DNC: Bad News about Prunes

Jacob Schor ND FABNO

July 18, 2008

Subject: Prunes increase IGF-I; something we would prefer to avoid doing when worried about cancer.

Our recent article on prunes and osteoporosis made it sound like all good news.  There is a potential problem to prunes and it isn’t just their laxative effect.

The prune and osteoporosis article is posted at:

http://denvernaturopathic.com/prunesandosteoporosis.htm

The problem is that 2002 human trial.  Remember they fed menopausal women either dried apples or prunes.  The prunes but not the apples, “…significantly increased serum levels of insulin-like growth factor-I (IGF-I) and bone-specific alkaline phosphatase (BSAP) activity.” 

There is a little detail in this abstract that needs to be pointed out.  Insulin-like growth factor-I (IGF-I), while associated with greater rates of bone formation, is associated with both increased risk of cancer and faster rates of cancer growth.  Growth factors after all stimulate cell growth.  Maybe eating dried plums is not a good idea for someone with osteoporosis but who also has cancer.  Or someone at risk of developing cancer?

That prunes increase bone density by stimulating IGF-I is not the best news.  It complicates things.

When asked about this concern,  the California Dried Plum Board quickly enlisted Dr. Ajmandi, the researcher who’s published almost all of the papers on dried plums and osteoporosis who responded:

 “Although IGF-I has been associated with tumor growth and cell proliferation, this is due to the nature of cancer cells (being selfish), employing most growth factors to their advantage. This is not cause and effect, rather cancer cells up regulated the production of most growth factors in order to grow faster. In normal individuals this should not be the case for instance when we are young we have the highest circulating levels of IGF-1 and as we age its levels diminish while cancer incident increases.”

In other words, Arjmandi feels increased IGF-I is a result of the cancer and not a cause. This is an interesting explanation for why we would see IGF-1 levels high with existing cancer but does not satisfactorily explain the association between high IGF-I and increased risk for developing disease. 

Arjmandi’s view surprises me.  Even before he published his 2002 results, the question had pretty much been settled; elevated IGF-I increases risk of developing cancer.  An excellent review appeared in the October 2000 issue of the British Medical Journal. http://bmj.bmjjournals.com/cgi/content/full/321/7265/847

Quoting from this article:

“The role of insulin-like growth factor-I in promoting cancer has been investigated for many years, but recently the quality and quantity of evidence has increased. In particular, a number of prospective studies using stored blood collected up to 14 years before the onset of disease have shown associations between insulin-like growth factor-I and prostate cancer, premenopausal breast cancer, and colon cancer……

The risk of cancer is higher among people with raised concentrations of insulin-like growth factor-I, and it is lower among those with high concentrations of insulin-like growth factor binding protein-3 (the main binding protein). The associations are similar when people whose blood samples were taken soon before diagnosis are excluded from analyses, suggesting that the observed relations are not due to the release of the growth factor by preclinical cancers…… The increasing direct epidemiological evidence that relates insulin-like growth factor-I to the risk of cancer is consistent with more circumstantial evidence.” 

The writers point out that acromegaly, a condition in which high concentrations of growth hormone stimulate production of high concentrations of insulin-like growth factor-I, is associated with an increased risk of colorectal cancer, breast cancer, prostate, thyroid, and blood cancers.

It may be that high levels of IGF-I early in life are what triggers cancer later in life.  Caloric restriction in early childhood both lowers IGF-I and cancer risk.  Thus our ‘prune worry’ may not be important for adults.  Unfortunately there are other factors that may link IGF-I to cancer:

“Alternatively, insulin-like growth factor-I might increase the risk of cancer through its anti-apoptotic activity. In this case it prevents the programmed death of cells that have been transformed thus interrupting an important process which retards the development of cancer.”

In other words high IGF-I levels would hinder the body’s ability to ‘prune’ away pre-cancerous cells as they develop and this risk would not be limited to childhood.

This IGF and cancer business is a hot research topic at the moment and a great deal of research is being published.

For example, earlier this week Prostate published a paper by Neuhouser et al that tells us that elevated IGF-I is associated with increased risk of Benign Prostate Hyperplasia (BPH).     Another paper published last week did not find an association between genetically elevated IGF-I and breast cancer risk.   Back in May, a paper correlated IGF-I and IGF-I binding protein levels with breast cancer risk factors. In the July issue of Current Opinions in Oncology, Scotlandi argues the IGF-I receptor makes a good target for future chemotherapy drugs to aim at blocking.  

Back in 2002, Sandhu et al reported that varying IGF-1 levels might explain why colon cancer risk varies so much geographically and why it depends so much on diet.    Figuring out a strategy to lower IGF-I through dietary modification has become the new goal in colon cancer prevention.

In May, researchers from MD Anderson reported that mice with lowered IGF-I were far less susceptible to skin cancer than normal mice.  They knew that calorie restriction lowers cancer risk.  They also knew that calorie restriction also lowers IGF-I levels.  In a previous study they found that mice with elevated IGF-I were more susceptible to skin cancer.  In this study they took mice that are born with low IGF-I levels, about 75% below normal, and tried to give them skin cancer following a standard protocol using carcinogenic chemicals.  They report these low IGF-I mice were remarkably resistant to cancer.

