Kvecher, A.J. Kovatich, M.J. Ellis, T.A. King, H. Hu, F.J. Couch, R. J. Mural, T. Stricker, K. White, O. Olopade, J.N. Ingle, C. Luo, Y. Chen, J.R. Marks, F. Waldman, M. Wiznerowicz, R. Bose, L.W. Chang, A.H. Beck, A.M. GonzalezAngulo, T. Pihl, M. Jensen, R. Sfeir, A. Kahn, A. Chu, P. Kothiyal, Z. Wang, E. Snyder, J. Pontius, B. Ayala, M. Backus, J. Walton, J. Baboud, D. Berton, M. Nicholls, D. Srinivasan, R. Raman, S. Girshik, P. Kigonya, S. Alonso, R. Sanbhadti, S. Barletta, D. Pot, M. Sheth, J.A. Demchok, K.R. Shaw, L. Yang, G. Eley, M.L. Ferguson, R.W. Tarnuzzer, J. Zhang, L.A. Dillon, K. Buetow, P. Fielding, B.A. Ozenberger, M.S. Guyer, H.J. Sofia, J.D. Palchik, Comprehensive molecular portraits of human breast tumours, Nature 490 (2012) 61–70. [6] A. Shlien, D. Malkin, Copy number variations and cancer susceptibility, Curr. Opin. Oncol. 22 (2010) 55–63. [7] L.V. Wain, J.A. Armour, M.D. Tobin, Genomic copy number variation, human health, and disease, Lancet 374 (2009) 340–350. [8] D.F. Easton, K.A. Pooley, A.M. Dunning, P.D. Pharoah, D. Thompson, D. G. Ballinger, et al., Genome-wide association study identifies novel breast cancer susceptibility loci, Nature 447 (2007) 1087–1093. [9] D.J. Hunter, P. Kraft, K.B. Jacobs, D.G. Cox, M. Yeager, S.E. Hankinson, et al., A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer, Nat. Genet. 39 (2007) 870–874. [10] B. Gold, T. Kirchhoff, S. Stefanov, J. Lautenberger, A. Viale, J. Garber, et al., Genome-wide association study provides evidence for a breast cancer risk locus at 6q22.33, Proc. Natl. Acad. Sci. USA 105 (2008) 4340–4345.
25
[11] S.N. Stacey, A. Manolescu, P. Sulem, S. Thorlacius, S.A. Gudjonsson, G.F. Jonsson, et al., Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer, Nat. Genet. 40 (2008) 703–706. [12] K. Visvanathan, P. Hurley, E. Bantug, P. Brown, N.F. Col, J. Cuzick, et al., Use of pharmacologic interventions for breast cancer risk reduction: American Society of Clinical Oncology clinical practice guideline, J. Clin. Oncol. 31 (2013) 2942–2962. [13] E.A. Waters, K.A. Cronin, B.I. Graubard, P.K. Han, A.N. Freedman, Prevalence of tamoxifen use for breast cancer chemoprevention among U.S. women, Cancer Epidemiol. Biomark. Prev. 19 (2010) 443–446. [14] N. Gronich, G. Rennert, Beyond aspirin-cancer prevention with statins, metformin and bisphosphonates, Nat. Rev. Clin. Oncol. 10 (2013) 625–642. [15] B.E. Bachmeier, V. Mirisola, F. Romeo, L. Generoso, A. Esposito, R. Dell’eva, et al., Reference profile correlation reveals estrogen-like trancriptional activity of Curcumin, Cell. Physiol. Biochem.: Int. J. Exp. Cell. Physiol. Biochem. Pharmacol. 26 (2010) 471–482. [16] X. Liao, P. Lochhead, R. Nishihara, T. Morikawa, A. Kuchiba, M. Yamauchi, et al., Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival, N. Engl. J. Med. 367 (2012) 1596–1606. [17] A. Albini, S. Indraccolo, D.M. Noonan, U. Pfeffer, Functional genomics of endothelial cells treated with anti-angiogenic or angiopreventive drugs, Clin. Exp. Metastasis 27 (2010) 419–439. [18] A. Albini, F. Tosetti, V.W. Li, D.M. Noonan, W.W. Li, Cancer prevention by targeting angiogenesis, Nat. Rev. Clin. Oncol. 9 (2012) 498–509. [19] W. Yue, C.S. Yang, R.S. DiPaola, X.L. Tan, Repurposing of metformin and aspirin by targeting AMPK-mTOR and inflammation for pancreatic cancer prevention and treatment, Cancer Prev. Res. (Phila) 7 (2014) 388–397. [20] C. Marini, B. Salani, M. Massollo, A. Amaro, A.I. Esposito, A.M. Orengo, et al., Direct inhibition of hexokinase activity by metformin at least partially impairs glucose metabolism and tumor growth in experimental breast cancer, Cell Cycle 12 (2013) 3490–3499. [21] R.D. Semba, L. Ferrucci, B. Bartali, et al., REsveratrol levels and all-cause mortality in older community-dwelling adults, JAMA Intern. Med. (2014). [22] A.B. Kunnumakkara, P. Anand, B.B. Aggarwal, Curcumin inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling proteins, Cancer Lett. 269 (2008) 199–225. [23] H. Hatcher, R. Planalp, J. Cho, F.M. Torti, S.V. Torti, Curcumin: from ancient medicine to current clinical trials, Cell. Mol. Life Sci. 65 (2008) 1631–1652. [24] B.E. Bachmeier, P. Killian, U. Pfeffer, A.G. Nerlich, Novel aspects for the application of Curcumin in chemoprevention of various cancers, Front. Biosci. 2 (2010) 697–717. [25] A.C. Bharti, N. Donato, S. Singh, B.B. Aggarwal, Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor-kappa B and IkappaBalpha kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis, Blood 101 (2003) 1053–1062. [26] P.H. Killian, E. Kronski, K.M. Michalik, O. Barbieri, S. Astigiano, C. P. Sommerhoff, et al., Curcumin inhibits prostate cancer metastasis in vivo by targeting the inflammatory cytokines CXCL1 and -2, Carcinogenesis 33 (2012) 2507–2519. [27] E. Kronski, M.E. Fiori, O. Barbieri, S. Astigiano, V. Mirisola, P.H. Killian, et al., miR181b is induced by the chemopreventive polyphenol curcumin and inhibits breast cancer metastasis via down-regulation of the inflammatory cytokines CXCL1 and -2, Mol. Oncol. 