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Chemotherapy, Radiation and Protective Herbs & Nutrients in Oral Cancer

Natural Strategies in Collaborative Cancer Care

Compiled by John Connor, M.Ac.,  L.Ac.,

May 20, 2010

Table of Contents

·        Introduction

·        Some Basic Strategies In Cancer Prevention And Treatment

·        Nourishing And Cancer Preventive Protocol In Oral Cancer

·        Natural Compounds That Inhibit VEGF

·        Natural Compounds That Normalize p53

·        Natural Compounds That Reduce Bcl-2

·        Understanding Cachexia

·        Useful Nutrients And Botanicals During Radiation Of Oral Cancer

·        Tests Too Perform To Determine If The Cancer Cells Will Be Sensitive To Radiation Therapy

·        Understanding Transcription Factors

·        What Is Hypoxia-Inducible Factor (HIF)-1?

·        What Is Carbonic Anhydrase (CA-9)?

·        Compounds That Target HIF-1alpha In Cancer

·        Studies Referenced On Pub-Med Related To This Article

·        References

Introduction

Although progress has been made in reducing incidence and mortality rates and improving survival, cancer still accounts for more deaths than heart disease in persons younger than 85 years of age.  Further progress can be accelerated by applying existing cancer control knowledge across all segments of the population and by supporting new discoveries in cancer prevention, early detection and treatment. (Jemal et al 2009) 

Some basic strategies in cancer prevention and treatment

1.      To build, nourish and enhance the vitality of the person.

One of the first things one needs to be aware of in the prevention and treatment of cancer is to insure that the person has adequate nutrition by focusing on building, nourishing and enhancing the vitality through a balanced diet composed of fresh organic vegetables, fruits, whole grains, fish, eggs, olive oil etc; and by avoiding all refined sugars, flours, trans-fatty acids, processed foods, etc.  For example, Advanced Glycation End products (AGEs) are highly damaging reactive molecules created from prolonged levels of glucose reacting with proteins. AGEs activate TNF-alpha which leads to inflammation and is a mediator associated with cachexia (loss of weight and muscle mass).

2.      To reduce genetic instability by reducing oxidative stress. With aging, the risks of many common forms of cancer increase as the amount of oxidative stress in cells increases (Wallace, 2005)  Oxidative stress is particularly prevalent in cancer, where many malignant cell types possess an abnormal redox metabolism involving down-regulation of antioxidant enzymes and impaired mitochondria.

3.        To inhibit abnormal expression of genes by normalizing the activity of transcription factors such as: NF-kappaB, AP-1 and STAT families as well as the steroid receptors. A very important transcription factor is p53.  It is known as the “Guardian of the Genome”. Certain natural compounds can be used to normalize p53 in order to help prevent and treat cancer.  Other natural compounds can be used to downregulate Bcl-2 which is an NF-kappaB regulated gene. Bcl-2 as well as VEGF-R are tumor-specific biomarkers in Head and Neck cancer. (Tsao et al 2004)

4.        To inhibit abnormal signal transduction by blocking the actions of kinase enzymes. Tyrosine-specific protein kinases phosphorylate tyrosine amino acid residues, and like serine/threonine-specific kinases are used in signal transduction. They act primarily as growth factor receptors and in downstream signaling from growth factors; some examples: Platelet-derived growth factor receptor (PDGFR) ;Epidermal growth factor receptor (EGFR); Insulin receptor and insulin-like growth factor 1 receptor (IGF1R); Stem cell factor (SCF) receptor (also called c-kit).

5.        To inhibit abnormal signal transduction by blocking the actions of ras proteins.  Mutations in the Ras family of proto-oncogenes (comprising H-Ras, N-Ras and K-Ras) are very common, being found in 20% to 30% of all human tumours.

6.        To encourage normal cell-to-cell communication by improving gap junction communication and by normalizing CAM activity. Cell Adhesion Molecules (CAMs) are proteins located on the cell surface involved with the binding with other cells or with the extracellular matrix (ECM) in the process called cell adhesion.

7.      To inhibit tumor angiogenesis. VEGF (Vascular Endothelial Growth Factor) has been demonstrated to be a major contributor to angiogenesis, increasing the number of capillaries in a given network.  As noted above VEGF-R is a tumor-specific biomarker in Head and Neck cancer

8.      To inhibit invasion and metastasis by inhibiting enzymes that digest local tissues and by reducing the ability of tumor cells to migrate.   Metastasis has long been known as cancer's true killer, but it hasn't been well understood. Now that researchers are teasing apart the steps in the metastatic cascade, they are trying to arrest the process by taking a range of new vascular biology approaches, including targeting a tumor's blood vessels, its communications system, and its lymph system. Other research is looking at the tumor's microenvironment, certain transcription factors, chemokines, and signaling pathways.  Patients don't usually die from their primary tumor; 90% of patients with solid tumors die from metastases, according to Joan Massagué, Ph.D., chairman of cancer biology and genetics at New York's Memorial Sloan-Kettering Cancer Center. (Brower 2007)

9.      To increase the immune response.  Cancer patients usually exhibit immuno-suppression and are at high risk of infection. Eating foods that improve immune functions, improves the prognosis of cancer patients significantly. The combination of acupuncture, stress reduction, proper diet and specific herbs is very helpful in strengthening the immune response.