IGF-I and the message it signals to the cells appears to turn off the normal apoptotic processes inside skin cells preventing them from self destructing as they become cancerous.   Actually it’s not just colon cancer or skin cancer where IGF-I seems to turn off apoptosis, we see the same sort of research looking at cancer stem cells, prostate cancer cells, kidney cancer and others.

Nothing in these or other papers appears to support of Arjmandi’s assertion.

There is little question that bone cells thrive on IGF-1.  They get stronger and more resistant to fracture when IGF-I levels are high.   Having low IGF-I levels worsen joint problems from osteoarthritis.   One current theory under investigation to explain osteoarthritis is that increased level of binding proteins prevent IGF-I from performing its normal role in stimulating bone formation.   This results in a failure to keep up with bone repair in the joints where wear and tear is more pronounced. 

The bottom line to me is that prunes are good for bones and may be bad for cancer. 

Prunes are very likely to stimulate and increase new bone formation, leading to denser and stronger bones.  Prunes may also stimulate cancer formation, progression and metastasis.  Eating extra prunes might be a very good idea for women with osteopenia, osteoporosis, and both men and women who have recently had a fracture or joint replacement.  At the same time eating lots of prunes may be a bad idea for anyone with cancer or at high risk of getting cancer. 

At least in theory.  I have found no direct evidence that eating prunes increases cancer risk.  Then again, who would have thought to look for an association?  The one paper that makes a stab at this does so from the opposite perspective, asking whether prunes protect against colon cancer.  Given their high polyphenol content and high antioxidant effect [prunes have one of the highest ORAC score of any fruit], it was assumed that prunes would protect against colon cancer.   Researchers from Minnesota fed rats varying amounts of prunes and then dosed the poor things with carcinogens. The prunes did not prevent tissue damage or precancerous lesions from appearing as the researchers had hoped.   Eating the prunes did lower some chemical markers associated with disease development.   I’ve suggested to the lead researcher that the prunes might have had a more pronounced benefit if they were not increasing IGF-I.  He doesn’t see it this way. He also tells me that he is a close friend of Arjmandi’s.

Many of the plant extracts that we utilize in preventing or treating cancer have a pronounced effect on IGF-I.  They either decrease its production or decrease its action by increasing production of binding proteins specific for IGF-I. Resveratrol, soy and tea extracts, curcumin, and quercetin all lower IGF-I.  Milk thistle and lycopene  both increase IGF binding proteins, decreasing IGF action.  

Prunes, it seems, do the opposite. 

Our tendency is always unwittingly to want to see things in black and white, as good or bad.  Biology is rarely that simple.  Trying to judge the value or danger of a food by any single chemical action is asking for confusion.  At this point we must be clear that prunes have not been shown to cause, speed up or in any way change cancer.  All we know is that they increase production of IGF-I in post-menopausal women.  In some situations this might be seen as a good thing, in other situations not so.

BMJ 2000;321:847-848 ( 7 October )

Cancer and insulin-like growth factor-I

http://bmj.bmjjournals.com/cgi/content/full/321/7265/847

Prostate. 2008 Jul 10. [Epub ahead of print]Click here to read

    Insulin-like growth factor-I, insulin-like growth factor binding protein-3 and risk of benign prostate hyperplasia in the prostate cancer prevention trial.

    Neuhouser ML, Schenk J, Song YJ, Tangen CM, Goodman PJ, Pollak M, Penson DF, Thompson IM, Kristal AR.

    Cancer Prevention Program, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.

    BACKGROUND: We investigated whether peptides involved in cellular proliferation and apoptosis, [insulin-like growth factor I (IGFI) and its major binding protein (insulin-like growth factor binding protein 3)], predicted risk of benign prostate hyperplasia (BPH). METHODS: We conducted a nested-case-control study in the placebo arm of the prostate cancer prevention trial (PCPT). Cases (n = 727) were men with surgical or medical treatment for BPH; two or more IPSS scores >14; or two scores of at least five points over baseline one of which was >/=12. Controls (n = 727) were frequency matched by age to cases, reported no BPH treatment, and no IPSS score >8. Cases and controls remained on the PCPT placebo and were followed closely until their 7-year PCPT anniversary. Baseline serum was analyzed for IGFI and IGFBP3. Unconditional logistic regression and polytomous regression estimated the multivariate-adjusted odds ratio (OR) for BPH risk. RESULTS: IGFBP3 was inversely and the IGFI:IGFBP3 ratio was positively associated with BPH risk, but findings were statistically significant only for men with severe symptoms (OR = 0.60, 95% CI = 0.40-0.90 for the fifth vs. first quintile of IGFBP3, P-trend = 0.01). Associations did not differ by age (<65 or >/=65 years), and there was a suggestion that the IGFI:IGFBP3 - BPH risk association may be stronger among overweight men. CONCLUSIONS: A high IGFI:IGFBP3 ratio was associated with increased BPH risk, and high serum IGFBP3 was associated with decreased BPH risk among men with severe symptoms. These results confirm findings from other recent studies. Prostate (c) 2008 Wiley-Liss, Inc.

PLoS ONE. 2008 Jul 2;3(7):e2578.Click here to read Click here to read Links

    IGF-1, IGFBP-1, and IGFBP-3 polymorphisms predict circulating IGF levels but not breast cancer risk: findings from the Breast and Prostate Cancer Cohort Consortium (BPC3).

