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SG - Molecular Cancer Research

by Sandra Goodman PhD(more info)

listed in seminars, originally published in issue 160 - July 2009

Molecular Cancer Research



HUANG and COLLEAGUES, Women's Hospital, School of Medicine, Zhejiang University, P.R. China study the association between carotenoids and breast cancer risk

BACKGROUND: 
There has been considerable interest in the role of carotenoids in the chemoprevention of cancer. However, the protective effect of carotenoids on breast cancer has been inconclusive.

METHODOLOGY:
To investigate whether intake of lycopene, alpha-carotene, beta-carotene, beta-cryptoxanthin, and lutein/zeaxanthin is inversely associated with breast cancer risk, a case-control study was conducted in China during 2004-2005.

The cases were 122 female patients aged 24-87 years with histopathologically confirmed breast cancer. 632 healthy women age-matched were randomly recruited from outpatient clinics. Habitual dietary intake and lifestyle were collected by face-to-face interview using a validated and reliable food frequency questionnaire. The USDA nutrient composition database was used to calculate intake of the specific carotenoids. Unconditional logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs), accounting for age, locality, education, body mass index, smoking, passive smoking, physical activity, number of children breastfed, menopausal status, oral contraceptive use, biopsy-confirmed benign breast diseases, family history of breast cancer, and total energy intake.

RESULTS:
Compared with the highest versus lowest quartile of intake, the adjusted ORs were 0.26 (95% CI 0.14-0.46) for lycopene, 0.38 (95% CI 0.21-0.71) for beta-carotene, 0.43 (95% CI 0.23-0.82) for beta-cryptoxanthin, and 0.37 (95% CI 0.20-0.68) for total carotenoids, with statistically significant tests for trend. There was no association with breast cancer for alpha-carotene and lutein/zeaxanthin.

CONCLUSIONS:
It is concluded that higher intake of lycopene, beta-carotene and beta-cryptoxanthin is associated to a lower risk of breast cancer among Chinese women. More research to examine the relationship between carotenoids and breast cancer risk is warranted.

Huang JP, Zhang M,  Holman CD and  Xie X. Dietary carotenoids and risk of breast cancer in Chinese women. Asia Pacific Journal of Clinical Nutrition 16 Suppl 1: 437-42. 2007.

 
CRISPEN and COLLEAGUES, Fox Chase Cancer Center, Philadelphia, PA 19111, USA studied the interaction with and modulation of Vitamin E succinate upon transcriptional factors involved in the development and progression of prostate cancer.

BACKGROUND:
NF-kappaB and AP-1 transcriptional factors contribute to the development and progression of prostate malignancy by regulating the expression of genes involved in proliferation, apoptosis, angiogenesis, and metastasis.

METHODS:
NF-kappaB and AP-1 activities were examined by TransAm assay. Cytokines levels were assessed by ELISA. ICAM-1 and gp130 expression was examined by flow cytometry. Cell adhesion was examined by the ability of cells to adhere to fibronectin-coated plates. Cell viability was determined by propidium iodide staining.

RESULTS:
Treatment with alpha-tocopherol succinate (VES) inhibits NF-kappaB but augments AP-1 activity, reduces expression of IL-6, IL-8, and VEGF, suppresses cell adhesion, ICAM-1 and gp130 expression in androgen-independent PC-3, DU-145, and CA-HPV-10 cells. VES supplementation also decreases the expression of anti-apoptotic XIAP and Bcl-X(L) proteins and sensitizes androgen-dependent LNCaP cells to androgen deprivation.

CONCLUSIONS:
Our findings propose a potential mechanism of VES-mediated anti-tumour activity and support the role of vitamin E analogs as potential chemopreventative agents against prostate cancer.
Crispen PL, Uzzo RG,  Golovine K,  Makhov P,  Pollack A,  Horwitz EM, Greenberg RE, Kolenko VM. Vitamin E succinate inhibits NF-kappaB and prevents the development of a metastatic phenotype in prostate cancer cells: implications for chemoprevention. Prostate.  67(6):582-90, May 1 2007.

Comment:
The above studies shows how Vitamin E succinate interacts in different ways with the complex array of genes involved in the development and progression of prostate cancer – genes involved in proliferation, apoptosis, angiogenesia and metastasis.


LIU and COLLEAGUES,  Department of Structural & Cellular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA researched at the molecular level, the inhibition of prostate cancer by selenium.

BACKGROUND:
A previous prevention trial showed that selenium supplementation was effective in reducing (by 50%) the incidence of prostate cancer.

METHODOLOGY:
Selenium has been reported to inhibit the growth of prostate cancer cells in vitro. Multiple mechanisms are likely to be operative in the underlying effect of selenium.