8 (2014) 581–595. [28] N.D. Perkins, Integrating cell-signalling pathways with NF-kappaB and IKK function, Nat. Rev. Mol. Cell. Biol. 8 (2007) 49–62. [29] M. Karin, Nuclear factor-kappaB in cancer development and progression, Nature 441 (2006) 431–436. [30] B.E. Bachmeier, I.V. Mohrenz, V. Mirisola, E. Schleicher, F. Romeo, C. Hohneke, et al., Curcumin downregulates the inflammatory cytokines CXCL1 and -2 in breast cancer cells via NFkappaB, Carcinogenesis 29 (2008) 779–789. [31] C.S. Beevers, L. Chen, L. Liu, Y. Luo, N.J. Webster, S. Huang, Curcumin disrupts the Mammalian target of rapamycin-raptor complex, Cancer Res. 69 (2009) 1000–1008. [32] Y. Zhou, S. Zheng, J. Lin, Q.J. Zhang, A. Chen, The interruption of the PDGF and EGF signaling pathways by curcumin stimulates gene expression of PPARgamma in rat activated hepatic stellate cell in vitro, Lab. Invest. 87 (2007) 488–498. [33] W. Pan, H. Yang, C. Cao, X. Song, B. Wallin, R. Kivlin, et al., AMPK mediates curcumin-induced cell death in CaOV3 ovarian cancer cells, Oncol. Rep. 20 (2008) 1553–1559. [34] T.H. Leu, S.L. Su, Y.C. Chuang, M.C. Maa, Direct inhibitory effect of curcumin on Src and focal adhesion kinase activity, Biochem. Pharmacol. 66 (2003) 2323–2331. [35] S. Prakobwong, S.C. Gupta, J.H. Kim, B. Sung, P. Pinlaor, Y. Hiraku, et al., Curcumin suppresses proliferation and induces apoptosis in human biliary cancer cells through modulation of multiple cell signaling pathways, Carcinogenesis 32 (2011) 1372–1380. [36] F.M. Robertson, M. Bondy, W. Yang, H. Yamauchi, S. Wiggins, S. Kamrudin, et al., Inflammatory breast cancer: the disease, the biology, the treatment, CA Cancer J. Clin. 60 (2010) 351–375. [37] N. Yamaguchi, T. Ito, S. Azuma, E. Ito, R. Honma, Y. Yanagisawa, et al., Constitutive activation of nuclear factor-kappaB is preferentially involved in the proliferation of basal-like subtype breast cancer cell lines, Cancer Sci. 100 (2009) 1668–1674. [38] B. Bachmeier, A.G. Nerlich, C.M. Iancu, M. Cilli, E. Schleicher, R. Vene, et al., The chemopreventive polyphenol Curcumin prevents hematogenous breast cancer
26
[39]
[40]
[41] [42] [43]
U. Pfeffer et al. / New Horizons in Translational Medicine 2 (2014) 20–26
metastases in immunodeficient mice, Cell Physiol. Biochem. 19 (2007) 137–152. M.L. Slattery, E.M. John, G. Torres-Mejia, A. Lundgreen, J.S. Herrick, K. B. Baumgartner, et al., Genetic variation in genes involved in hormones, inflammation and energetic factors and breast cancer risk in an admixed population, Carcinogenesis 33 (2012) 1512–1521. W.G. Nelson, T.L. DeWeese, A.M. DeMarzo, The diet, prostate inflammation, and the development of prostate cancer, Cancer Metastasis Rev. 21 (2002) 3–16. K.S. Sfanos, A.M. De Marzo, Prostate cancer and inflammation: the evidence, Histopathology 60 (2012) 199–215. T. Nguyen, X.K. Liu, Y. Zhang, C. Dong, BTNL2, a butyrophilin-like molecule that functions to inhibit T cell activation, J. Immunol. 176 (2006) 7354–7360. L.M. Fitzgerald, A. Kumar, E.A. Boyle, Y. Zhang, L.M. McIntosh, S. Kolb, et al., Germline missense variants in the BTNL2 gene are associated with prostate cancer susceptibility, Cancer Epidemiol. Biomarkers Prev. 22 (2013) 1520–1528.
[44] G. Garcea, D.P. Berry, D.J. Jones, R. Singh, A.R. Dennison, P.B. Farmer, et al., Consumption of the putative chemopreventive agent curcumin by cancer patients: assessment of curcumin levels in the colorectum and their pharmacodynamic consequences, Cancer Epidemiol. Biomarkers Prev. 14 (2005) 120–125. [45] D. Wang, R.N. Dubois, The role of COX-2 in intestinal inflammation and colorectal cancer, Oncogene 29 (2010) 781–788. [46] J.J. Johnson, H. Mukhtar, Curcumin for chemoprevention of colon cancer, Cancer Lett. 255 (2007) 170–181. [47] K. Curtin, R.K. Wolff, J.S. Herrick, R. Abo, M.L. Slattery, Exploring multilocus associations of inflammation genes and colorectal cancer risk using hapConstructor, BMC Med. Genet. 11 (2010) 170. [48] M.N. Weedon, H. Lango, C.M. Lindgren, C. Wallace, D.M. Evans, M. Mangino, et al., Genome-wide association analysis identifies 20 loci that influence adult height, Nat. Genet. 40 (2008) 575–583.
Contents lists available at ScienceDirect
New Horizons in Translational Medicine journal homepage: www.elsevier.com/locate/nhtm
Research Articles
Curcumin: Towards molecularly targeted chemoprevention of cancer Ulrich Pfeffer a,n, Adriana Amaro a, Beatrice Bachmeier b, Giovanna Angelini a a b
Functional Genomics, IRCCS AOU San Martino – IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich, Munich, Germany
ar t ic l e i nf o
a b s t r a c t
Available online 27 August 2014
Everybody is at risk for cancer yet environmental factors, life style and diet as well as genetic factors influence the individual cancer risk. Targeted or personalized cancer prevention is based on the knowledge of the molecular characteristics of the tumor to be prevented, the molecular mechanisms of action of the compounds to be used and the genetic make-up of the person who opts for prevention medicine. Genetic factors are to a certain extent specific for cancer types or even subtypes as it has been shown for breast cancer. The growing knowledge of such genotype cancer risk associations will allow for the definition of personalized prevention strategies. Prevention in intermediate risk populations requires non-toxic, well tolerated and cheap compounds, such as Curcumin. Its main activity is the inhibition of nuclear factor kappa B (NFkB) activation. NFkB is involved in many cancers where it acts through the generation of chronic inflammation that can be contrasted with anti-inflammatory drugs such as Curcumin. Targeted prevention of cancer also increases the possibility to conduct serious clinical experimentation with target based patient selection.