    Patel AV, Cheng I, Canzian F, Le Marchand L, Thun MJ, Berg CD, Buring J, Calle EE, Chanock S, Clavel-Chapelon F, Cox DG, Dorronsoro M, Dossus L, Haiman CA, Hankinson SE, Henderson BE, Hoover R, Hunter DJ, Kaaks R, Kolonel LN, Kraft P, Linseisen J, Lund E, Manjer J, McCarty C, Peeters PH, Pike MC, Pollak M, Riboli E, Stram DO, Tjonneland A, Travis RC, Trichopoulos D, Tumino R, Yeager M, Ziegler RG, Feigelson HS; Breast and Prostate Cancer Cohort Consortium.

    Department of Epidemiology and Surveillance Research, American Cancer Society, Atlanta, Georgia, United States of America. apatel@cancer.org

    IGF-1 has been shown to promote proliferation of normal epithelial breast cells, and the IGF pathway has also been linked to mammary carcinogenesis in animal models. We comprehensively examined the association between common genetic variation in the IGF1, IGFBP1, and IGFBP3 genes in relation to circulating IGF-I and IGFBP-3 levels and breast cancer risk within the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). This analysis included 6,912 breast cancer cases and 8,891 matched controls (n = 6,410 for circulating IGF-I and 6,275 for circulating IGFBP-3 analyses) comprised primarily of Caucasian women drawn from six large cohorts. Linkage disequilibrium and haplotype patterns were characterized in the regions surrounding IGF1 and the genes coding for two of its binding proteins, IGFBP1 and IGFBP3. In total, thirty haplotype-tagging single nucleotide polymorphisms (htSNP) were selected to provide high coverage of common haplotypes; the haplotype structure was defined across four haplotype blocks for IGF1 and three for IGFBP1 and IGFBP3. Specific IGF1 SNPs individually accounted for up to 5% change in circulating IGF-I levels and individual IGFBP3 SNPs were associated up to 12% change in circulating IGFBP-3 levels, but no associations were observed between these polymorphisms and breast cancer risk. Logistic regression analyses found no associations between breast cancer and any htSNPs or haplotypes in IGF1, IGFBP1, or IGFBP3. No effect modification was observed in analyses stratified by menopausal status, family history of breast cancer, body mass index, or postmenopausal hormone therapy, or for analyses stratified by stage at diagnosis or hormone receptor status. In summary, the impact of genetic variation in IGF1 and IGFBP3 on circulating IGF levels does not appear to substantially influence breast cancer risk substantially among primarily Caucasian postmenopausal women.

Curr Opin Oncol. 2008 Jul;20(4):419-27.Click here to read Links

    Targeting insulin-like growth factor 1 receptor in sarcomas.

    Scotlandi K, Picci P.

    Laboratory of Oncologic Research, Istituti Ortopedici Rizzoli, Bologna, Italy. katia.scotlandi@ior.it

    PURPOSE OF REVIEW: The present review examines the rationale for targeting insulin-like growth factor-I receptor in sarcoma therapy and highlights some key issues that need to be addressed as clinical trials targeting insulin-like growth factor-I receptor proceed. RECENT FINDINGS: Preclinical evidence supports proof of principle for targeting insulin-like growth factor-I receptor signaling in sarcomas. The insulin-like growth factor system is activated by or associated with most of the fusion oncoproteins that genetically characterize a group of sarcomas, but alterations in this pathway appear as a common feature. Correlation of cancer risk with insulin-like growth factor-I receptor signaling expression and polymorphisms has also been described. Blockade of insulin-like growth factor-I receptor functions results in an inhibition of tumor growth and metastasis, both when the targeted drugs were used as single agents and in combined therapies. Antibodies against insulin-like growth factor-I receptor and small kinase inhibitors represent, at this point, the most probable clinical options. SUMMARY: Sarcomas are good candidates for the design of a clinical study targeting insulin-like growth factor-I receptor. An attention to schedule with chemotherapy agents and new drugs, measurement of relevant indicators of response and better molecular understanding of the metabolic functions of insulin-like growth factor-I receptor and its functional relationship with insulin receptor are necessary to proceed safely with the design of anti-insulin-like growth factor strategies.

J Natl Cancer Inst. 2002 Jul 3;94(13):972-80.Click here to read Links

    Insulin, insulin-like growth factor-I (IGF-I), IGF binding proteins, their biologic interactions, and colorectal cancer.

    Sandhu MS, Dunger DB, Giovannucci EL.

    Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, UK. manju.sandhu@srl.cam.ac.uk

    Secular changes and worldwide variations in incidence rates of colorectal cancer, along with results from twin and migrant studies, provide compelling evidence that environmental factors influence the risk of this disease. Among the most important of these factors are diet and associated factors, such as physical activity and body size. Recent data suggest that dietary and related factors may influence colorectal cancer risk via their effects on serum insulin concentrations and on the bioavailability of insulin-like growth factor-I (IGF-I). Epidemiologic studies have shown that IGF-I is positively associated with the risk of colorectal cancer, and experimental studies have shown that IGF-I has mitogenic and antiapoptotic actions on colorectal cancer cells. IGF-I bioactivity is regulated in part by its six binding proteins (IGFBP-1 to IGFBP-6); insulin inhibits the production of IGFBP-1 and perhaps IGFBP-2. As a result, chronically elevated fasting and postprandial insulin levels may lead to a decrease in circulating IGFBP-1 and IGFBP-2 concentrations and, consequently, an increase in IGF-I bioavailability. Insulin may also increase the circulating IGF-I/IGFBP-3 ratio by increasing hepatic growth hormone sensitivity. The increased IGF-I bioavailability may, over time, increase the risk of colorectal cancer. This new evidence for biologic interactions among insulin, IGF-I, and IGFBPs in the context of colorectal carcinogenesis provides a potential mechanism through which diet and associated factors may increase the risk of this cancer.