10.  To reduce inflammation.  Inflammation has been linked to various steps in tumorigenesis. Serum IL-6 concentration has been shown to be associated with head and neck squamous cell carcinoma progression. (Mojtahedi et al 2010)  Some pro-inflammatory pathways that can be targeted include: IL-6, TNF-alpha, COX-2, LOX-5 and NF-kappaB.

When natural compounds such as herbs and nutrients are used in these strategies some of them will directly inhibit cancer cells causing them to die, revert to normalcy or just stop proliferating.  Others will inhibit cancer progression indirectly by inducing changes in the local environment that are unfavorable to angiogenesis, invasion or metastasis.

Of the hundreds of compounds known to be active against cancer it is important to know that:

1)      They are safe and useful in cancer prevention and treatment.  As more and more scientific studies are published on the safety and efficacy of foods, herbs, nutrients and botanicals this will make them more acceptable to the medical community in their use for cancer prevention and treatment.

2)      They are active at concentrations that are achievable in humans after oral administration.

3)      They are nontoxic to the patient at the required dose.

Nourishing and Cancer Preventive Protocol in Oral Cancer

Glutamine – is safe and can beneficially contribute to diminishing the risk of high-dose chemotherapy and radiation.  Potential mechanisms of glutamine effects include maintenance of mucosal integrity, improved immune competence, inhibition of cell proliferation, increased apoptosis rate, increased synthesis of glutathione and induction of heat shock protein synthesis. (Kuhn et al 2009)

Glutamine (in Beyond Whey) and curcumin (in Botanical Treasures) combat cachexia (loss of weight and muscle mass) of the body.

Curcumin – activates a pathway crucial to the suppression of oral carcinogenesis.  (Chang et al 2010)  Malignant oral cells are more sensitive to Curcumin. (Chakravarti et al 2010)

Vitamin D – Researchers observed inverse associations between dietary vitamin D intake and risk of squamous cell carcinoma of the esophagus and, perhaps, oral/pharyngeal cancer, which were most pronounced among heavy current smokers and heavy consumers of alcohol. (Lipworth et al 2009)

Vitamin E – reduces damage to the bone caused by free radicals. (Singh et al 2010) (Lyons & Ghazali 2008) 

Green Tea Extract – may suppress oral pre-malignant lesions. (Tsao et al 2009) 

N-acetyl cysteine) – enhances apoptosis through inhibition of NF-κB. (Biol Chem 2004) 

Milk Thistle (Silibinin) – may prevent or reduce chemotherapy as well as radiotherapy-induced toxicity. (Ramasamay & Agarwal 2008)  Silibinin inhibits HIF-1α. (Jong et al 2009) (Garcia-Marciera & Mateo 2009)

Antioxidants and other nutrients - do not interfere with chemotherapy or radiation therapy and can enhance the killing of therapeutic modalities for cancer, decrease their side effects and protect normal tissue. (Simone et al 2007)

Zinc –Zinc deficiency was associated with increased tumor size, overall stage of the cancer and increased unplanned hospitalizations.  (Nutritional and Zinc Status of Head and Neck Cancer Patients: An Interpretive Review.  Prasad et al 1998)

Melatonin – may protect the oral cavity from tissue damage caused by oxidative stress. (Gomez-Mareno et al 2009)

Inositol hexaphosphate (IP-6) – has a synergistic effect with paclitaxel in treatment of oral cavity squamous cell carcinoma. (Janus et al 2007)

Ginkgo biloba – induces apoptosis of oral cavity cancer cells. (Kim et al 2005)

VEGF – vascular endothelial growth factor - is one of the most powerful stimulants of tumor angiogenesis. VEGF mRNA expression is upregulated by a wide array of oncogenes (including H-ras and K-ras, V-raf, src, PTEN, p53, Wnt, and c-jun, among others) and growth factors (including EGF, TGF-α, TGF-β, insulin-like growth factor-1, and PDGF). (Houck et al 1992) (Sima et al 1995) (Shweiki et al 1992) (Toi et al 2001) (Kerbal & Niklinska et al 2001) (Folkman 2002)  

VEGF can promote the growth of rhabdomyosarcoma cells through VEGFR1. (Li et al 2006)

VEGF-R is a tumor specific biomarker in head and neck cancer. (Tsao et al 2004)  Nasal polyp fibroblasts (NPFs) contribute to the pathogenesis of nasal polyps by producing VEGF to promote angiogenesis under hypoxic conditions. Epigallocatechin-3-gallate substantially diminishes HIF-1 alpha and VEGF synthesis in NPFs. (Lin et al 2008)

Natural Compounds that Inhibit VEGF:

Artemisia annua (Chen et al 2004)

Camellia sinensis (green tea extract) (Lin et al 2008)

Curcuma longa (turmeric) (Schaaf et al 2010)

Ginkgo biloba (Zhang et al 2002)

Magnolia seed cones – 90% honokiol (Wen et al 2009) (Ahn et al 2006)

Ocimum spp. (Basil) Ursolic acid (Yan et al 2010)

Polygonum cuspidatum (Japanese knotweed) (Wang et al 2004) (Cao et al 2005) – 20% resveratrol

Pterostilbene – (Pan et al 2009)

Scutellaria baicalensis (Yoon et al 2009)

Silybum marianum (milk thistle) (Gallo et al 2003)

Taxus breviflora (Pacific yew) – taxol and other related taxins

Viscum album (Mistletoe) (Park et al 2001)

Vitus vinifera (grape seed extract) (Bai et al 2003)

 p53 – the Guardian of the Genome.

