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More research is needed to establish the benefit-risk profile of curcumin

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More research is needed to establish the benefit-risk profile of curcumin
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  Therapeutic use of human alpha-fetoprotein in clinical patients:is a cancer risk involved? Gerald J. Mizejewski Division of Translational Medicine, Wadsworth Center, New York State Department of Health, Empire State Plaza, Albany, NY  Dear Editor, In the course of the last decade, the possibility of employing full-length human alpha-fetoprotein (AFP) (FL-AFP) as atherapeutic agent for autoimmune diseases in clinical patientshas become a reality in ongoing clinical trials. 1 This is due,in part, to advances in both recombinant protein technology and improved methodologies in the isolation and large scalepurification of naturally-occurring proteins. Although it isnow possible to produce FL-AFP in scaled-up quantities,does this justify its use as a therapeutic agent (protein) inadult diseases and disorders? Are there safety issues involvedwith its use in patients, of what do they consist, and what arethe possible risks, if any? The present commentary is a callto proceed slowly and with extreme caution in administering an oncofetal protein to human adult patients, a proteinwhose precise function and physiological roles are not yetfully understood.Even though the literature is replete with the biologicalactivities ascribed to the FL-AFP, little is known regarding the administration of pharmacologic doses to human adultsthat normally display scant (5–8 ng/ml) levels in their blood-stream. Unless a patient has liver/germ cell cancer, hepatitis,cirrhosis, or a genetic disorder (i.e., ataxia telangiectasia), low AFP concentrations remain relatively constant throughoutlife. In contrast, the AFP levels in embryonic and fetal lifecan range from 20 ug/ml in amniotic fluids to 5 mg/ml infetal serum. 2 These concentrations, however, occur in cellsand tissues undergoing frequent cell proliferation, adhesion,migration, differentiation and growth in the constantly changing milieu of the embryonic/fetal organism. Thus,FL-AFP exists and flourishes in fluctuating fetal environ-ments requiring both molecular flexibility and adaptability.This is in dire contrast to albumin which interacts mostly with fully-differentiated cells and tissues of the adultorganism.The potential risks involved with administering FL-AFP toclinical patients have, as root concerns, AFP’s ability to transi-tion into multiple conformational variant states depending onits environmental surroundings such as pH, temperature,osmolality, excess ligand concentrations, oxidation and heat/glucose shock. 3 The silent danger of treating adult humanpatients with therapeutic doses of FL-AFP lies in its reversibleand transient denaturation (conformational) states whichbestow on AFP a rigid-to-flexible vacillation that exits betweena compactly-folded form and an extended or open form.HAFP has a remarkably hydrophilic- exposed molecular sur-face at neutral pH and possesses extensive hydrophobic binding sites located in concealed molecular crevices. The immuno-chemistry of the FL-AFP molecule has further revealed clustersof five major antigenic epitopes and one major occult epitopewhich gives rise to open and cryptic forms of AFP depending on its natured  versus  denatured state, respectively. 4,5 Finally,FL-AFP has also been demonstrated to dimerize with otherproteins, such as nuclear receptors (i.e., retinoic receptor), tran-scription factors and caspases all of which can result in pro-moting growth of tumor cells. 6,7 FL-AFP has been reported to transition through a moltenglobule form dependent on extremes of pH, a situation com-monly found in the cytoplasm of cells following proteinuptake. 8 The FL-AFP molecule is known to undergo a slightdenaturation and unfolding through a molten globule state,which encompasses a loosening of the tertiary packing whileleaving the secondary structure of the molecule intact. 9 Incontrast, the unfolding–refolding transition states are lesscommon with human albumin, due to its more rigid compactstructure resulting from a higher number of disulfide bridgesin the molecule. AFP’s tertiary form is known to be underligand binding control; thus, ligand concentration can affectits biological activities. 