Keywords: Inflammation Polyphenols Cancer risk SNP COX2
Focal points:
Bedside
Prevention might retard cancer development for years if specifically targeted. Growing knowledge of genetic determinants of cancer risk allows for the selection of individuals for targeted prevention. Benchside Genetic variants associated with the risk for specific cancer (sub-)types have been identified and additional research is needed in this promising field. The molecular mechanisms of cancer development and their relation with risk variants must be investigated and compounds that can interfere with these mechanisms must be identified. Industry A major effort in cancer prevention is needed and justified by a large potential market. The major challenge is the design of non-toxic compounds suitable for preventive treatments of healthy people who are at risk of developing cancer Community Active cancer prevention as opposed to early detection of cancer must become a focus of communication. Governments More effort in preventive cancer medicine is needed and justified by accumulating evidence for targeted prevention. Cancer prevention can add years of healthy life and can reduce cancer therapy associated costs. & 2014 European Society for Translational Medicine. Published by Elsevier Ltd. All rights reserved.
n
Correspondence to: Functional Genomics, IRCCS AOU San Martino – IST, Largo Rosanna Benzi 10, 16132 Genova, Italy. Tel.: þ 39 3283853547. E-mail address: [email protected] (U. Pfeffer).
http://dx.doi.org/10.1016/j.nhtm.2014.08.005 2307-5023/& 2014 European Society for Translational Medicine. Published by Elsevier Ltd. All rights reserved.
U. Pfeffer et al. / New Horizons in Translational Medicine 2 (2014) 20–26
1. Introduction Cancer is a disease of probability. Just like all biological processes, DNA replication is prone to errors, in this case, mutations. Mutations are not always repaired and repair sometimes introduces the wrong nucleotide. Most cells with DNA damage or mutations probably undergo apoptosis but with a certain probability, mutations are fixed and can determine increased proliferation and avoidance of apoptosis. Additional mutations eventually help the transformed cells to pass the hurdles of multistep carcinogenesis, many of which also need a contribution from the microenvironment [1,2]. All these steps, fortunately, occur with a low probability. Yet given the huge number of cells in the human organism and the length of a life cancer development becomes probable. Without afflicting the underlying probabilistic nature, life style (smoke, diet, physical activity, reproduction history), environmental (exposure to carcinogens) and genetic factors modify the cancer risk. Cancer risk increases with increasing age. If people do not die from other diseases before, their likelihood to develop and eventually die from cancer grows. Improving prevention of other (i.e. cardiovascular) diseases increases the lifetime cancer risk. Therefore, one in two or three persons in affluent countries will receive a cancer diagnosis at some point of her life. In other words: everybody is at risk. Everybody is eligible for cancer prevention measures.
2. Cancer prevention Cancer prevention as it is conceived here is not early detection. Mass screening as for example by mammography for breast cancer
21
or serum PSA levels for prostate cancer leads to early detection and, to a certain (highly discussed) extent, prevention of the development of aggressive and eventually life threatening disease. Cancer prevention as opposed to early detection aims at avoiding or retarding the development of cancer. The simplest measure of cancer prevention is the avoidance of carcinogens such as cigarette smoke, asbestos and chemical pollution in air, water, earth and food. This is mainly a public health issue and, except for smoking, cannot be modified by the intervention on the single person. The second simplest measure is to adopt a healthy life style in terms of diet, physical activity and appropriate timing of reproduction. This is what the physician will counsel her patients in the absence of specific genetic risk factors since in the low risk group no specific intervention and no side effects are tolerable. Often it is not possible to totally avoid carcinogen exposure; life style intervention does not work in each case and even in the absence of specific carcinogens and an unhealthy life style there is a cancer risk due to genetic factors. In these situations cancer prevention becomes important. An intermediate risk can be approached through targeted non-toxic prevention; interventions with side effects are limited to specific high risk situations (Fig. 1). A realistic aim of cancer prevention in intermediate- and highrisk populations could be the retardation of the onset of cancer development by several years while the complete avoidance appears to be out of sight. Yet a retardation of several years in the development of a cancer is likely to correspond to a similar extension of life and, most importantly, of healthy life. This must be compared to what is obtained by state-of-the-art pharmacological cancer therapies whose effects are often counted in months and rarely in years of survival, especially once the cancer is
Fig. 1. Targets of cancer prevention: population, cancer risk and side effects. The dimension of the population eligible for cancer prevention inversely correlates with the risk and tolerable side effects: For the general population facing a low risk of cancer, life style interventions are appropriate, the smaller but still numerous medium risk population could use non-toxic compounds such as Curcumin or other polyphenols as a prevention measure. Chemoprevention drugs with some toxicity can be proposed to the small high risk population with strong risk factors. The low risk population has no specific genetic risk factors and no accumulation of cancers in the family, intermediate risk is determined by cancer risk associated SNP and a weak familiarity, persons with cancer gene mutations and/or a clear accumulation of cancer cases in first line parents constituting a high risk population. Aspirin is only indicated for the high risk population since in the elderly, it has a relevant risk of inducing bleeding.
22
U. Pfeffer et al. / New Horizons in Translational Medicine 2 (2014) 20–26
metastatic. Moreover, even efficacious conventional therapy might come at the price of earlier senescence thus reducing the total life span [3] whereas prevention is likely to extend it. Prevention has therefore a potential to deliver a major advancement in the fight against cancer. This potential has so far been left mostly unexplored because the need to treat healthy people, not cancer patients, requires treatments that correspond to the following criteria: (i) absence of toxicity, (ii) low cost, (iii) suitability for long term treatments, and (iv) high compliance. These criteria are not matched by conventional drugs. On the other hand, evidence of cancer preventive effects of unconventional compounds derived from traditional or alternative medicine is often anecdotal and does not meet scientific criteria such as rigorous testing in controlled clinical trials. Evidence derived from preclinical studies has accumulated for at least some compounds yet in the absence of markers useful for the selection of risk populations and lack of surrogate efficacy markers make the translation into the clinical practice almost impossible. Moreover, the lack of economic interest due to the inability to obtain patents for these compounds prohibits the conduction of large, long term cohort studies needed to establish the efficacy. This applies particularly to primary prevention where the age corrected incidence of cancer is to be lowered. However, cancer prevention can also be applied after diagnosis and treatment of cancer where the progression of the diseases in terms of occurrence of secondary primaries and local and distant metastasis is to be prevented (adjuvant therapy). In some instances where the clinician opts for watchful waiting, cancer prevention could be applied to suppress progression of an existing cancer. Many drugs are available for adjuvant therapy and growth control of unresected primaries. Unconventional compounds may find an application for diseases without adequate adjuvant therapy as well as in certain low risk situations where the patient might opt against drugs with side effects.