The highest frequency of p53 mutations reported in human cancers are lung, 56%; colon, 50%; esophagus,45%; ovary, pancreas and skin, 44%; stomach, 41%; head and neck, 37%; bladder, 34%; prostate, 30% and breast, endometrium and mesothelioma, 22%.

Natural Compounds that Normalize p53

6-Gingerol (Park et al 2006)

Coriolus versicolor (Ho et al 2005)

Curcumin (Boik 2001 p.55)

EGCG (Lee et al 2010)

Tocotrienols (Agarwal et al 2004) and Vit E succinate

OPCs

Oridonin (Rabdosia) (Cui et al 2007)

Paw paw seed

Quercetin (Beniston et al 2001)(Shi et al 2003)

Resveratrol (She et al 2001)(Pearce et al 2007)(Tang et al 2006)

Rhemannia glutinosa (Chao et al 2006)

Withanone (Ashwagandha extract) (Widodo et al 2008)

Note: Diets rich in refined sugars and starches, as well as rich in red meat promote p53 mutation. (Slattery et al 2002)

Bcl-2 – is an NF-kappaB regulated gene that functions by blocking the apoptosis pathway, thus immortalizing cancer cells. It has been suggested that Bcl-2 over expression results in the up regulation of VEGF expression with increased neoangiogenesis in human cancer xenografts. Bcl-2 is a tumor specific biomarker in head and neck cancer. (Tsao et al 2004)

Natural Compounds that Reduce Bcl-2

Andrographolide (Zhou et al 2006) – Andrographis

Baicalin and baicalein (Chen et al 2000) - Scutellaria baicalensis

Beta-lapachone – Lapacho (Woo et al 2005)

Carnosol – Rosemary (Dorrie et al 2001)

Casticin – Yarrow (Achillea millefolium) (Khadidja et al 2006)

Chelidonium alkaloids – Chelidonine (Habermehl et al 2006)

Curcumin (Bharti et al 2003) (Schaaf et al 2010)

DIM – (Hong et al 2002)

Echinocystic acid (EA) (Tong et al 2004) – Panax ginseng

EGCG (Lee et al 2010) and Theophylline - Green tea (Leone et al 2003)(Byrd et al 2000)

EPA – from fish oil (Chiu and Wan 1999)

Gingerol – Ginger (Wang et al 2003)

Hibiscus protocatechuic acid (PCA) (Tseng et al 2000)

Mistletoe – (Choi et al 2004)

OPCs – grape seed extract – (Bagchi et al 2000)  

Parthenolide – feverfew (Zhang et al 2004)

Resveratrol – (Aziz et al 2006)

Understanding Cachexia

Cachexia is a catabolic process in which there is loss of weight and muscle mass resulting in weakness. Catabolic processes involve the breakdown of tissues.  And conversely anabolic processes involve the building up of tissues in the body. 

One mechanism which tries to explain cachexia involves a substance called Tumor Necrosis Factor-Alpha (TNF-alpha).  TNF-alpha has a direct catabolic effect on skeletal muscle and adipose tissue.  It produces muscle atrophy through depression of protein synthesis and an increase in protein degradation, involving the formation of reactive oxygen species leading to the upregulation of the transcription factor Nuclear Factor-kappa B (NF-kappaB). 

What we are trying to do in the situation involving cachexia is therefore twofold: 1) To halt the catabolic breakdown of muscle tissue (cachexia) and 2) To nourish and build up muscles through anabolic supplements.  All of the botanicals and nutrients that we are using here are aimed at one or both of these two processes. 

Useful Nutrients and Botanicals during Radiation of Oral Cancer

1. Resveratrol – inhibits Hypoxia-Inducible Factor-1 (HIF-1) and VEGF (Vascular Endothelial Growth Factor). (Zhang et al 2005)

2. Curcumin – has radiosensitization effects. (Javvadi et al 2010) (Li et al 2007)  Curcumin inhibited HNSCC cell growth and augmented the effect of radiation in vitro and in vivo. (Khafif et al 2009)

3. Panax ginseng – has radioprotective effects on the GI tract and bone marrow cells. (Park et al 2009) (Kim et al 2007) 

4. Anti-oxidants – have protective effects on proton total-body radiation. (Wambi et al 2009)  Antioxidants and other nutrients do not interfere with chemotherapy or radiation therapy and can enhance the killing of therapeutic modalities for cancer, decrease their side effects and protect normal tissue. (Simone et al 2007)

5. Selenium – may reduce the burden for patients undergoing radiation and has a positive effect on radiation-associated secondary lymphedema including endolaryngeal edema. (Micke et al 2009) (Gehrisch & Dorr 2007) 