10,11 Moreover, a relationship existsbetween the conformational state and the biological activity of AFP as exemplified in a report that tumor and fetal formsof AFP were found to differ in their conformationally-de-pendent expressions of epitope variants. 12 Such transitional variants could conceivably be formed following the injectionof FL-AFP into clinical patients and could result in unwantedtargeting and aberrant signal transduction of AFP leading toconditions of inappropriate and untimely cell growth inhibi-tion and/or enhancement.A further potential risk in the therapeutic use of FL-AFP,especially after multiple treatments, is the long-term effectson the growth, development and progression of small tumorfoci which may not always be observable during human clini-cal trials. An effect that might result from extended adminis-tration of pharmacologic doses of FL-AFP is the initiation of tumor formation as previously described. 13,14 This inductioncould result from the transformation of pretumor to tumorcells which have evaded immune surveillance in cancer-sus-ceptible individuals, such as in hepatitis or cirrhotic patents;such groups are at risk for developing hepatomas (see later).FL-AFP has also been reported to promote or up-regulatetumor cell proliferation, cell cycle progression, angiogenesis       L     e      t      t     e     r     s      t     o      t       h     e      E       d      i      t     o     r Int. J. Cancer:  128 , 239–249 (2011) V C  2010 UICC International Journal of Cancer IJC  and the inhibition of apoptosis in human clinical tumors,employing cells derived from hepatocellular carcinomapatients. 15 Although FL-AFP has been reported to induceapoptosis in cancer cells under certain conditions, 16 the ma- jority of published studies reveal that FL-AFP inhibits apo-ptosis in multiple cancer cell types thus promoting tumor cellproliferation, growth and progression. 7,17–19 The mechanism of action of tumor growth enhancementby AFP was shown to involve the shielding of human hepa-toma cells from tumor necrosis factor (TNF)-induced apo-ptosis, 20 and to promote the escape of tumor cells from lym-phocytic attack (immune surveillance) by blocking thecaspase apoptotic pathway. 21 FL-AFP was further shown topromote cell proliferation in tumor cells and fibroblasts by the up-regulation of K-Ras p21, elevations of cyclic AMP andProtein Kinase A, and raised intracytoplasmic Ca þþ  lev-els. 22,23 FL-AFP had previously been found to promote thecell proliferation of human hepatomas, Erlich ascites carcino-mas and mammary tumor cells, but not leukemic cells. 18,19,24 The AFP-induced growth enhancement in some tumor cellsranged from 120 to 150%, while 80 to 200% occurred in theErlich carcinoma cells. 19 Studies of AFP knockdown by means of siRNA was shown to cause a notable delay in theG1 to S-Phase transition of the cell cycle, together with theinhibition of cell proliferation in hepatomas. 25,26 It was fur-ther shown that FL-AFP could promote the growth of tumorcells in a dose-dependent fashion; such tumors included hep-atomas, lymphoblastomas, Jurket lymphomas and fibroblasto-mas. 26 Finally FL-AFP, in conjunction with its cell surface re-ceptor, was reported to act in synergism with growth factors(EGF, PDGF, IGF-1), cytokines (IFN-alpha, TNF), oncogenes(c-FOS, c-JUN, n-RAS) and transcription factors in promot-ing the growth of mammary and colon tumor cells. 24,27–31 The concept of FL-AFP enhancing and accelerating thegrowth of human tumors at first seems to contradict the pub-lished findings that high AFP levels during pregnancy has aprotective effect against risk of breast cancer in latter life. 32,33 However, upon circumspection, it can be discerned that suchreports do not include real-time clinical therapy results, butrather, data encompassing epidemiological findings andtrends derived from statistical risk calculations, medical his-tories, logistic regression models and stored records frompopulation-based data sets. At best, such studies representstatistically significant trends for large cohort groups (popula-tions), but not individual patients’ results. Other findings of FL-AFP in association with reduced breast cancer risk arederived from nonhuman (rat) pregnancy models and humancell cultures not linked to actual clinical patient tissue sam-ples. 34 These human population-based cohort studies had nomeans to determine or consider the presence of isoforms orconformational variants of AFP during pregnancy. However,recent clinical reports have described an assay to detect andmeasure conformationally-transformed AFP (tAFP) concen-trations during normal pregnancy; such levels are elevated inconditions of intrauterine growth retardation and threatenedpreterm labor. 