RESULTS:
The authors report that Kruppel-like factor 4 (KLF4), a transcription factor of the KLF family, is an important target of selenium. We found that selenium up-regulates KLF4 expression and increases the DNA-binding activity of KLF4 in both the androgen-dependent LNCaP and the androgen-independent PC-3 human prostate cancer cells.

The increase of KLF4 mRNA is accounted for primarily by enhanced transcription, although the contribution of a slight abatement in mRNA degradation cannot be ruled out. KLF4 knockdown using short interference RNA significantly weakens the effects of selenium on DNA synthesis inhibition, apoptosis induction, and the expression of three KLF4 target genes, cyclin D1, p21/WAF1, and p27/Kip1. In addition, the overexpression of KLF4 not only leads to an induction of apoptosis in the control cells, but also enhances the DNA synthesis-suppressive and-proapoptotic activities of selenium.

CONCLUSIONS:
Taken together, the authors’ results suggest that KLF4 plays a key role in mediating the growth-inhibitory effect of selenium in prostate cancer cells.

Liu S, Zhang H,  Zhu L,  Zhao L and  Dong Y. Kruppel-like factor 4 is a novel mediator of selenium in growth inhibition.  Molecular Cancer Research: MCR  6(2): 306-13, Feb 2008.


KIM and COLLEAGUES,  Department of Oncologic Pathology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa, Japan investigated the anti-tumour properties of ginger for colon and lung cancer

BACKGROUND:
Zerumbone (ZER), present in subtropical ginger Zingiber zerumbet Smith, possesses anti-growth and anti-inflammatory properties in several human cancer cell lines. ZER also down-regulates the cyclooxygenase-2 and inducible nitric oxide synthase expression via modulation of nuclear factor (NF)-kappaB activation in cell culture systems. These findings led the authors to investigate whether ZER is able to inhibit carcinogenesis in the colon and lung, using 2 different preclinical mouse models.

METHODOLOGY:
In Experiment 1, 85 male ICR mice were initiated using a single intraperitoneal (i.p.) injection with azoxymethane (AOM, 10 mg/kg bw) and promoted by 1.5% dextran sulfate sodium (DSS) in drinking water for 7 days for rapid induction of colonic neoplasms. Animals were then fed the diet containing 100, 250 or 500 ppm ZER for 17 weeks. In Exp. 2, a total of 50 female A/J mice were given a single i.p. injection of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (10 micromol/mouse) to induce lung proliferative lesions.

They were then fed the diet mixed with 100, 250 or 500 ppm ZER for 21 weeks. At the termination of the experiments (wk 20 of Exp. 1 and wk 22 of Exp. 2), all animals were subjected to complete necropsy examination to determine the pathological lesions in both tissues.

RESULTS:
Oral administration of ZER at 100, 250 and 500 ppm significantly inhibited the multiplicity of colonic adenocarcinomas. The treatment also suppressed colonic inflammation.

In the lung carcinogenesis, ZER feeding at 250 and 500 ppm significantly inhibited the multiplicity of lung adenomas in a dose-dependent manner. Feeding with ZER resulted in inhibition of proliferation, induction of apoptosis, and suppression of NFkappaB and heme oxygenase (HO)-1 expression in tumours developed in both tissues.

CONCLUSIONS:
Our findings suggest that dietary administration of ZER effectively suppresses mouse colon and lung carcinogenesis through multiple modulatory mechanisms of growth, apoptosis, inflammation and expression of NFkappaB and HO-1 that are involved in carcinogenesis in the colon and lung.

Kim M,  Miyamoto S, Yasui Y, Oyama T,  Murakami A and  Tanaka T. Zerumbone, a tropical ginger sesquiterpene, inhibits colon and lung carcinogenesis in mice. International Journal of Cancer. 124(2):264-71. Jan 15 2009.


HUANG and COLLEAGUES,  Department of Food Science and Biotechnology, National Chung-Hsing University, Taichung 40227, Taiwan studied the inhibition of tumour metastasis by lycopene at the molecular level.

Lycopene has been shown to inhibit tumour metastasis in vitro, but it is unclear whether lycopene is antimetastatic in vivo.

METHODOLOGY:
Nude mice were orally supplemented 2 times per week for 12 wk with a low or high dose of lycopene [1 or 20 mg/kg body weight (BW)] or with beta-carotene (20 mg/kg BW). Two weeks after the beginning of supplementation, mice were injected once with human hepatoma SK-Hep-1 cells via the tail vein. Plasma levels of matrix metalloproteinase (MMP)-2 and vascular endothelial growth factor (VEGF) increased gradually in tumour-injected mice (tumour controls) following tumour injection, but were markedly lowered by lycopene or beta-carotene supplementation.