6. L-selenomethionine, Vitamin C, Vitamin E succinate, alpha-lipoic acid and N-acetyl cysteine – are effective for radioprotection of hemoatopoietic cells. (Wambi et al 2009) 

7. Milk Thistle (Silibinin) – may prevent or reduce chemotherapy as well as radiotherapy-induced toxicity. (Ramasamay & Agarwal 2008)  Silibinin inhibits HIF-1α. (Jong et al 2009) (Garcia-Marciera & Mateo 2009)

8.        Zinc sulfate – is beneficial in decreasing the severity of radiation-induced mucositis and oral discomfort. (Ertekin et al 2004)  Zinc deficiency was associated with increased tumor size, overall stage of the cancer and increased unplanned hospitalizations.  (Nutritional and Zinc Status of Head and Neck Cancer Patients: An Interpretive Review.  Prasad et al 1998)

Tests to Perform to Determine if the Cancer Cells will be Sensitive to Radiation Therapy

1. Hypoxia-inducible factor (HIF)-1 (For an explanation of HIF-1 please see the article on HIF-1.)

2. Carbonic Anhydrase (CA-9) -- CA-9 in head and neck cancer predicts resistance to platinum–based radiochemotherapy. (Int. J. Radiat Biol 2008 Jan; 84(1): 47-52)  (For a further explanation of CA-9 please see the article on CA-9.)

Understanding Transcription Factors

Transcription factors are proteins that bind to specific DNA sequences and thereby control the transfer (or transcription) of genetic information from DNA to mRNA.  They are essential for the regulation of gene expression.  There are approximately 2600 proteins in the human genome that contain DNA-binding domains and most of these are presumed to function as transcription factors.  They use a variety of mechanisms for the regulation of gene expression such as: 1) Histone acetyltransferease (HAT) activity – this acetylates histone proteins, which weakens the association of DNA histones, which make the DNA more accessible to transcription and thereby upregulate transcription and 2) Histone deacetylase (HDAC) activity.  This deacetylates histone proteins, which strengthens the association of DNA histones, which make the DNA less accessible to transcription and thereby down regulate transcription.

Not only do transcription factors act downstream of signaling cascades related to biological stimuli but they can also be downstream of signaling cascades involved in environmental stimuli.  Examples include heat shock factor (HSF), which up regulates genes necessary for survival at higher temperatures and hypoxia inducible factor (HIF), which upregulates genes necessary for cell survival in low-oxygen environments.

It is common in biology for important processes to have multiple layers of regulation and control.  This is also true with transcription factors: not only do transcription factors control the rates of transcription to regulate the amounts of gene products (RNA and protein) available to the cell, but transcription factors themselves are regulated (often by other transcription factors)  Examples of transcription factors include: p53, HSF1, and NF-kappaB. (Answers.com Genetics Encyclopedia)

What is Hypoxia-Inducible Factor (HIF)-1?

Hypoxia is a deficiency of oxygen reaching tissues in the body and is created by a tumor.  Hypoxia-inducible factor (HIF)-1 is a transcriptional activator that is involved in the activity of the phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B)/FKBP-rapamycin-associated protein (FRAP) signalling cascade. HIF-1 plays a critical role in the pathophysiology of numerous human diseases as it activates the transcription of various genes whose products are involved in angiogenesis and cellular adaptation to hypoxia. Targeting HIF-1 inactivation can suppress tumor angiogenesis and improves the effectiveness of other angiogenic targets and chemotherapy, and radiation therapy. HIF-1 can be targeted at multiple levels, for example, prior to HIF-1α synthesis, after HIF-1α translation, and in the process of HIF-1 activation.

HIF-1 is among the primary genes involved in the homeostatic process that allows cells to adapt to stress.  Although this response is crucial to protect against some diseases of aging, including ischemia and neurodegenerative disorders, HIF-1 has an opposite role in cancer in which it promotes tumorigenesis. “HIF-1 can increase vascularization in hypoxic areas such as localized ischemia and tumors. It is a transcription factor for dozens of target genes; HIF-1 is also essential for immunological responses and is a crucial physiological regulator of homeostasis, vascularization, and anaerobic metabolism. Furthermore, HIF-1 is increasingly studied because of its perceived therapeutic potential. As it causes angiogenesis, enhancement of this gene within ischemic patients could promote the vessel proliferation needed for oxygenation. In contrast, as HIF-1 allows for survival and proliferation of cancerous cells due to its angiogenic properties, inhibition potentially could prevent the spread of cancer.” In summary:

Within the Eclectic Triphasic Medical System, HIF-1 is a target for various plant compounds to suppress cancer.  Hypoxia relates to the ability of the “cancer energy” to no longer need any oxygen for survival or growth.  This also causes resistance to radiation and chemotherapy.

What is Carbonic Anhydrase (CA-9)?