35,36 These authors proposed that some per-centage of the AFP molecules become altered or transformedinto tAFP  via  passage through the placenta since the mater-nal tAFP levels were 10 times greater than those in fetal sam-ples. One can only speculate whether tAFP (a growth inhibi-tor) may have been involved in those published studies of reduced breast cancer risk. Finally, the presence of hereditary persistance of AFP following pregnancy (serum levels  ¼  20–100 ng/ml) could provide an agrument that this benign auto-somal dominant disorder is nonpathological in adult life.However, this condition is not always beign and has beenreported to be coincident with tall stature, advanced boneage and growth, testis disease and sometimes germ celltumors. 37 As HAFP is largely a growth promoting molecule, thetherapeutic injection of FL-AFP(70 Kd) into normal and/ordiseased adults could be potentially hazardous and shouldrequire extensive, long-term clinical evaluation. The FL-AFPmolecule is bristling with innumerable biologically-activepeptide sites, 38 some of which may not be fully exposeduntil AFP is introduced into differing or highly variablebiochemical/biophysical microenvironments. Upon stimula-tion, the biologic response induced by these exposed peptidesegments cannot be predicted or controlled and could pro-duce undesired or dangerous side effects. This was precisely the reason why the United States FDA banned the sale anddistribution of the human AFP immunoassay reagents as amedical device(kits) in 1971, a ban which endured until1984. 39 Recent examples of uncontrolled or unwanted AFPbiologic responses have included reports showing that AFPcan inhibit natural killer cell activity; thus AFP can inhibitimmunity against tumors. 40 AFP has also been reported toenhance cytokine, chemokine, growth factor, H 2 O 2  and ni-trite/nitrate levels in human keratinocytes. 41 Finally, expres-sion of the fetal AFP transcript and its concomitant DNAsynthesis has long been utilized as an indicator for activa-tion of the liver stem cell compartment, while AFP itself isa cell-surface marker of stem cell proliferation. 42 It is withmore than 50 years of published reports in the field of AFPresearch that a cancer risk warning can now be issued.Unless under developmental stage control, FL-AFP shouldbe viewed as a biological ‘‘loose cannon.’’ Therefore, func-tion-site specific AFP-derived peptides might offer a safer,more conservative approach for possible future therapy of human clinical patients for diseases such as myastheniagravis, systemic lupus, Hashomoto’s thyroiditis, multiplesclerosis, arthritis and perhaps other inflammatory/autoim-mune disorders.  Acknowledgements The author extends his thanks and gratitude to Dr. Jennifer L. Wright fortime expenditure in the typing and processing of the manuscript and refer-ences of this report.  Yourssincerely,GeraldJ.Mizejewski       L     e      t      t     e     r     s      t     o      t       h     e      E       d      i      t     o     r 240  Letters to the Editor Int. J. Cancer:  128 , 239–249 (2011) V C  2010 UICC  References 1. Dudich E. MM-093, a recombinant human alpha-fetoprotein for thepotential treatment of rheumatoid arthritis and other autoimmunediseases.  Curr Opin Mol Ther   2007;9:603–10.2. Mizejewski GJ. Levels of alpha-fetoprotein during pregnancy andearly infancy in normal and disease states.  Obstet Gynecol Surv   2003;58:804–26.3. Mizejewski GJ. Alpha-fetoprotein structure and function: relevanceto isoforms, epitopes, and conformational variants.  Exp Biol Med  2001;226:377–408.4. Karamova ER, Yazova AK, Goussev AI, Abelev GI.Conformational variants of human alpha-fetoprotein.  Tumour Biol  1998;19:310–7.5. Karamova ER, Yazova AK, Yakimenko EF, Abelev GI. New approaches for the detection and characterization of alpha-fetoprotein epitope variants.  