3. The concept of targeted cancer prevention Targeted or personalized cancer prevention is based on the knowledge of the molecular characteristics of the tumor to be
prevented, the molecular mechanisms of action of the compounds to be used and the genetic make-up of the person who opts for prevention medicine (Fig. 2). Recent advances in the molecular characterization of human tumors have revealed a wealth of knowledge on specific molecular characteristics [4]. Breast cancer, for instance, can now be classified in probably four large molecular classes, the estrogen receptor ERα positive subtypes luminal A and B that greatly differ with respect to their proliferative potential and the associated risk of distant relapse, the HER2 subtype carrying an amplification of the epidermal growth factor 2 (ERRB2) encoding gene on chromosome 17q12, and the triple negative subtype characterized by the lack of expression of ERα, the progesterone receptor and ERRB2 [5]. Each of these subtypes can be considered a specific disease with particular molecular characteristics. On the other hand, genome wide association studies deliver an ever growing number of genetic variations that are associated with the cancer risk. So far, most studies have considered only single nucleotide polymorphisms (SNPs) but more recently, the presence of deletions, insertions, amplifications, and inversions involving hundreds of basepairs has shown to be frequent in the general population and most likely contribute to the cancer risk [6,7]. The growing knowledge of functional aspects of the genome even outside protein encoding regions will lead to a further identification of molecular factors that may be associated with the cancer risk of each individual. Yet most importantly, genetic factors do not necessarily increase the general cancer risk but can contribute to the risk for a specific cancer type or even a specific subtype as it has been shown for breast cancer [8–11]. Hence it is possible, to a certain extent, to weight the additional risk for a specific subtype of cancer conferred by the person's genotype. If this subtype deploys molecular targets for prevention the triangle of targeted prevention (Fig. 2) can be completed. Again, breast cancer sets the stage since hardly any other cancer is better characterized than ERα positive breast cancers. ERα has been explored as a target not only for the prevention of distant metastases in the adjuvant setting but also for primary prevention [12]. However, this is limited by considerable side effects of the anti-estrogens or aromatase inhibitors used. The actual use of tamoxifen for cancer
Fig. 2. The concept of targeted prevention. Targeting of cancer prevention requires the personal risk assessment based on the knowledge of the genetic background of each individual. If a risk for a specific cancer type or subtype is present the knowledge of the molecular characteristics of this cancer (sub-)type allows for the selection of specific molecular targets. These targets must be matched by compounds with known molecular mechanisms of action that affect these targets.
U. Pfeffer et al. / New Horizons in Translational Medicine 2 (2014) 20–26
prevention remains therefore low [13]. Other chemoprevention drugs, such as the anti-osteoporosis drug bisphosphonate and cholesterol lowering statins also have a profile of side effects, so that their use must be limited to the original indications or cancer prevention in high risk populations [14]. In a near future, patient selection based on genetic risk factors for ERα positive breast cancer will become feasible and other weak dietary estrogens that compete with endogenous estrogens for binding to the receptor might be used. We have recently shown that Curcumin also shows weak estrogenic activity on gene transcription [15]. A paramount example of targeted prevention of cancer progression is acetyl-salicylic acid, Aspirin, a non-steroidal anti-inflammatory drug in use since more than hundred years. Recent evidence derived from clinical studies in colon cancer shows that Aspirin can drastically reduce the progression rate of colon cancers that carry a mutation in the PIK3CA gene encoding the catalytic subunit of the phosphatidylinositol-4,5-bisphosphate 3-kinase. The mutation leads to enhanced activation of the prostaglandin-endoperoxide synthase 2 also known as cyclooxygenase 2 (PTGS, COX2), one of the targets of Aspirin. This effect leads to a highly significant difference in disease free and overall survival (Fig. 3) [16]. If the PIK3CA mutation is associated with a specific subtype of colon cancer and a related risk profile, Aspirin could become interesting also for primary prevention. Another example of targeted prevention is “angioprevention”, cancer prevention obtained through the suppression of angiogenesis in a prevention setting [17,18]. The biguanide drug, metformin, that activates the main metabolic switch AMP-kinase (AMPK) [14,19] and probably other key metabolism regulators such as hexokinase [20], in use as a first line treatment of type 2 diabetes, has also been proposed for cancer prevention, eventually in combination with Aspirin [19]. Targeting for prevention is also needed because, against widely held beliefs, up-take of preventive compounds with the diet has most likely no or weak effects on cancer development and survival as recently shown for resveratrol, a compound contained in red wine [21]. Efficacious prevention strategies require the intake of non-toxic compounds at pharmacological doses and their prescription should therefore be based on a measurable risk.