Hypoxia-inducible Carbonic Anhydrase (CA-9) relates to angiogenic pathways. Carbonic anhydrases can be added to the list of known hypoxia-inducible factor-responsive genes. Higher levels of CA-9 reveal an overall higher microvessel density. Hypoxia-induced changes allow tumor cells to survive under sustained hypoxic microenvironments, resulting in achievement of more aggressive phenotypes. Hypoxia also contributes to acidification of the tumor environment. There is a direct association of elevated CA-9 expression with VEGF, EGF receptor, c-erbB-2 (HER-2 neu), and MUC1 expression. CA-9 levels can be measured and elevated levels within a tumor can predict poor sensitivity to radiation therapy.

Compounds that Target Hypoxia Inducible Factor-1alpha in Cancer

Curcumin, Epigallocatechin-3-gallate (EGCG), Silibinin, Resveratrol, Tocotrinol succinate

Studies Referenced on Pub-Med Relative to this Article

Cancer Prev Res (Phila Pa). 2010 Mar;3(3):331-8. Epub 2010 Feb 9.

Chakravarti N, Kadara H, Yoon DJ, Shay JW, Myers JN, Lotan D, Sonenberg N, Lotan R.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.

Curcumin has shown some promise in the prevention of oral carcinogenesis by mechanism(s) that are still not completely resolved. Messenger RNA translation is mediated in eukaryotes by the eIF4F complex composed of eukaryotic translation initiation factors eIF4E, eIF4G, and eIF4A. Overexpression of some of these components or the inactivation of initiation repressor proteins (4E-BP1) has been implicated in cancer development including oral carcinogenesis by affecting cell survival, angiogenesis, and tumor growth and invasion. In this study, we examined the possibility that curcumin affects the translational machinery differently in normal, immortalized normal, leukoplakia, and malignant cells. Curcumin treatment in vitro inhibited the growth of immortalized oral mucosa epithelial cells (NOM9-CT) and the leukoplakia cells (MSK-Leuk1s) as well as in the UMSCC22B and SCC4 cells derived from head and neck squamous cell carcinoma. Curcumin only exerted minor effects on the growth of normal oral epithelial cells (NOM9). In the immortalized, leukoplakia, and cancer cells, curcumin inhibited cap-dependent translation by suppressing the phosphorylation of 4E-BP1, eIF4G, eIF4B, and Mnk1, and also reduced the total levels of eIF4E and Mnk1. Our findings show that immortalized normal, leukoplakia, and malignant oral cells are more sensitive to curcumin and show greater modulation of protein translation machinery than the normal oral cells, indicating that targeting this process may be an important approach to chemoprevention in general and for curcumin in particular.

PMID: 20145189 [PubMed - in process]

Int J Cancer. 2010 Feb 2. [Epub ahead of print]

Chang KW, Hung PS, Lin IY, Hou CP, Chen LK, Tsai YM, Lin SC.

Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei, Taiwan.

Curcumin is a common food ingredient derived from the plant Curcuma longa and is a potent drug against tumorigenesis. Both insulin-like growth factor binding protein-5 (IGFBP-5) and CCAAT/enhancer-binding protein alpha (C/EBPalpha) are suppressors of head and neck carcinogenesis. We identified curcumin as an inducer of IGFBP-5 expression in multiple types of oral keratinocytes; furthermore, curcumin induces IGFBP-5 promoter activity in SAS oral cancer cells. Promoter deletion mapping identified a region (nt -71 to nt -59 relative to the transcription start site) as containing a C/EBPalpha-binding element that is indispensable for curcumin-mediated IGFBP-5 upregulation. Chromatin immunoprecipitation assays revealed that in vivo binding of C/EBPalpha to this region was remarkably increased in the presence of curcumin. Curcumin increased nuclear C/EBPalpha expression and IGFBP-5 expression through p38 activation and this was abrogated by SB203580 treatment. Furthermore, MKK6 expression activated p38 and C/EBPalpha, increasing IGFBP-5 promoter activity and expression. Finally, curcumin-induced IGFBP-5 expression is associated with the suppression of xenograft tumorigenesis in mice due to oral cancer cells. We conclude that curcumin activates p38, which, in turn, activates the C/EBPalpha transactivator by interacting with binding elements in the IGFBP-5 promoter. The consequential upregulation of C/EBPalpha and IGFBP-5 by curcumin is crucial to the suppression of oral carcinogenesis.

PMID: 20127863 [PubMed - as supplied by publisher]

Ann Oncol. 2009 Sep;20(9):1576-81. Epub 2009 Jun 1.

Lipworth L, Rossi M, McLaughlin JK, Negri E, Talamini R, Levi F, Franceschi S, La Vecchia C.

International Epidemiology Institute, Rockville, MD 20850, USA. loren@iei.us

BACKGROUND: Data on the association between vitamin D and upper digestive tract neoplasms are limited. METHODS: In two case-control studies in Italy, we examined the relation between dietary vitamin D intake and squamous cell carcinoma of the esophagus (SCCE; 304 cases) and oral/pharyngeal cancer (804 cases). Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by multiple logistic regression. RESULTS: Adjusted ORs for SCCE and oral/pharyngeal cancer were 0.58 (95% CI 0.39-0.86) and 0.76 (95% CI 0.60-0.94), respectively, for the highest tertile of vitamin D intake. Using a reference group of those in the highest tertile of vitamin D who were never/former smokers, ORs were 8.7 (95% CI 4.1-18.7) for SCCE and 10.4 (95% CI 6.9-15.5) for oral/pharyngeal cancer among heavy smokers in the lowest vitamin D tertile; similarly, compared with those in the highest tertile of vitamin D who drank <3 alcoholic drinks/day, corresponding ORs were 41.9 (95% CI 13.7-128.6) for SCCE and 8.5 (95% CI 5.7-12.5) for oral/pharyngeal cancer, among heavy alcohol drinkers in the lowest vitamin D tertile. CONCLUSION: We observed inverse associations between dietary vitamin D intake and risk of SCCE and, perhaps, oral/pharyngeal cancer, which were most pronounced among heavy current smokers and heavy consumers of alcohol.