Asia Pac J Clin Nutr. 2008;17 Suppl 1:257-60.Links

    Inhibition of colon cancer cell growth by dietary components: role of the insulin-like growth factor (IGF) system.

    Park JH.

    Hallym University, Department of Food Sciences and Nutrition, Chuncheon, Korea. jyoon@hallym.ac.kr

    Large bowel cancer is one of the leading causes of deaths from cancer in Western countries, and the incidence of colorectal cancer is increasing with the steady increase in life expectancy. Modification of diet and lifestyle provide measures of reducing the risk of developing colon cancer. Evidence suggests that the components of the insulin-like growth factor (IGF) system may be appropriate targets for cancer prevention and therapy. A positive correlation was found between dietary and lifestyle, plasma IGF-I, and colon cancer incidence rates. Diet, nutrition, and other lifestyle features affect the expression and production of IGF-1 and other members of the IGF family. The purpose of this review is to examine current evidence obtained from our recent studies and others that investigated the role of dietary components in the regulation of the IGF system and colon cancer cell growth.

Cancer Res. 2008 May 15;68(10):3680-8.Click here to read Links

    Reduced susceptibility to two-stage skin carcinogenesis in mice with low circulating insulin-like growth factor I levels.

    Moore T, Carbajal S, Beltran L, Perkins SN, Yakar S, Leroith D, Hursting SD, Digiovanni J.

    The University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas, USA.

    Calorie restriction has been shown to inhibit epithelial carcinogenesis and this method of dietary restriction reduces many circulating proteins, including insulin-like growth factor I (IGF-I). Previously, we identified a relationship between elevated tissue IGF-I levels and enhanced susceptibility to chemically induced skin tumorigenesis. In this study, liver IGF-I-deficient (LID) mice, which have a 75% reduction in serum IGF-I, were subjected to the standard two-stage skin carcinogenesis protocol using 7,12-dimethylbenz(a)anthracene as the initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as the promoter. We observed a significant reduction in epidermal thickness and labeling index in LID mice treated with either vehicle or TPA. A significant decrease in both tumor incidence and tumor multiplicity was observed in LID mice undergoing two-stage skin carcinogenesis relative to wild-type littermates. Western blot analyses of epidermal extracts revealed reduced activation of both the epidermal growth factor and IGF-I receptors in response to TPA treatment in LID mice. In addition, reduced activation of both Akt and the mammalian target of rapamycin (mTOR) was observed in LID mice following TPA treatment relative to wild-type controls. Signaling downstream of mTOR was also reduced. These data suggest a possible mechanism whereby reduced circulating IGF-I leads to attenuated activation of the Akt and mTOR signaling pathways, and thus, diminished epidermal response to tumor promotion, and ultimately, two-stage skin carcinogenesis. The current data also suggest that reduced circulating IGF-I levels which occur as a result of calorie restriction may lead to the inhibition of skin tumorigenesis, at least in part, by a similar mechanism.

J Invest Dermatol. 2008 Jun;128(6):1358-60.Click here to read Links

    Comment on:

        J Invest Dermatol. 2008 Jun;128(6):1499-505.

    Unraveling the mysteries of IGF-1 signaling in melanoma.

    Lee JT, Brafford P, Herlyn M.

    Department of Molecular & Cellular Oncogenesis, The Wistar Institute, Philadelphia, PA 19104, USA.

    The inherent ability of a cell to undergo apoptosis governs a number of developmental processes essential to proper mammalian development. Into adulthood, the pathways that potentiate the apoptotic response are extremely diverse and finely regulated to prevent potential diseases. Of these, cancer is often associated with loss of an apoptotic response. Hanahan and Weinberg (2000) list evasion of apoptosis as a hallmark feature acquired during neoplastic transformation. The impact of this event is dramatic on several levels; avoidance of apoptosis not only prevents programmed cell death in an array of cell types but also promotes chemotherapeutic resistance during anticancer regimens.

Biochem Biophys Res Commun. 2008 Jul 11;371(4):752-5. Epub 2008 May 6.Click here to read Links

    The anti-apoptotic effect of IGF-1 on tissue resident stem cells is mediated via PI3-kinase dependent secreted frizzled related protein 2 (Sfrp2) release.

    Gehmert S, Sadat S, Song YH, Yan Y, Alt E.

    Department of Molecular Pathology, University of Texas M.D. Anderson Cancer Center, SCRB2, Box 951, 7435 Fannin Street, Houston, TX 77030, USA.