4. Curcumin for targeted prevention How does this apply to Curcumin? Curcumin is a polyphenol extracted from turmeric (Curcuma longa) and is used as a spice (the yellow component of curry) and for the treatment of inflammation related diseases in traditional Indian and Chinese medicine. There is ample evidence for the anti-tumoral activities of Curcumin derived from in vitro and in vivo studies summarized in recent reviews [22–24]. Curcumin inactivates NFkB through the stabilization of IkB that blocks the translocation of the transcription factor complex into the nucleus and thus abolishes its effects on the transcription of anti-apoptotic, pro-inflammatory and pro-metastatic genes. Curcumin stabilizes IkB through the inhibition of the kinase IkK [25]. In the absence of Curcumin, the active IkK phosphorylates IkB directing the latter towards degradation in the proteasome. Curcumin acts like synthetic inhibitors such as SC-514 by blocking phosphorylation of IkB and activation of NFkB. SC-514 and Curcumin do not show additive or synergistic effects when used in combination [26]. Curcumin also acts through the induction of miR181b that also affects NFkB signaling [27]. IkKα and IkKβ form the catalytic subunits of the IkK complex that contains IkKγ (nemo) as a regulatory subunit. The complex controls NFkB activity through the phosphorylation of IkBα. Phosphorylated IkBα is ubiquitinylated and rapidly degraded by the proteasome. Free of IkBα, the NFkB subunit p65 can translocate into the nucleus
23
and activate the transcriptional inflammation and anti-apoptosis program (for a review see [28]). NFkB is a major regulator of inflammation and controls the transcription of inflammatory cytokines [29]. Curcumin interrupts a positive feedback loop of the NFkB induced cytokines CXCL-1 and -2 that enhance NFkB signaling and stimulate the expression of anti-apoptotic and prometastatic genes [26,30]. Several additional cellular signaling pathways have been described to be affected by Curcumin such as the metabolic sensor mTOR (mammalian target of rapamycin) [31], peroxisome proliferator-activated receptor gamma (PPARγ) [32], AMPK [33], SRC [34] and STAT3 [35]. The analysis of IkK deficient cells with constitutively inactive NFkB shows that at least some of these additional activities are NFkB independent [35] but the contribution of the effects on these signaling molecules to the anti-tumoral effect has not systematically been studied. The potential of Curcumin to inhibit the activation of NFkB indicates its use for the prevention of cancer subtypes that depend on the stimulatory effects of inflammatory cytokines for their growth and/or survival. Inflammatory breast cancer is a rare, aggressively growing form of breast cancer with a 5-year survival rate of less than 5% [36] and no specific risk factors are known. Hence, a role for Curcumin in primary or secondary prevention of IBC appears unlikely. NFkB is, however, also involved in non-IBC, triple negative breast cancer where its constitutive activation is linked to the proliferative potential [37]. Inhibition of NFkB by Curcumin in the triple negative breast cancer cell line MDA-MB-231 leads to reduced expression of inflammatory cytokines and pro-metastatic genes that translate into reduced formation of metastases in a murine model of hematogeneous metastasis [30,38]. Polymorphisms in the genes encoding NFkB and IkK have been found to be associated with breast cancer risk [39]. These findings make a major point for Curcumin as a targeted prevention of breast cancer. Inflammation also plays a major role in the etiology of prostate cancer [40,41] and the frequent conditions of benign prostatic hyperplasia and proliferative inflammatory atrophy enhance the prostate cancer risk. Similar to what we observed for breast cancer, the metastatization of prostate cancer is also tamed by Curcumin through its action on NFkB and the inflammatory cytokines CXCL-1 and -2 [26]. Pre-neoplastic inflammation related conditions are often diagnosed and can be approached by the addition of Curcumin to existing therapies. Moreover, early stage, highly differentiated prostate cancers are not necessarily removed by surgery and during watchful waiting, Curcumin might find an application. The recent identification of a rare polymorphism in the butyrophilin-like 2 gene (BTNL2), a putative negative regulator of T-cell proliferation [42], that is associated with prostate cancer risk for sporadic and familiar forms of the cancer [43] opens a door to the identification of high risk subjects who should adopt primary prevention protocols. Inflammation certainly contributes to colon carcinogenesis and inflammatory bowel disease is a risk factor. Orally administered Curcumin reaches the highest concentrations in the colorectum [44] and the NFkB regulated COX2 gene, a recognized prevention target, is frequently overexpressed in colon cancer [45]. Chemoprevention with Curcumin has therefore been proposed [46]. Interestingly, polymorphisms in genes of the NFkB pathway have shown to be associated with colon cancer risk [47] eventually allowing for selection of subjects at intermediate risk for primary prevention.
5. Present limitations of molecularly targeted cancer prevention Targeted cancer prevention as outlined here has a great potential. The identification of an elevated risk for a specific cancer
24
U. Pfeffer et al. / New Horizons in Translational Medicine 2 (2014) 20–26
Fig. 3. Mortality among patients with colorectal cancer, according to regular use or nonuse of Aspirin after diagnosis and PIK3CA mutation status. Panels A and B show colorectal cancer-specific mortality among patients with (a-c) mutant-PIK3CA tumors and those with (b-d) wild-type PIK3CA tumors, respectively, and Panels C and D show overall mortality in the respective subgroups of patients (reproduced from Ref. [16] with permission).
subtype with particular molecular characteristics is an important pre-requisite for the formulation of appropriate targeting strategies. The evidence cited here shows that this is in principle feasible but suffers from the general limitations of the identification of complex genotype–phenotype associations. The best example for these limitations is the genome wide association study that identified twenty loci that are associated with adult height in humans: a perfect linear correlation between the number of loci and the height was found yet these loci only explain 6 cm of height [48]. Similarly, cancer risk associations only identify a minor part of the actual risk. The missing part of the genetically determined risk is probably due to non-SNP variations such as copy number variations that can be identified by CNV microarrays or next generation sequencing or to rare or even private variations that can be identified by personal genome sequencing. The translation of these findings into targeted prevention studies relies on the understanding of the biological function of the variations identified. Although this requires considerable effort, in a near future the three pillars (Fig. 2) of targeted prevention will be known for many cancers.
6. Conclusions The advancement of our understanding of the mechanisms of carcinogenesis and the molecular characteristics and driving forces of cancer subtypes makes it possible to identify compounds that can be used to contrast tumor development in its very early phases before diagnosis. Preventive treatments need, however, the definition of the specific risk of each person. There is evidence that specific genetic variants confer an increased risk for specific tumor subtypes yet only a minor part of the genetically determined risk is presently known. Targeted prevention of cancer will become a reality through
matching well characterized compounds with specific tumor subtypes for which the person is susceptible inasmuch she carries specific risk associated genetic variants. Curcumin, an inhibitor of NFkB signaling, could be one of those compounds to be used for the prevention of inflammation associated cancers once the genetic basis of inflammation associated development of cancer is consolidated.