PMID: 19487490 [PubMed - indexed for MEDLINE]

Clin J Am Soc Nephrol. 2008 Sep;3(5):1548-54. Epub 2008 Jun 11.

Holick MF.

Department of Medicine, Section of Endocrinology, Nutrition, and Diabetes, Vitamin D, Skin and Bone Research Laboratory, Boston University Medical Center, Boston, Massachusetts, USA. mfholick@bu.edu

Vitamin D deficiency is a worldwide health problem. The major source of vitamin D for most humans is sensible sun exposure. Factors that influence cutaneous vitamin D production include sunscreen use, skin pigmentation, time of day, season of the year, latitude, and aging. Serum 25-hydroxyvitamin D [25(OH)D] is the measure for vitamin D status. A total of 100 IU of vitamin D raises blood level of 25(OH)D by 1 ng/ml. Thus, children and adults who do not receive adequate vitamin D from sun exposure need at least 1000 IU/d vitamin D. Lack of sun exposure and vitamin D deficiency have been linked to many serious chronic diseases, including autoimmune diseases, infectious diseases, cardiovascular disease, and deadly cancers. It is estimated that there is a 30 to 50% reduction in risk for developing colorectal, breast, and prostate cancer by either increasing vitamin D intake to least 1000 IU/d vitamin D or increasing sun exposure to raise blood levels of 25(OH)D >30 ng/ml. Most tissues in the body have a vitamin D receptor. The active form of vitamin D, 1,25-dihydroxyvitamin D, is made in many different tissues, including colon, prostate, and breast. It is believed that the local production of 1,25(OH)(2)D may be responsible for the anticancer benefit of vitamin D. Recent studies suggested that women who are vitamin D deficient have a 253% increased risk for developing colorectal cancer, and women who ingested 1500 mg/d calcium and 1100 IU/d vitamin D(3) for 4 yr reduced risk for developing cancer by >60%.

PMID: 18550652 [PubMed - indexed for MEDLINE]

Cancer Metastasis Rev. 2007 Jun;26(2):241-8.

Moeller BJ, Richardson RA, Dewhirst MW.

Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA,.

A large body of clinical evidence exists to suggest that tumor hypoxia negatively impacts radiotherapy. As a result, there has been longstanding active research into novel methods of improving tumor oxygenation, targeting hypoxic tumor cells, and otherwise modulating the effect hypoxia has on how tumors respond to radiation. Over time, as more has been learned about the many ways hypoxia affects tumors, our understanding of the mechanisms connecting hypoxia to radiosensitivity has become increasingly broad and complicated. This has opened up new potential avenues for interrupting hypoxia's negative effects on tumor radiosensitivity. Here, we will review what is currently known about the spectrum of influence hypoxia has over the way tumors respond to radiation. Particular focus will be placed on recent discoveries suggesting that hypoxia-inducible factor-1 (HIF-1), a transcription factor that upregulates its target genes under hypoxic conditions, plays a major role in determining tumor radiosensitivity. HIF-1 and/or its target genes may represent therapeutic targets which could be manipulated to influence hypoxia's impact on tumor radiosensitivity.

PMID: 17440683 [PubMed - indexed for MEDLINE]

Br J Oral Maxillofac Surg. 2008 Dec;46(8):653-60. Epub 2008 Jun 17.

Lyons A, Ghazali N.

Department of Oral & Maxillofacial Surgery, 23rd Floor Guy's Tower, London SE1 9RT, United Kingdom.

During the past 80 years a number of theories about the pathogenesis of osteoradionecrosis (ORN) have been proposed, with consequent implications for its treatment. Until recently tissue hypoxia and its consequences were accepted as the primary cause, and this led to the use of hyperbaric oxygen (HBO) for both treatment and prevention of complications of radiotherapy in the head and neck. The benefit of HBO has not been validated. A new theory for the pathogenesis of ORN has proposed that damage to bone is caused by radiation-induced fibrosis. Cells in bone are damaged as a result of acute inflammation, free radicals, and the chronic activation of fibroblasts by a series of growth factors. New treatments have therefore been devised that include pentoxifylline, a vasodilator that also inhibits fibrosis, and tocopherol (vitamin E) to reduce damage caused by free radicals. Impressive results in terms of reversing the process of ONR have been reported using these agents. It has been suggested that this theory and these agents could be the basis of future treatment and prevention of ORN.

PMID: 18562055 [PubMed - indexed for MEDLINE]

Int J Radiat Biol. 2010 Jan;86(1):12-21.