Tumour Biol   2003;24:1–8.6. Li M, Li H, Li C Guo L, Zhou S. Cytoplasmic alpha-fetoproteinfunctions as a co-repressor in RA-RAR signaling to promote the growthof human hepatoma Bel 7402 cells.  Cancer Lett   2009;285:190–9.7. Li M, Li H, Li C, Zhou S, Guo L, Jiang W. Alpha fetoprotein is anovel protein-binding partner for caspase-3 and blocks the apoptoticsignaling pathway in human hepatoma cells.  Int J Cancer   2009;124:2845–54.8. Hajeri-Germond M, Naval J, Trojan J, Uriel J. The uptake of alpha-foetoprotein by C-1300 mouse neuroblastoma cells.  Br J Cancer  1985;51:791–7.9. Uversky VN, Kirkitadze MD, Narizhneva NV. Structural propertiesof alpha-fetoprotein from human cord serum: the protein moleculeat low pH possesses all the properties of the molten globule.  FEBSLett   1995;364:165–7.10. Uversky VN, Narizhneva NV, Ivanova TV. Rigidity of human alpha-fetoprotein tertiary structure is under ligand control.  Biochemistry  1997;36:13638–45.11. Nunez EA, Benassayag C, Vallette G, Martin ME. The physicochemicaland biological properties of alpha-fetoprotein depend of its ligandenvironment.  J Nucl Med Allied Sci  1989;33:18–26.12. Yazova AK, Goussev AI, Christiansen M. Human fetal and tumoralpha-fetoproteins differ in conformationally dependent epitope variants expression.  Immunol Lett   2003;85:261–70.13. Gershwin ME, Castles JJ, Ahmed A. The influence of alpha-fetoprotein on Moloney sarcoma virus oncogenesis: evidence forgeneration of antigen nonspecific suppressor T cells.  J Immunol  1978;121:2292–8.14. Gershwin ME, Castles JJ, Makishima R. Accelerated plasmacytomaformation in mice treated with alpha-fetoprotein.  J Natl Cancer Inst  1980;64:145–9.15. Mitsuhashi N, Kobayashi S, Doki T. Clinical significance of alpha-fetoprotein: involvement in proliferation, angiogenesis, and apoptosis of hepatocellular carcinoma.  J Gastroenterol Hepatol   2008;23:e189–97.16. Semenkova LN, Dudich EI, Dudich IV. Induction of apoptosis inhuman hepatoma cells by alpha-fetoprotein.  Tumour Biol   1997;18:261–73.17. Laderoute MP, Pilarski LM. The inhibition of apoptosis by alpha-fetoprotein (AFP) and the role of AFP receptors in anti-cellularsenescence.  Anticancer Res  1994;14:2429–38.18. Wang XW, Xie H. Alpha-fetoprotein enhances the proliferation of human hepatoma cells in vitro.  Life Sci  1999;64:17–23.19. Wang XW, Xu B. Stimulation of tumor-cell growth by alpha-fetoprotein.  Int J Cancer   1998;75:596–9.20. Li M, Zhou S, Liu X, Li P. Alpha-fetoprotein shieldshepatocellular carcinoma cells from apoptosis induced by tumornecrosis factor-related apoptosis-inducing ligand.  Cancer Lett   2007;249:227–34.21. Li M, Liu X, Zhou S, Li P, Li G. Effects of alpha fetoprotein onescape of Bel 7402 cells from attack of lymphocytes.  BMC Cancer  2005;5:96.22. Li MS, Li PF, He SP, Du GG, Li G. The promoting molecularmechanism of alpha-fetoprotein on the growth of human hepatomaBel7402 cell line.  World J Gastroenterol   2002;8:469–75.23. Li MS, Li PF, Yang FY. The intracellular mechanism of alpha-fetoprotein promoting the proliferation of NIH 3T3 cells.  Cell Res 2002;12:151–6.24. Leal JA, Gangrade BK, Kiser JL, May JV, Keel BA. Humanmammary tumor cell proliferation: primary role of platelet-derivedgrowth factor and possible synergism with human alpha-fetoprotein. Steroids  1991;56:247–51.25. Wang YS, Ma XL, Qi TG, Liu XD, Meng YS, Guan GJ. Downregulationof alpha-fetoprotein siRNA inhibits proliferation of SMMC-7721 cells. World J Gastroenterol   2005;11:6053–5.26. Tang H, Tang XY, Liu M. Targeting alpha-fetoprotein represses theproliferation of hepatoma cells via regulation of the cell cycle.  ClinChim Acta  2008;394:81–8.27. Dudich E, Semenkova L, Gorbatova E. Growth-regulative activity of human alpha-fetoprotein for different types of tumor and normalcells.  Tumour Biol   1998;19:30–40.28. Esteban C, Trojan J, Macho A. Activation of an alpha-fetoprotein/receptor pathway in human normal and malignant peripheral bloodmononuclear cells.  Leukemia  1993;7:1807–16.29. Liu Y, Chiu JF. Transactivation and repression of the alpha-fetoprotein gene promoter by retinoid X receptor and chickenovalbumin upstream promoter transcription factor.  Nucleic Acids Res 1994;22:1079–86.30. Keel BA, Eddy KB, Cho S. Synergistic action of purifiedalpha-fetoprotein and growth factors on the proliferation of porcinegranulosa cells in monolayer culture.  