Acknowledgments This work was made possible by an institutional “5xmille” grant to UP. AA is recipient of a fellowship PO CRO Fondo Sociale Europeo Regione Liguria 2007–2013 Asse IV “Capitale Umano”. We thank Renata Scarzello for secretarial assistance. Executive summary
Targeted prevention of cancer consists in the match of well
characterized compounds with the molecular mechanisms involved in specific cancer (sub-)types in the presence of specific genetic risk factors. Single nucleotide polymorphisms have been shown to be associated with the risk for specific cancer subtypes, i.e. estrogen receptor α (ER) positive breast cancer. Curcumin has strong anti-inflammatory effects mediated by the inhibition of nuclear factor kappa B (NFkB). NFkB is involved in the development of several cancers including breast and prostate cancer. In the presence of a genetically determined risk for inflammation associated cancer, Curcumin could be the preventive compound of choice.
U. Pfeffer et al. / New Horizons in Translational Medicine 2 (2014) 20–26
Inflammation associated polymorphisms that increase the prostate cancer risk have recently been identified.
References [1] D. Hanahan, R.A. Weinberg, The hallmarks of cancer, Cell 100 (2000) 57–70. [2] D. Hanahan, R.A. Weinberg, Hallmarks of cancer: the next generation, Cell 144 (2011) 646–674. [3] H.K. Sanoff, A.M. Deal, J. Krishnamurthy, C. Torrice, P. Dillon, J. Sorrentino, et al., Effect of cytotoxic chemotherapy on markers of molecular age in patients with breast cancer, J. Natl. Cancer Inst. 106 (2014) dju057. [4] Cancer Genomics: Molecular Classification, Prognosis and Response Prediction, in: U. Pfeffer (Ed.), Springer Science and Business Media, Dordrecht, 2013. [5] D.C. Koboldt, R.S. Fulton, M.D. McLellan, H. Schmidt, J. Kalicki-Veizer, J. F. McMichael, L.L. Fulton, D.J. Dooling, L. Ding, E.R. Mardis, R.K. Wilson, A. Ally, M. Balasundaram, Y.S. Butterfield, R. Carlsen, C. Carter, A. Chu, E. Chuah, H.J. Chun, R.J. Coope, N. Dhalla, R. Guin, C. Hirst, M. Hirst, R. A. Holt, D. Lee, H.I. Li, M. Mayo, R.A. Moore, A.J. Mungall, E. Pleasance, A. Robertson, J.E. Schein, A. Shafiei, P. Sipahimalani, J.R. Slobodan, D. Stoll, A. Tam, N. Thiessen, R.J. Varhol, N. Wye, T. Zeng, Y. Zhao, I. Birol, S.J. Jones, M. A. Marra, A.D. Cherniack, G. Saksena, R.C. Onofrio, N.H. Pho, S.L. Carter, S. E. Schumacher, B. Tabak, B. Hernandez, J. Gentry, H. Nguyen, A. Crenshaw, K. Ardlie, R. Beroukhim, W. Winckler, G. Getz, S.B. Gabriel, M. Meyerson, L. Chin, P.J. Park, R. Kucherlapati, K.A. Hoadley, J. Auman, C. Fan, Y.J. Turman, Y. Shi, L. Li, M.D. Topal, X. He, H.H. Chao, A. Prat, G.O. Silva, M.D. Iglesia, W. Zhao, J. Usary, J.S. Berg, M. Adams, J. Booker, J. Wu, A. Gulabani, T. Bodenheimer, A.P. Hoyle, J.V. Simons, M.G. Soloway, L.E. Mose, S. R. Jefferys, S. Balu, J.S. Parker, D. Hayes, C.M. Perou, S. Malik, S. Mahurkar, H. Shen, D.J. Weisenberger, T. Triche Jr, P.H. Lai, M.S. Bootwalla, D.T. Maglinte, B.P. Berman, D.J. Van Den Berg, S.B. Baylin, P.W. Laird, C.J. Creighton, L. A. Donehower, G. Getz, M. Noble, D. Voet, G. Saksena, N. Gehlenborg, D. DiCara, J. Zhang, H. Zhang, C.J. Wu, S.Y. Liu, M.S. Lawrence, L. Zou, A. Sivachenko, P. Lin, P. Stojanov, R. Jing, J. Cho, R. Sinha, R.W. Park, M. D. Nazaire, J. Robinson, H. Thorvaldsdottir, J. Mesirov, P.J. Park, L. Chin, S. Reynolds, R.B. Kreisberg, B. Bernard, R. Bressler, T. Erkkila, J. Lin, V. Thorsson, W. Zhang, I. Shmulevich, G. Ciriello, N. Weinhold, N. Schultz, J. Gao, E. Cerami, B. Gross, A. Jacobsen, R. Sinha, B. Aksoy, Y. Antipin, B. Reva, R. Shen, B.S. Taylor, M. Ladanyi, C. Sander, P. Anur, P.T. Spellman, Y. Lu, W. Liu, R.R. Verhaak, G.B. Mills, R. Akbani, N. Zhang, B.M. Broom, T.D. Casasent, C. Wakefield, A.K. Unruh, K. Baggerly, K. Coombes, J.N. Weinstein, D. Haussler, C.C. Benz, J.M. Stuart, S.C. Benz, J. Zhu, C.C. Szeto, G.K. Scott, C. Yau, E.O. Paull, D. Carlin, C. Wong, A. Sokolov, J. Thusberg, S. Mooney, S. Ng, T.C. Goldstein, K. Ellrott, M. Grifford, C. Wilks, S. Ma, B. Craft, C. Yan, Y. Hu, D. Meerzaman, J. M. Gastier-Foster, J. Bowen, N.C. Ramirez, A.D. Black, R.E. Pyatt, P. White, E. J. Zmuda, J. Frick, T.M. Lichtenberg, R. Brookens, M.M. George, M.A. Gerken, H. A. Harper, K.M. Leraas, L.J. Wise, T.R. Tabler, C. McAllister, T. Barr, M. HartKothari, K. Tarvin, C. Saller, G. Sandusky, C. Mitchell, M.V. Iacocca, J. Brown, B. Rabeno, C. Czerwinski, N. Petrelli, O. Dolzhansky, M. Abramov, O. Voronina, O. Potapova, J.R. Marks, W.M. Suchorska, D. Murawa, W. Kycler, M. Ibbs, K. Korski, A. Spychała, P. Murawa, J.J. Brzeziński, H. Perz, R. Łaźniak, M. Teresiak, H. Tatka, E. Leporowska, M. Bogusz-Czerniewicz, J. Malicki, A. Mackiewicz, M. Wiznerowicz, X.V. Le, B. Kohl, V.T. Nguyen, R. Thorp, V. B. Nguyen, H. Sussman, D.P. Bui, R. Hajek, P.H. Nguyen, V.T. Tran, Q.T. Huynh, K. Z. Khan