Singh VK, Brown DS, Kao TC.

Radiation Countermeasures Program, Armed Forces Radiobiology Research Institute, Bethesda, Maryland 20889-5603, USA. singh@afrri.usuhs.mil

PURPOSE: The purpose of this study was to further elucidate the role of granulocyte-colony stimulating factor (G-CSF)-induced in response to alpha-tocopherol succinate (TS) administration in protecting mice from total body irradiation (TBI). MATERIAL AND METHODS: The dose, route, and schedule of TS administration for optimal G-CSF induction were determined by giving TS through subcutaneous (sc) and oral routes to male CD2F1 mice. The level of cytokine in serum was determined by multiplex Luminex. The role of G-CSF on survival after TBI was determined by first treating mice with a protective dose (400 mg/kg) of TS 24 h before exposure to a lethal dose (9.2 Gy, 0.6 Gy/min) of cobalt-60 gamma-irradiation. The treated mice were then given neutralising antibody to G-CSF 16 h before TBI to abrogate the radioprotective efficacy of TS. The efficacy of whole blood samples obtained from TS-treated mice was evaluated to protect naïve lethally irradiated mice. The hematopoietic stem cells in blood from TS-treated mice were analysed by fluorescence-activated cell sorting (FACS). RESULTS: Maximal levels of G-CSF were observed in peripheral blood 24 h after sc administration of TS. When TS-treated mice were given neutralising antibody to G-CSF, TS failed to protect against TBI. After being challenged with an LD90/30 (lethal dose causing 90% mortality over 30 days) dose of gamma-radiation, mice infused with whole blood from TS- and AMD3100 (1,1'-{1,4-phenylenebis(methylene)}bis-1,4,8,11-tetraazacyclotetradecane octahydrochloride)-treated mice exhibited significantly higher survival compared with those infused with whole blood from vehicle-injected mice. FACS data revealed that hematopoietic stem cells were mobilised into the peripheral blood. CONCLUSIONS: The results indicate that G-CSF-induced by the administration of TS, mobilises hematopoietic stem cells and is responsible for the protection from ionising radiation.

PMID: 20070211 [PubMed - indexed for MEDLINE]

Mol Cancer Ther. 2005 Oct;4(10):1465-74.

Zhang Q, Tang X, Lu QY, Zhang ZF, Brown J, Le AD.

Center for Craniofacial Molecular Biology, University of Southern California, School of Dentistry, Los Angeles 90033, USA.

Hypoxia-inducible factor-1alpha (HIF-1alpha) is overexpressed in many human tumors and their metastases, and is closely associated with a more aggressive tumor phenotype. In this study, we investigated the effect of resveratrol, a natural product commonly found in grapes and various other fruits, on hypoxia-induced HIF-1alpha protein accumulation and vascular endothelial growth factor (VEGF) expression in human tongue squamous cell carcinomas and hepatoma cells. Our results showed that resveratrol significantly inhibited both basal level and hypoxia-induced HIF-1alpha protein accumulation in cancer cells, but did not affect HIF-1alpha mRNA levels. Pretreatment of cells with resveratrol significantly reduced hypoxia-induced VEGF promoter activities and VEGF expression at both mRNA and protein levels. The mechanism of resveratrol inhibition of hypoxia-induced HIF-1alpha accumulation seems to involve a gradually shortened half-life of HIF-1alpha protein caused by an enhanced protein degradation through the 26S proteasome system. In addition, resveratrol remarkably inhibited hypoxia-mediated activation of extracellular signal-regulated kinase 1/2 and Akt, leading to a marked decrease in hypoxia-induced HIF-1alpha protein accumulation and VEGF transcriptional activation. Functionally, we observed that resveratrol also significantly inhibited the hypoxia-stimulated invasiveness of cancer cells. These data suggested that HIF-1alpha/VEGF could be a promising drug target for resveratrol in the development of an effective chemopreventive and anticancer therapy in human cancers.

PMID: 16227395 [PubMed - indexed for MEDLINE]

Cancer Res. 2010 Mar 1;70(5):1941-50. Epub 2010 Feb 16.

Javvadi P, Hertan L, Kosoff R, Datta T, Kolev J, Mick R, Tuttle SW, Koumenis C.

Authors' Affiliations: Departments of Cancer Biology, Radiation Oncology, and Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.

Curcumin, a plant polyphenol, is a widely studied chemopreventive agent with demonstrated antitumor activities in preclinical studies and low toxicity profiles in multiple clinical trials against human malignancies. We previously showed that curcumin radiosensitizes cervical tumor cells without increasing the cytotoxic effects of radiation on normal human fibroblasts. Here we report that an inhibitory activity of curcumin on the antioxidant enzyme thioredoxin reductase-1 (TxnRd1) is required for curcumin-mediated radiosensitization of squamous carcinoma cells. Stable knockdown of TxnRd1 in both HeLa and FaDu cells nearly abolished curcumin-mediated radiosensitization. TxnRd1 knockdown cells showed decreased radiation-induced reactive oxygen species and sustained extracellular signal-regulated kinase 1/2 activation, which we previously showed was required for curcumin-mediated radiosensitization. Conversely, overexpressing catalytically active TxnRd1 in HEK293 cells, with low basal levels of TxnRd1, increased their sensitivity to curcumin alone and to the combination of curcumin and ionizing radiation. These results show the critical role of TxnRd1 in curcumin-mediated radiosensitization and suggest that TxnRd1 levels in tumors could have clinical value as a predictor of response to curcumin and radiotherapy. Cancer Res; 70(5); 1941-50.