    Previous studies suggest that IGF-1 may be used as an adjuvant to stem cell transfer in order to improve cell engraftment in ischemic tissue. In the current study, we investigated the effect of IGF-1 on serum deprivation and hypoxia induced stem cell apoptosis and the possible mechanisms involved. Exposure of adipose tissue derived stem cells (ASCs) to serum deprivation and hypoxia resulted in significant apoptosis in ASC which is partially prevented by IGF-1. IGF-1's anti-apoptotic effect was abolished in ASCs transfected with Sfrp2 siRNA but not by the control siRNA. Using Western blot analysis, we demonstrated that serum deprivation and hypoxia reduced the expression of nuclear beta-catenin, which is reversed by IGF-1. IGF-1's effect on beta-catenin expression was abolished by the presence of PI3-kinase inhibitor LY294002 or in ASCs transfected with Sfrp2 siRNA. These results suggest that IGF-1, through the release of the Sfrp2, contributes to cell survival by stabilizing beta-catenin.

Int J Cancer. 2008 Jun 17. [Epub ahead of print]Click here to read Links

    Systemic IGF-I administration stimulates the in vivo growth of early, but not advanced, renal cell carcinoma.

    Rosendahl AH, Holly JM, Celander M, Forsberg G.

    Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden.

    Insulin-like growth factor I (IGF-I) is a potent mitogen and antiapoptotic factor. Although elevated serum IGF-I levels have been associated with increased cancer risk, it is not yet clear whether IGF-I sensitivity is sustained throughout tumor progression. To evaluate the biological effects of IGF-I during renal cell carcinoma (RCC) establishment and progression, we administered recombinant human IGF-I to severe combined immuno-deficient mice bearing early or more established Caki-2 human RCC tumors. IGF-I significantly enhanced the tumor growth 2.4-fold when administered early after tumor inoculation. This IGF-I-induced growth was accompanied with enhanced tumor cell proliferation, tumor vascularization, as well as increased intratumoral insulin-like growth factor binding protein 3 (IGFBP-3) and pSmad2 levels. In contrast, IGF-I administrated to more established RCC tumors showed no effect on tumor growth, with subsequently much lower Ki-67, IGFBP-3 and pSmad2 levels. Taken together, these data suggest that systemic IGF-I has potent actions during early RCC tumor development with a sustained long-term effect on proliferation and neovascularization although with progression, later tumors appear to become desensitized to systemic IGF-I effects. (c) 2008 Wiley-Liss, Inc.

    PMID: 18561321 [PubMed - as supplied by public

J Biomech. 2008;41(5):1044-52. Epub 2008 Jan 28.Click here to read Links

    Effects of TGF-beta1 and IGF-I on the compressibility, biomechanics, and strain-dependent recovery behavior of single chondrocytes.

    Koay EJ, Ofek G, Athanasiou KA.

    Department of Bioengineering, Rice University, MS-142, PO Box 1892, Houston, TX 77251-1892, USA.

    The responses of articular chondrocytes to physicochemical stimuli are intimately linked to processes that can lead to both degenerative and regenerative processes. Toward understanding this link, we examined the biomechanical behavior of single chondrocytes in response to growth factors (IGF-I and TGF-beta1) and a range of compressive strains. The results indicate that the growth factors alter the biomechanics of the cells in terms of their stiffness coefficient ( approximately two-fold increase over control) and compressibility, as measured by an apparent Poisson's ratio ( approximately two-fold increase over control also). Interestingly, the compressibility decreased significantly with respect to the applied strain. Moreover, we have again detected a critical strain threshold in chondrocytes at approximately 30% strain in all treatments. Overall, these findings demonstrate that cellular biomechanics change in response to both biochemical and biomechanical perturbations. Understanding the underlying biomechanics of chondrocytes in response to such stimuli may be useful in understanding various aspects of cartilage, including the study of osteoarthritis and the development of tissue-engineering strategies.

Arthritis Rheum. 2006 Dec;54(12):3850-8.Click here to read Links

    Effects of chronic growth hormone and insulin-like growth factor 1 deficiency on osteoarthritis severity in rat knee joints.

    Ekenstedt KJ, Sonntag WE, Loeser RF, Lindgren BR, Carlson CS.

    Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN 55108, USA. eken0003@umn.edu

    OBJECTIVE: To determine the effects of chronic deficiency of growth hormone (GH) and insulin-like growth factor 1 (IGF-1) on osteoarthritis (OA) severity. METHODS: Thirty-five rats were divided into 4 treatment groups at 4 weeks of age: 1 control group (normal GH/IGF-1 levels [heterozygous]) and 3 groups of dwarves with a genetic mutation that results in GH deficiency. The first dwarf group received GH for 64 weeks (GH replete) and the second received GH until 14 weeks of age, followed by saline for 50 weeks (adult-onset GH/IGF-1 deficiency [AO-GHD]). The third dwarf group received saline injections only (lifetime GH deficient [GHD]). Sections of the medial knee joint compartment were graded and measured histologically; data were summarized using factor analysis, and treatment effects were assessed using analysis of variance and adjusting for body weight. RESULTS: Terminal IGF-1 levels and body weights were significantly affected by treatment (P = 0.002 and P < 0.001, respectively). Factor analysis yielded a total of 5 factors, the first 3 of which were not significantly affected by treatment. Factor 4 (weighted by medial tibial plateau articular cartilage width and area) was significantly affected by treatment (P < 0.012), with larger values in the AO-GHD group than in the GHD group (P < 0.05). Factor 5 (weighted primarily by articular cartilage structure and loss of toluidine blue staining scores) also was significantly affected by treatment (P < 0.001), and was significantly lower (less severe lesions) in the GH replete group than in all other treatment groups (P < 0.05). Despite the presence of cartilage lesions, osteophytes and subchondral sclerosis were not observed in GH/IGF-1-deficient animals. CONCLUSION: These results indicate that chronic GH/IGF-1 deficiency causes an increased severity of articular cartilage lesions of OA without the bony lesions normally seen in this disease.