, R. Penny, D. Mallery, E. Curley, C. Shelton, P. Yena, J.N. Ingle, F.J. Couch, W.L. Lingle, T.A. King, A.M. Gonzalez-Angulo, G.B. Mills, M.D. Dyer, S. Liu, X. Meng, M. Patangan, F. Waldman, H. Stöppler, W. Rathmell, L. Thorne, M. Huang, L. Boice, A. Hill, C. Morrison, C. Gaudioso, W. Bshara, K. Daily, S. C. Egea, M. Pegram, C. Gomez-Fernandez, R. Dhir, R. Bhargava, A. Brufsky, C. D. Shriver, J.A. Hooke, J.L. Campbell, R.J. Mural, H. Hu, S. Somiari, C. Larson, B. Deyarmin, L. Kvecher, A.J. Kovatich, M.J. Ellis, T.A. King, H. Hu, F.J. Couch, R. J. Mural, T. Stricker, K. White, O. Olopade, J.N. Ingle, C. Luo, Y. Chen, J.R. Marks, F. Waldman, M. Wiznerowicz, R. Bose, L.W. Chang, A.H. Beck, A.M. GonzalezAngulo, T. Pihl, M. Jensen, R. Sfeir, A. Kahn, A. Chu, P. Kothiyal, Z. Wang, E. Snyder, J. Pontius, B. Ayala, M. Backus, J. Walton, J. Baboud, D. Berton, M. Nicholls, D. Srinivasan, R. Raman, S. Girshik, P. Kigonya, S. Alonso, R. Sanbhadti, S. Barletta, D. Pot, M. Sheth, J.A. Demchok, K.R. Shaw, L. Yang, G. Eley, M.L. Ferguson, R.W. Tarnuzzer, J. Zhang, L.A. Dillon, K. Buetow, P. Fielding, B.A. Ozenberger, M.S. Guyer, H.J. Sofia, J.D. Palchik, Comprehensive molecular portraits of human breast tumours, Nature 490 (2012) 61–70. [6] A. Shlien, D. Malkin, Copy number variations and cancer susceptibility, Curr. Opin. Oncol. 22 (2010) 55–63. [7] L.V. Wain, J.A. Armour, M.D. Tobin, Genomic copy number variation, human health, and disease, Lancet 374 (2009) 340–350. [8] D.F. Easton, K.A. Pooley, A.M. Dunning, P.D. Pharoah, D. Thompson, D. G. Ballinger, et al., Genome-wide association study identifies novel breast cancer susceptibility loci, Nature 447 (2007) 1087–1093. [9] D.J. Hunter, P. Kraft, K.B. Jacobs, D.G. Cox, M. Yeager, S.E. Hankinson, et al., A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer, Nat. Genet. 39 (2007) 870–874. [10] B. Gold, T. Kirchhoff, S. Stefanov, J. Lautenberger, A. Viale, J. Garber, et al., Genome-wide association study provides evidence for a breast cancer risk locus at 6q22.33, Proc. Natl. Acad. Sci. USA 105 (2008) 4340–4345.
25
[11] S.N. Stacey, A. Manolescu, P. Sulem, S. Thorlacius, S.A. Gudjonsson, G.F. Jonsson, et al., Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer, Nat. Genet. 40 (2008) 703–706. [12] K. Visvanathan, P. Hurley, E. Bantug, P. Brown, N.F. Col, J. Cuzick, et al., Use of pharmacologic interventions for breast cancer risk reduction: American Society of Clinical Oncology clinical practice guideline, J. Clin. Oncol. 31 (2013) 2942–2962. [13] E.A. Waters, K.A. Cronin, B.I. Graubard, P.K. Han, A.N. Freedman, Prevalence of tamoxifen use for breast cancer chemoprevention among U.S. women, Cancer Epidemiol. Biomark. Prev. 19 (2010) 443–446. [14] N. Gronich, G. Rennert, Beyond aspirin-cancer prevention with statins, metformin and bisphosphonates, Nat. Rev. Clin. Oncol. 10 (2013) 625–642. [15] B.E. Bachmeier, V. Mirisola, F. Romeo, L. Generoso, A. Esposito, R. Dell’eva, et al., Reference profile correlation reveals estrogen-like trancriptional activity of Curcumin, Cell. Physiol. Biochem.: Int. J. Exp. Cell. Physiol. Biochem. Pharmacol. 26 (2010) 471–482. [16] X. Liao, P. Lochhead, R. Nishihara, T. Morikawa, A. Kuchiba, M. Yamauchi, et al., Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival, N. Engl. J. Med. 367 (2012) 1596–1606. [17] A. Albini, S. Indraccolo, D.M. Noonan, U. Pfeffer, Functional genomics of endothelial cells treated with anti-angiogenic or angiopreventive drugs, Clin. Exp. Metastasis 27 (2010) 419–439. [18] A. Albini, F. Tosetti, V.W. Li, D.M. Noonan, W.W. Li, Cancer prevention by targeting angiogenesis, Nat. Rev. Clin. Oncol. 9 (2012) 498–509. [19] W. Yue, C.S. Yang, R.S. DiPaola, X.L. Tan, Repurposing of metformin and aspirin by targeting AMPK-mTOR and inflammation for pancreatic cancer prevention and treatment, Cancer Prev. Res. (Phila) 7 (2014) 388–397. [20] C. Marini, B. Salani, M. Massollo, A. Amaro, A.I. Esposito, A.M. Orengo, et al., Direct inhibition of hexokinase activity by metformin at least partially impairs glucose metabolism and tumor growth in experimental breast cancer, Cell Cycle 12 (2013) 3490–3499. [21] R.D. Semba, L. Ferrucci, B. Bartali, et al., REsveratrol levels and all-cause mortality in older community-dwelling adults, JAMA Intern. Med. (2014). [22] A.B. Kunnumakkara, P. Anand, B.B. Aggarwal, Curcumin inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling proteins, Cancer Lett. 269 (2008) 199–225. [23] H. Hatcher, R. Planalp, J. Cho, F.M. Torti, S.V. Torti, Curcumin: from ancient medicine to current clinical trials, Cell. Mol. Life Sci. 65 (2008) 1631–1652. [24] B.E. Bachmeier, P. Killian, U. Pfeffer, A.G. Nerlich, Novel aspects for the application of Curcumin in chemoprevention of various cancers, Front. Biosci. 