Endocrinology   1991;129:217–25.31. Yano H, Basaki Y, Oie S. Effects of IFN-alpha on alpha-fetoproteinexpressions in hepatocellular carcinoma cells.  J Interferon CytokineRes  2007;27:231–8.32. Richardson BE, Hulka BS, Peck JL. Levels of maternal serum alpha-fetoprotein (AFP) in pregnant women and subsequent breast cancerrisk.  Am J Epidemiol   1998;148:719–27.33. Melbye M, Wohlfahrt J, Lei U. alpha-fetoprotein levels in maternalserum during pregnancy and maternal breast cancer incidence.  J Natl Cancer Inst   2000;92:1001–5.34. Jacobson HI, Lemanski N, Narendran A. Hormones of pregnancy,alpha-feto protein, and reduction of breast cancer risk.  Adv Exp Med Biol   2008;617:477–84.35. Gonzalez-Bugatto F, Foncubierta E, Bailen Mde L. Maternal and fetalserum transformed alpha-fetoprotein levels in normal pregnancy.  J Obstet Gynaecol Res  2009;35:271–6.36. Gonzalez-Bugatto F, Bailen, Mde L, Fernandez-Macias R.Transformed alpha-fetoprotein (t-AFP) levels in women withthreatened preterm labor.  Gynecol Obstet Invest   2009;68:199–204.37. Li X, Alexander S. Hereditary persistance of alpha-fetoprotein. Pediatric Blood Cancer   2009;52:403–5.38. Mizejewski G. Mapping of structure-function peptide sites on the humanalpha-fetoprotein amino acid sequence.  Deep Insight Section  2009:1–65.39. Edmonds LD. Trends in incidence of neural tube defectsin the United States in alpha-fetoprotein and congenitaldisorders. In: Mizejewski GJ, Porter HI, eds. Alpha Fetaprotein andCongenital Disorders. FL: Academic Press, 1985. 295–308.40. Belyaev NN, Bogdanov AY, Savvulidi PG, et al. The influenceof alpha-fetoprotein on natural suppressor cell activity and erhlichcarcinoma growth.  Korean J Physiol Pharmocol   2008;12:193–7.41. Potapovich AI, Pastore S, Kostyuk VA. Alpha-fetoprotein as amodulator of the pro-inflammatory response of humankeratinocytes.  Brit J Pharmocol   2009;158:1236–47.42. Evarts RP, Hu Z, Fujio K, Marsden ER, Thorgeirsson SS. Activationof hepatic stem cell compartment in the rat: role of transforming growth factor alpha, hepatocyte growth factor, and fibroblast growthfactor in early proliferation.  Cell Growth Differentiation  1993;4:555–61.       L     e      t      t     e     r     s      t     o      t       h     e      E       d      i      t     o     r Letters to the Editor  241 Int. J. Cancer:  128 , 239–249 (2011) V C  2010 UICC   Abbreviations:  AFP: alpha-fetoprotein; Ca±±: calcium ions; cyclic-AMP: cyclic adenosine monophosphate; EGF: epidermal growthfactor; FDA: Food and Drug Administration; HAFP: humanalphafetoprotein; IGF1: insulin growth factor-1; PDGF: plalet-derivedgrowth factor; RAS: oncogene product; TNF: tumor necrosis factor. DOI:  10.1002/ijc.25292 History:  Received 29 Jan 2010; Accepted 11 Feb 2010; Online 3 Mar2010 Correspondence to:  Gerald J. Mizejewski, Division of TranslationalMedicine, Wadsworth Center, New York State Department of Health,Empire State Plaza, Albany, NY 12201, USA, Tel: 518-486-5900, Fax:518-402-5002, E-mail: mizejew@wadsworth.org  Curcumin does not bind or intercalate into DNA and a note onthe gray side of curcumin Biji T. Kurien 1 , Skyler P. Dillon 1,2 , Yaser Dorri 1,2 , Anil D’Souza 1,2 and R. Hal Scofield 1,2,3 1 Arthritis and Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, OK 2 Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, OK 3 Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma, OK Dear Editor, Burgos-Moron  et al  ., in their letter to the Editor 1 entitled‘‘The dark side of curcumin’’ suggest that curcumin can becytotoxic and can induce DNA damage. The authors of thisletter cite several lines of evidence in support of their con-tention including a 1976 paper by Goodpasture and Arrighi 2 that shows interference with chromosomal condensation,signs of chromosome banding, breakage, fragmentation anddisintegration, mitotic arrest and decrease in nucleic acidsynthesis when turmeric (solubilized in absolute ethanol)was incubated with cultured Don cells (cells of the Chinesehamster,  Cricetulus griseus ) or Indian muntjac cells (  Muntia-cus muntjac  ). Goodpasture and Arrighi 2 point out that sev-eral DNA-intercalating agents induce chromosomal banding patterns  in vitro . They also point out that compounds bind-ing to DNA at specific places during G 2  or prophase couldinterfere with the binding of chromosomal proteins neces-sary for chromosomal condensation as they prepare formitosis. 