  Orthop Res. 2008 Apr;26(4):465-74.Click here to read Links

    The quantitative and functional relation between insulin-like growth factor-I (IGF) and IGF-binding proteins during human osteoarthritis.

    Morales TI.

    Harvard Medical School and Massachusetts General Hospital, Orthopaedics, Jackson 1223, 55 Fruit Street, Boston, Massachusetts 02114, USA. tmorales@partners.org

    A previous hypothesis stated that during osteoarthritis (OA) increased insulin-like growth factor (IGF) binding proteins (IGFBPs) sequester IGFs and limit their access to the cell. The objective of this article was to test this by: (1) quantifying IGF and IGFBP-3 as well as their ratios in human OA cartilages, and (2) measuring the metabolic responses of diseased cartilage to IGF-I and its IGFBP-insensitive analogs. Knee or hip OA cartilages were staged for OA by histology. Cartilage slices were either extracted for assays of IGF proteins, or maintained intact as organ cultures. Proteoglycan (PG) metabolism +/- IGFs was measured by use of the (35)S-sulfate precursor. IGFBP-3 (ng/mg protein) was weakly correlated with OA score by regression analysis (R(2) = 0.122; p = 0.040; n = 35). IGF-I (ng/mg protein) was constant across all OA groups (ANOVA; p = .428, n = 18) and the IGF-I/IGFBP-3 ratios were > 1 in most samples. All OA cartilages responded to hrIGF-I by increasing PG synthesis [average 2.29-fold +/- 0.55 (+/-SD) at saturation, n = 12] irrespective of OA score. The des (1-3) IGF-I analog (which lacks the three N-terminal amino acids) had similar maximal effects (average 2.23-fold stimulation +/- 0.71, n = 10), but it was more effective in two out of three samples at suboptimal doses. The effect of hrIGF-I, des (1-3) IGF-I, or the B-chain analog on degradation was minimal. In summary, catabolism was insensitive to IGF-I, and this was probably not due to IGFBPs. By contrast, IGF-I exerted a robust stimulation of anabolism at sufficiently high doses, even though IGFBPs could tone down the ligand effect at low doses. (c) 2007 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Nutr Cancer. 2005;53(1):117-25.Links

    Effect of dried plums on colon cancer risk factors in rats.

    Yang Y, Gallaher DD.

    Department of Food Science and Nutrition, University of Minnesota, St. Paul 55108, USA.

    Dried plums (that is, prunes) are a fruit that show promise as a food to lower colon cancer risk, based on their high content of dietary fiber and polyphenolics. In this study, we have examined the effect of diets containing dried plums on the number of colonic precancerous lesions (aberrant crypts, ACs), fecal bile acid concentration, and cecal bacterial enzyme activities related to colon cancer risk. Rats were fed one of four diets: a basal diet (a modified AIN-93G diet), a low-concentration dried plum diet (LCDP, 4.75% dried plum powder), a high-concentration dried plum diet (HCDP, 9.5% dried plum powder), or a diet matched to the carbohydrate content of the HCDP diet (CH-M) for 10 days. All animals were then administered azoxymethane (15 mg/kg, s.c., given two times, 1 wk apart) and fed their respective diets for 9 additional weeks. The number of AC foci (ACF), large ACF (>3 AC/ACF), or ACF multiplicity (AC/ACF) did not differ among the four groups. When compared with the basal diet, rats fed the LCDP diet had significantly lower concentrations of total fecal bile acids, deoxycholic acid, and hyodeoxycholic acid. Rats fed the HCDP diet had significantly lower fecal concentrations of lithocholic acid and hyodeoxycholic acid. The LCDP and HCDP diets significantly decreased the cecal activity of 7alpha-dehydroxylase, and the LCDP also had lower beta-glucuronidase activity. The LCDP, HCDP, and CH-M groups had significantly greater cecal nitroreductase activities than the basal group. There was a significant correlation between 7alpha-dehydroxylase activity and fecal lithocholic acid concentration. Compared with the basal diet, both the LCDP and HCDP diets greatly increased cecal supernatant oxygen radical absorbance capacity (ORAC). These results suggest that, although dried plums did not reduce ACF number, they favorably altered other colon cancer risk factors.

Private communications, July 2008

Mol Nutr Food Res. 2008 Jun;52(6):683-91.Click here to read Links

    Resveratrol inhibits migration and invasion of human breast-cancer cells.

    Tang FY, Su YC, Chen NC, Hsieh HS, Chen KS.