2 (2010) 697–717. [25] A.C. Bharti, N. Donato, S. Singh, B.B. Aggarwal, Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor-kappa B and IkappaBalpha kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis, Blood 101 (2003) 1053–1062. [26] P.H. Killian, E. Kronski, K.M. Michalik, O. Barbieri, S. Astigiano, C. P. Sommerhoff, et al., Curcumin inhibits prostate cancer metastasis in vivo by targeting the inflammatory cytokines CXCL1 and -2, Carcinogenesis 33 (2012) 2507–2519. [27] E. Kronski, M.E. Fiori, O. Barbieri, S. Astigiano, V. Mirisola, P.H. Killian, et al., miR181b is induced by the chemopreventive polyphenol curcumin and inhibits breast cancer metastasis via down-regulation of the inflammatory cytokines CXCL1 and -2, Mol. Oncol. 8 (2014) 581–595. [28] N.D. Perkins, Integrating cell-signalling pathways with NF-kappaB and IKK function, Nat. Rev. Mol. Cell. Biol. 8 (2007) 49–62. [29] M. Karin, Nuclear factor-kappaB in cancer development and progression, Nature 441 (2006) 431–436. [30] B.E. Bachmeier, I.V. Mohrenz, V. Mirisola, E. Schleicher, F. Romeo, C. Hohneke, et al., Curcumin downregulates the inflammatory cytokines CXCL1 and -2 in breast cancer cells via NFkappaB, Carcinogenesis 29 (2008) 779–789. [31] C.S. Beevers, L. Chen, L. Liu, Y. Luo, N.J. Webster, S. Huang, Curcumin disrupts the Mammalian target of rapamycin-raptor complex, Cancer Res. 69 (2009) 1000–1008. [32] Y. Zhou, S. Zheng, J. Lin, Q.J. Zhang, A. Chen, The interruption of the PDGF and EGF signaling pathways by curcumin stimulates gene expression of PPARgamma in rat activated hepatic stellate cell in vitro, Lab. Invest. 87 (2007) 488–498. [33] W. Pan, H. Yang, C. Cao, X. Song, B. Wallin, R. Kivlin, et al., AMPK mediates curcumin-induced cell death in CaOV3 ovarian cancer cells, Oncol. Rep. 20 (2008) 1553–1559. [34] T.H. Leu, S.L. Su, Y.C. Chuang, M.C. Maa, Direct inhibitory effect of curcumin on Src and focal adhesion kinase activity, Biochem. Pharmacol. 66 (2003) 2323–2331. [35] S. Prakobwong, S.C. Gupta, J.H. Kim, B. Sung, P. Pinlaor, Y. Hiraku, et al., Curcumin suppresses proliferation and induces apoptosis in human biliary cancer cells through modulation of multiple cell signaling pathways, Carcinogenesis 32 (2011) 1372–1380. [36] F.M. Robertson, M. Bondy, W. Yang, H. Yamauchi, S. Wiggins, S. Kamrudin, et al., Inflammatory breast cancer: the disease, the biology, the treatment, CA Cancer J. Clin. 60 (2010) 351–375. [37] N. Yamaguchi, T. Ito, S. Azuma, E. Ito, R. Honma, Y. Yanagisawa, et al., Constitutive activation of nuclear factor-kappaB is preferentially involved in the proliferation of basal-like subtype breast cancer cell lines, Cancer Sci. 100 (2009) 1668–1674. [38] B. Bachmeier, A.G. Nerlich, C.M. Iancu, M. Cilli, E. Schleicher, R. Vene, et al., The chemopreventive polyphenol Curcumin prevents hematogenous breast cancer
26
[39]
[40]
[41] [42] [43]
U. Pfeffer et al. / New Horizons in Translational Medicine 2 (2014) 20–26
metastases in immunodeficient mice, Cell Physiol. Biochem. 19 (2007) 137–152. M.L. Slattery, E.M. John, G. Torres-Mejia, A. Lundgreen, J.S. Herrick, K. B. Baumgartner, et al., Genetic variation in genes involved in hormones, inflammation and energetic factors and breast cancer risk in an admixed population, Carcinogenesis 33 (2012) 1512–1521. W.G. Nelson, T.L. DeWeese, A.M. DeMarzo, The diet, prostate inflammation, and the development of prostate cancer, Cancer Metastasis Rev. 21 (2002) 3–16. K.S. Sfanos, A.M. De Marzo, Prostate cancer and inflammation: the evidence, Histopathology 60 (2012) 199–215. T. Nguyen, X.K. Liu, Y. Zhang, C. Dong, BTNL2, a butyrophilin-like molecule that functions to inhibit T cell activation, J. Immunol. 176 (2006) 7354–7360. L.M. Fitzgerald, A. Kumar, E.A. Boyle, Y. Zhang, L.M. McIntosh, S. Kolb, et al., Germline missense variants in the BTNL2 gene are associated with prostate cancer susceptibility, Cancer Epidemiol. Biomarkers Prev. 22 (2013) 1520–1528.
[44] G. Garcea, D.P. Berry, D.J. Jones, R. Singh, A.R. Dennison, P.B. Farmer, et al., Consumption of the putative chemopreventive agent curcumin by cancer patients: assessment of curcumin levels in the colorectum and their pharmacodynamic consequences, Cancer Epidemiol. Biomarkers Prev. 14 (2005) 120–125. [45] D. Wang, R.N. Dubois, The role of COX-2 in intestinal inflammation and colorectal cancer, Oncogene 29 (2010) 781–788. [46] J.J. Johnson, H. Mukhtar, Curcumin for chemoprevention of colon cancer, Cancer Lett. 255 (2007) 170–181. [47] K. Curtin, R.K. Wolff, J.S. Herrick, R. Abo, M.L. Slattery, Exploring multilocus associations of inflammation genes and colorectal cancer risk using hapConstructor, BMC Med. Genet. 11 (2010) 170. [48] M.N. Weedon, H. Lango, C.M. Lindgren, C. Wallace, D.M. Evans, M. Mangino, et al., Genome-wide association analysis identifies 20 loci that influence adult height, Nat. Genet. 40 (2008) 575–583.