RESULTS:
Ten weeks after tumour injection, mice were killed and tumour metastasis was found to be confined to the lungs. Compared with the tumour controls, high-lycopene supplementation lowered the mean number of tumours from 14 +/- 8 to 3 +/- 5 (P < 0.05) and decreased tumour cross-sectional areas by 62% (P < 0.05).

High-lycopene supplementation also decreased the positive rate of proliferating cellular nuclear antigen (PCNA), the level of VEGF, and protein expressions of PCNA, MMP-9, and VEGF in lung tissues. However, high-lycopene increased the protein expression of nm23-H1 (an antimetastatic gene) by 133% (P < 0.001). For most variables measured, effects of lycopene were dose dependent and the effect of beta-carotene was between those of high-dose and low-dose lycopene.

These results show that lycopene supplementation reduces experimental tumour metastasis in vivo and suggest that such an action is associated with attenuation of tumour invasion, proliferation, and angiogenesis.

Huang CS,  Liao JW and  Hu ML.   Lycopene inhibits experimental metastasis of human hepatoma SK-Hep-1 cells in athymic nude mice.[see comment]. Journal of Nutrition.  138(3):538-43. Mar 2008.  Comment in: J Nutr. 138(11): 2289. Nov 2008; author reply 2290; PMID: 18936233.


Zeng H and  Combs GF Jr,   United States Department of Agriculture, Agricultural Research Service, Grand Forks Human Nutrition Research Center, P. O. Box 9034, Grand Forks, ND 58202-9034, USA. hzeng@gfhnrc.ars.usda.gov <hzeng@gfhnrc.ars.usda.gov> [Review] [77 References] current knowledge regarding selenium and its anticancer effects.

Background: 
Selenium is an essential dietary component for animals including humans, and there is increasing evidence for the efficacy of certain forms of selenium as cancer-chemopreventive compounds.

Results:
Selenium appears to have a protective effect at various stages of carcinogenesis including both the early and later stages of cancer progression. Mechanisms for selenium-anticancer action are not fully understood; however, several have been proposed: antioxidant protection, enhanced carcinogen detoxification, enhanced immune surveillance, modulation of cell proliferation (cell cycle and apoptosis), inhibition of tumour cell invasion and inhibition of angiogenesis. Research has shown that the effectiveness of selenium compounds as chemopreventive agents in vivo correlates with their abilities to affect the regulation of the cell cycle, to stimulate apoptosis and to inhibit tumour cell migration and invasion in vitro.

Conclusions:
This article reviews the status of knowledge concerning selenium metabolism and its anticancer effects with particular reference to the modulation of cell proliferation and the inhibition of tumour cell invasion. [References: 77]

Zeng H and  Combs GF Jr. Selenium as an anticancer nutrient: roles in cell proliferation and tumour cell invasion.  Journal of Nutritional Biochemistry.  19(1):1-7, Jan 2008.

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About Sandra Goodman PhD

Sandra Goodman PhD, Co-founder and Editor of Positive Health, trained as a Molecular Biology scientist in Agricultural Biotechnology in Canada and the US. She has focused upon health issues since the 1980s in the UK. Author of 4 books, including Nutrition and Cancer: State-of-the-Art, Vitamin C – The Master Nutrient, Germanium: The Health and Life Enhancer and numerous articles, Dr Goodman was the lead author of the Consensus Document Nutritional and LifeStyle Guidelines for People with Cancer and compiled the Cancer and Nutrition Database for the Bristol Cancer Help Centre in 1993.

 

In publishing in Positive Health PH Online authoritative articles and book reviews by leading proponents of numerous alternative cancer treatment approaches, Dr Goodman has demonstrated her passion about the necessity of making available to all people, particularly those with cancer, considerable clinical expertise in areas of Nutrition and Complementary Therapies. She is a member of the Therapy Advisory Panel of the Penny Brohn Cancer Care, Scientific Expert Committee member of the Alliance for Natural Health and a Patron of the Avalon Complementary Medicine Trust in Wells, Somerset. Nutrition and Cancer.

 

Dr Goodman and Mike Howell, her long-term partner, seek individuals with the resources, structural organization and interest to continue and expand the legacy of Positive Health PH Online forward into the 21st century, adding facilities to conduct online seminars, fund raise for alternative cancer research, as well as to promote leading holistic organizations and businesses internationally. Follow her Blog and purchase Nutrition and Cancer: State-of-the-Art.  Dr S Goodman may be contacted privately for Research, Lectures and Editorial services via: sandra@drsgoodman.com     www.drsgoodman.com  sandra@positivehealth.com   and www.positivehealth.com

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