    Biomedical Science Laboratory, Department of Nutrition, China Medical University, Taichung, Taiwan. vincenttang@mail.cmu.edu.tw

    Metastasis is the primary cause of death from breast cancer. Cell migration and invasion play important roles in neoplastic metastasis. The insulin-like growth factor (IGF-1) stimulates cell migration through activation of PI-3K/Akt signaling pathway. IGF-1 induces the tumorigenicity of many types of cancer cells and is critical for metastatic cell spread in estrogen receptor (ER)-negative breast-cancer cells. Matrix metalloproteinase-2 (MMP-2) is a key enzyme in the degradation of extracellular matrices and its expression has been dysregulated in breast cancer invasion and metastasis. Resveratrol exhibited potential anticarcinogenic activities in several studies. However, the inhibitory effects of resveratrol on the expression of MMP-2, migration and invasion of breast-cancer cell have not been demonstrated yet. In the present study, we investigated the anti-invasive mechanism of resveratrol in human breast cancer MDA-MB 435cells. Here, we showed that IGF-1 is a potent stimulant of the migration of ER-negative human breast-cancer cells. Resveratrol could inhibit IGF-1-mediated cell migration of MDA-MB 435 in vitro. The inhibitory effect of resveratrol was mediated in part through the suppression of the activation of PI-3K/Akt signaling pathway. Furthermore, IGF-1-mediated expression of MMP-2 was significantly inhibited by resveratrol in concomitance with alteration of cell invasion.

Am J Clin Nutr. 2007 Sep;86(3):s882-8.Click here to read Links

    Dietary soy and tea combinations for prevention of breast and prostate cancers by targeting metabolic syndrome elements in mice.

    Zhou JR, Li L, Pan W.

    Nutrition and Metabolism Laboratory, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. jrzhou@bidmc.harvard.edu

    BACKGROUND: The prevalence of metabolic syndrome is high and is increasing in parallel with increasing incidences of breast and prostate cancers. The combination of soy with tea was shown to have synergistic effects on preventing breast and prostate tumors, but the effects of soy and tea combinations on metabolic syndrome-related elements have not been investigated. OBJECTIVE: We aimed to determine the effects of soy and tea components, alone and in combination, on abdominal adipose mass and serum concentrations of adipokines, growth factors, and sex hormones in male and female mice. DESIGN: Male and female FVB/N mice were treated with soy, tea components, or both. Food intake and body weight were monitored weekly. At the end of the experiment, abdominal white adipose tissue was weighed, and serum concentrations of biomarkers were measured. RESULTS: Whole teas, but not the tea polyphenol extracts, significantly reduced abdominal white adipose tissue by 43-60% in female mice and by 65-70% in male mice. The combination of soy phytochemical concentrate and green tea reduced serum insulin-like growth factor-I concentrations in both male and female mice in a synergistic manner. The soy phytochemical concentrate and tea combinations reduced serum estrogen concentrations in female mice in a synergistic manner. Soy phytochemical concentrate and teas also significantly reduced serum leptin concentrations in both male and female mice and testosterone concentrations in male mice. CONCLUSION: Further research is warranted to investigate whether soy and tea combinations may prevent breast or prostate cancer in a synergistic manner in part by alleviating metabolic disorders.

Life Sci. 2007 May 16;80(23):2161-9. Epub 2007 Apr 21.Click here to read Links

    The potentiation of curcumin on insulin-like growth factor-1 action in MCF-7 human breast carcinoma cells.

    Xia Y, Jin L, Zhang B, Xue H, Li Q, Xu Y.

    Department of Bioscience and Biotechnology, School of Environmental and Biological Science and Technology, Dalian University of Technology, Dalian, 116024, People's Republic of China.

    Curcumin has anticarcinogenic and chemopreventive properties in a variety of experimental cancer models. Our in vitro studies have shown that curcumin inhibits cell growth and induces apoptosis in MCF-7, a human breast carcinoma cell line. The insulin-like growth factor-1 (IGF-1) system, including IGFs (IGF-1 and IGF-2), IGF-1R (IGF-1 receptor) and IGFBPs (IGF binding proteins), has been implicated to play a critical role in the development of breast cancer. The aim of the present study was to investigate whether the growth inhibitory effects of curcumin were related to changes of the IGF-1 system in MCF-7 cells. IGF-1 at 50 microg/l in serum-free medium produced maximum proliferation and minimized apoptosis. However, curcumin exhibited a potent ability to blunt IGF-1-stimulated MCF-7 cell growth and reverse the IGF-1-induced apoptosis resistance. To determine whether curcumin intervenes in IGF-1 or IGFBP-3 secretion, MCF-7 cells were incubated in serum-free medium in the presence of various concentrations of curcumin for indicated time periods. Curcumin decreased the secretion of IGF-1 with a concomitant increase of IGFBP-3 in a dose-dependent manner. Receptor tyrosine kinase assays revealed that IGF-1-stimulated IGF-1R tyrosine kinase activation was also abrogated by curcumin in a dose-dependent manner. Real-time fluorescence quantitative reverse transcriptase-polymerase chain reaction (RFQ-RT-PCR) further revealed that curcumin suppressed IGF-1R gene expression at transcriptional level. In conclusion, the inhibition of cell growth and induction of apoptosis by curcumin in MCF-7 cells might be mediated, at least partially, by its ability to down-regulate the IGF-1 axis

J Cell Physiol. 2007 Sep;212(3):666-74.Click here to read Links

    IGF-I plus E2 induces proliferation via activation of ROS-dependent ERKs and JNKs in human breast carcinoma cells.

    Lin CW, Yang LY, Shen SC, Chen YC.

    Graduate Institute of Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan.