3 We investigated the ability of heat-solubilized cur-cumin 4,5 and curcumin in 0.5 N sodium hydroxide 6 or etha-nol to intercalate into DNA. As curcumin fluoresces at 446–549 nm when irradiated with ultra violet light (excitation355 nm), it is possible to visualize its binding or intercala-tion into DNA.Here, we first comment on the observation made by Bur-gos-Moron  et al  . 1 that curcumin has a dark side to it, in spiteof the numerous papers that have been published regarding itstherapeutic effects. 4–11 Second, we present data that showscurcumin, solubilized in water by heat, 0.5 N sodium hydrox-ide or ethanol do not intercalate into DNA. Even thoughturmeric was soluble in 100% DMSO, 12 the curcuminoidsprecipitated out when diluted in water. Hence, it was not pos-sible to use DMSO-solubilized curcumin in this experiment.Curcumin, a naturally occurring ‘‘nutraceutical,’’ is themost active component in the curry spice turmeric ( Curcumalonga ). This polyphenolic antioxidant has a long history of use in the traditional diet of Asian countries, especially inIndian herbal medicine. It has been shown to interact withmultiple targets to regress diseases safely and inexpensively.Curcumin has been reported to lower cholesterol, suppressdiabetes, enhance wound healing, modulate multiple sclerosisand Alzheimer’s disease and block HIV replication. In addi-tion, curcumin has been shown to inhibit tumsrcenesis, me-tastasis, platelet aggregation, inflammatory cytokine produc-tion, cataract formation, inflammatory bowel disease andmyocardial infarction. 4–11 Burgos-Moron  et al  . point out that (a) most therapeuticstudies with curcumin have been carried out using micromo-lar levels in  in vitro  studies; (b) plasma concentrations of people consuming high oral doses (8–12 g/day) of curcuminare just in the nanomolar range; (c) in  in vitro  studies, cancercells do not die unless the cells are exposed to 5–50  l M forseveral hours and such levels are not achieved  in vivo ;(d) proper studies of long-term side effects of curcumin havenot been undertaken; (e) just because curcumin is a commondietary constituent does not make it harmless; (f) increasing the solubility of curcumin will increase its cytotoxicity and(g) curcumin induces several toxic effects, of which the primeone is the induction of DNA damage.We mostly agree with Burgos-Moron  et al  . 1 However, wewould like to comment on the point that curcumin inducesDNA damage, since DNA alterations are important events incarcinogensis. Goodpasture and Arrighi’s work  2 shows dra-matic DNA damage and disintegration when 10 to 50  l g/mlof turmeric was incubated with cultured cells for periods upto 24 hr. Goodpasture and Arrighi 2 used mammalian cell cul-tures to study the effect of various food seasonings, especially turmeric, on chromosome morphology and cell cycle progres-sion. They showed that turmeric arrested mitosis, changedchromosome morphology and interfered in synthesis of nucleic acid.       L     e      t      t     e     r     s      t     o      t       h     e      E       d      i      t     o     r 242  Letters to the Editor Int. J. Cancer:  128 , 239–249 (2011) V C  2010 UICC  A turmeric fraction, solubilized in absolute ethanol, wasadded to cells. The authors show dramatic results, including chromosome breakage when Muntjac cells were treated withturmeric (10  l g/ml) for 4 hr and shattered chromosomes of Don cells incubated with turmeric (50  l g/ml) for 24 hr. Eventhough the authors state that absolute ethanol was added tocontrol cells, in amounts equal to that added for turmeric, noresults are provided for controls. No mention is made in thetext either, regarding the effect of ethanol on cells. Figure1in this letter shows metaphase chromosomes of normal Doncells, without specifying the solvent added to it. This is im-portant because it is the only control shown for all season-ings (curry powder, onion juice, paprika, cayenne pepper andturmeric) that were solubilized with water, Hanks’ balancedsalt solution or 95% ethanol. We believe, from the resultsshown, that the cells have undergone cell death, as describedin the next paragraph. Whether this is the effect of curcuminalone, curcumin plus ethanol or ethanol alone is not clear.Also, as suggested by Burgos-Moron  et al  ., 1 it has to be bornein mind that levels used in  in vitro  experiments have neverbeen achieved  in vivo .Low levels of ethanol (43–86 mM; similar to blood levelsduring alcohol consumption) has been shown to also induceapoptosis (increased caspase 3 activity) and bring about celldeath in human and rodent mast cells, whereas 860 and1,720 mM levels (50 and 100% ethanol levels, respectively)appear to be toxic to cells (causes decreased caspase activ-ity). 