    Induction of 17beta-estradiol (E2) and insulin-like growth factor-I (IGF-I) has been detected in breast carcinoma, however the interaction between E2 and IGF-I in the proliferation of breast carcinoma cells is still unclear. In the present study, we found that IGF-I enhances the E2-induced proliferation in MCF-7 human breast carcinoma cells in accordance with stimulation of colony formation via a soft agar assay. Activation of insulin receptor substrate-1 (IRS-1) protein and extracellular signal-related kinases (ERKs) and c-Jun N-terminal kinases (JNKs), but not p38 mitogen-activated protein kinase (MAPK), via phosphorylation induction was detected in MCF-7 cells treated with IGF-I plus E2 (E2/IGF-I). E2/IGF-I-induced proliferation was blocked by chemical inhibitors of ERKs (PD98059) and JNKs (SP600125). An increase in the expression of c-Jun protein was detected in E2/IGF-I-treated MCF-7 cells, and this was inhibited by PD98059 and SP600125. Transfection of the dominant negative MEKK and JNK plasmids significantly reduced E2/IGF-I-induced proliferation with suppression of c-Jun protein expression. An increase in peroxide production was detected in E2/IGF-I-treated cells, and N-acetyl-L-cysteine (NAC) and Tiron (TIR) addition significantly inhibited E2/IGF-I-induced cell proliferation with blocking of the phosphorylation of ERKs and JNKs, and the expression of c-Jun protein. Additionally, 3-OH flavone, baicalein, and quercetin showed effective inhibitory activities against E2/IGF-I-induced proliferation through suppressing proliferative events such as phosphorylation of IRS-1, ERKs, and JNKs proteins, and induction of c-Jun protein and colony formation. These results indicate that IGF-I interacts with E2 to promote the proliferation of breast carcinoma cells via ROS-dependent MAPK activation and c-Jun protein expression. The structure-related inhibition of E2/IGF-I-induced proliferative events by flavonoids is elucidated.

Cancer Res. 2000 Oct 15;60(20):5617-20.Click here to read Links

    Silibinin up-regulates insulin-like growth factor-binding protein 3 expression and inhibits proliferation of androgen-independent prostate cancer cells.

    Zi X, Zhang J, Agarwal R, Pollak M.

    Lady Davis Research Institute of Jewish General Hospital and Department of Oncology, McGill University, Montreal, Quebec, Canada.

    Silibinin, a naturally occurring flavonoid antioxidant found in the milk thistle, has recently been shown to have potent antiproliferative effects against various malignant cell lines, but the underlying mechanism of action remains to be elucidated. We investigated the effect of silibinin on androgen-independent prostate cancer PC-3 cells. At pharmacologically achievable silibinin concentrations (0.02-20 microM), we observed increased insulin-like growth factor-binding protein 3 (IGFBP-3) accumulation in PC-3 cell conditioned medium and a dose-dependent increase of IGFBP-3 mRNA abundance with a 9-fold increase over baseline at 20 microM silibinin. An IGFBP-3 antisense oligodeoxynucleotide that attenuated silibinin-induced IGFBP-3 gene expression and protein accumulation reduced the antiproliferative action of silibinin. We also observed that silibinin reduced insulin receptor substrate 1 tyrosine phosphorylation, indicating an inhibitory effect on the insulin-like growth factor I receptor-mediated signaling pathway. These results suggest a novel mechanism by which silibinin acts as an antiproliferative agent and justify further work to investigate potential use of this compound or its derivatives in prostate cancer treatment and prevention.

Am J Clin Nutr. 2007 Nov;86(5):1456-62.Click here to read Links

    Lycopene supplementation elevates circulating insulin-like growth factor binding protein-1 and -2 concentrations in persons at greater risk of colorectal cancer.

    Vrieling A, Voskuil DW, Bonfrer JM, Korse CM, van Doorn J, Cats A, Depla AC, Timmer R, Witteman BJ, van Leeuwen FE, Van't Veer LJ, Rookus MA, Kampman E.

    Division of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam, Netherlands.

    BACKGROUND: Higher circulating insulin-like growth factor I (IGF-I) concentrations have been related to a greater risk of cancer. Lycopene intake is inversely associated with cancer risk, and experimental studies have shown that it may affect the IGF system, possibly through an effect on IGF-binding proteins (IGFBPs). OBJECTIVE: The objective of our study was to investigate the effect of an 8-wk supplementation with tomato-derived lycopene (30 mg/d) on serum concentrations of total IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3. DESIGN: We conducted a randomized, placebo-controlled, double-blinded crossover study in 40 men and 31 postmenopausal women with a family history of colorectal cancer, a personal history of colorectal adenoma, or both. RESULTS: Lycopene supplementation significantly (P = 0.01) increased serum IGFBP-1 concentrations in women (median relative difference between serum IGFBP-1 concentrations after lycopene supplementation and after placebo, 21.7%). Serum IGFBP-2 concentrations were higher in both men and women after lycopene supplementation than after placebo, but to a lesser extent (mean relative difference 8.2%; 95% CI: 0.7%, 15.6% in men and 7.8%; 95% CI: -5.0%, 20.6% in women). Total IGF-I, IGF-II, and IGFBP-3 concentrations were not significantly altered by lycopene supplementation. CONCLUSIONS: This is the first study known to show that lycopene supplementation may increase circulating IGFBP-1 and IGFBP-2 concentrations. Because of high interindividual variations in IGFBP-1 and IGFBP-2 effects, these results should be confirmed in larger randomized intervention studies.