13 Ethanol has been shown to also induce apoptosis insome other cell types including liver (Hep G2) cells, macro-phages and neural crest cells in embryo. 13 Moreover, ethanolhas been shown to bring about hepatic cell cycle arrest. 14 Therefore, it is hard to conclude from Goodpasture andArrighi’s paper that turmeric is the sole factor responsible forthe DNA damage observed in the  in vitro  experiments.References 22–30 cited by Burgos-Moron  et al  . 1 for DNAdamage, either use metals such as copper to induce DNAdamage or use nonphysiological solvents to solubilize curcu-min. Therefore, it is hard to reconcile whether curcuminalone is responsible for the DNA damage observed.Insolubility of curcumin or turmeric in water has been theprime reason for the use of solvents like ethanol, DMSO 12 andalkali. 6 Recently, turmeric and curcumin has been solublized inwater with the use of heat, 4 resulting in a curcumin yield of about 7.4  l g/ml water. This heat treatment procedure still leftthe bulk of curcumin (98.5%) insoluble. 4 It would be of interestto use this heat solubilized turmeric/curcumin to investigatethe effects of curcumin on apoptosis and DNA damage in vari-ous cell lines. Curcumin/turmeric has been solubilized withdilute alkali. 6 Both, heat-solubilized and dilute alkali solubi-lized curcumin inhibited 4-hydroxy-2-nonenal (HNE)-medi-ated protein modification significantly, using an enzyme-linkedimmunosorbent assay that used HNE-modification of a solid-phase multiple antigen peptide substrate. 15 Very recently, curcumin has been shown to modulateBRCA1 protein and induce apoptosis in triple negative breastcancer cell lines. Triple negative breast cancers lack expres-sion of progesterone and estrogen receptors as well as do notoverexpress human epidermal growth factor receptor 2. 16 However, curcumin did not bring about apoptosis andBRCA1 modulation in nontransformed mammary epithelialcells. Thus, the results of these authors suggest that curcuminmay have limited nonspecific toxicity. Curcumin used inthese experiments was dissolved in ethanol and diluted two-fold when added to cells.Furthermore, in  in vivo  mice studies, Mukhopadhyay  et al  . in 1998 10 have shown that turmeric or curcumin (dis-solved in absolute ethanol at first and diluted 1:10 with waterbefore administration) given by oral gavage at 8 mg/kg body weight did not show clastogenic activity (chromosome aber-rations or cell death) even after 7 days of priming. However,neither curcumin or turmeric was able to prevent cyclophos-phamide or mitomycin-induced clastogenicity. 10 Additionally, studies carried out by Shukla  et al  . in 2002 11 evaluated the antimutagenic activity of curcumin using an  invivo  chromosomal aberration assay in Wistar rats. Curcumin(100–200 mg/kg body weight) was administered through gas-tric intubation for a period of 7 days before treatment withcyclophosphamide. Chromosomal aberration was observed incyclophosphamide-only treated animals, whereas no suchchange was observed in curcumin supplemented animals. 11 Just as Burgos-Moron  et al  . 1 suggest, we feel that it is im-portant for investigators to balance the beneficial effects withthe deleterious effects seen with curcumin. All efforts need tobe taken to show that curcumin is harmless. Since the publi-cation of the article by Burgos-Moron  et al  ., 1 a case of tran-sient complete atrioventricular block associated with curcu-min intake has been reported. 17 The patient had ingested 40–       L     e      t      t     e     r     s      t     o      t       h     e      E       d      i      t     o     r Figure 1.  Staining of 100 bp ladder with ethidium bromide andcurcumin. (  a  ) Stained with ethidium bromide, (  b  ) Stained withcurcumin in water and (  c   ) Stained with curcumin in 0.5 N sodiumhydroxide. Letters to the Editor  243 Int. J. Cancer:  128 , 239–249 (2011) V C  2010 UICC
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