PMID: 20160040 [PubMed - in process]

Cancer Res. 2007 Mar 1;67(5):1988-96.

Li M, Zhang Z, Hill DL, Wang H, Zhang R.

Department of Pharmacology and Toxicology, Comprehensive Cancer Center, University of Alabama at Birmingham, 1670 University Boulevard, Birmingham, AL 32594, USA.

The oncoprotein MDM2, a major ubiquitin E3 ligase of tumor suppressor p53, has been suggested as a novel target for human cancer therapy based on its p53-dependent and p53-independent activities. We have identified curcumin, which has previously been shown to have anticancer activity, as an inhibitor of MDM2 expression. Curcumin down-regulates MDM2, independent of p53. In a human prostate cancer cell lines PC3 (p53(null)), curcumin reduced MDM2 protein and mRNA in a dose- and time-dependent manner, and enhanced the expression of the tumor suppressor p21(Waf1/CIP1). The inhibitory effects occur at the transcriptional level and seem to involve the phosphatidylinositol 3-kinase/mammalian target of rapamycin/erythroblastosis virus transcription factor 2 pathway. Curcumin induced apoptosis and inhibited proliferation of PC3 cells in culture, but both MDM2 overexpression and knockdown reduced these effects. Curcumin also inhibited the growth of these cells and enhanced the cytotoxic effects of gemcitabine. When it was administered to tumor-bearing nude mice, curcumin inhibited growth of PC3 xenografts and enhanced the antitumor effects of gemcitabine and radiation. In these tumors, curcumin reduced the expression of MDM2. Down-regulation of the MDM2 oncogene by curcumin is a novel mechanism of action that may be essential for its chemopreventive and chemotherapeutic effects. Our observations help to elucidate the process by which mitogens up-regulate MDM2, independent of p53, and identify a mechanism by which curcumin functions as an anticancer agent.

PMID: 17332326 [PubMed - indexed for MEDLINE]

Laryngoscope. 2009 Oct;119(10):2019-26.

Khafif A, Lev-Ari S, Vexler A, Barnea I, Starr A, Karaush V, Haif S, Ben-Yosef R.

Department of Otolaryngology, Tel Aviv Sourasky Medical Center and Tel Aviv University School of Medicine, 6 Weizmann Street, Tel Aviv, Israel.

OBJECTIVES/HYPOTHESIS: To investigate whether curcumin enhances the cytotoxic effect of radiotherapy in head and neck squamous cell carcinoma (HNSCC). METHODS: HNSCC cell lines SCC-1, SCC-9, KB, as well as A431 cell line were treated with curcumin, irradiation, or their combination. Cell viability was evaluated by XTT assay. Cyclooxygenase-2 (COX-2), epithelial growth factor receptor (EGFR), and p-Erk1/2 were measured by Western blot analysis. CD-1 athymic nude mice with orthotopic implanted SCC-1 cells, were treated with control diet, curcumin containing diet, local single-dose radiation, or combination. RESULTS: Curcumin (IC50 range, 15-22 microM) and radiation inhibited cell viability in all cell lines were tested. The combination of curcumin and radiation resulted in additive effect. Curcumin decreased COX-2 expression and inhibited phosphorylation of EGFR in SCC-1 cells. In tumor-bearing mice the combination regimen showed a decrease in both tumor weight (25%, P = .09) and tumor size (15%, P = .23) compared to the nontreated mice. CONCLUSIONS:: Curcumin inhibited HNSCC cell growth and augmented the effect of radiation in vitro and in vivo. A possible mechanism is inhibition of COX-2 expression and EGFR phosphorylation.

PMID: 19655336 [PubMed - indexed for MEDLINE]

Acta Histochem. 2009 Sep 18. [Epub ahead of print]

Park E, Hwang I, Song JY, Jee Y.

College of Veterinary Medicine and Applied Radiological Science Research Institute, Cheju National University, Jeju 690-756, South Korea.

An acidic polysaccharide of Panax ginseng (APG), ginsan, has been reported to protect the hematopoietic system by increasing the number of bone marrow cells and spleen cells. Therefore, we evaluated the ability of APG to protect mice from radiation-induced damage of the small intestine. APG treatment caused the lengthening of villi and a numerical increase of crypt cells in the small intestine at 3.5 days after 7Gy irradiation compared to irradiated, non-treated controls. In addition, APG significantly inhibited irradiation-induced apoptosis by decreasing the amount of pro-apoptotic p53 and Bax as well as augmenting that of anti-apoptotic Bcl-2 at 24h after irradiation. These results indicate that APG might be a useful adjunct to therapeutic irradiation as a protective agent for the gastrointestinal tract of cancer patients.

PMID: 19767060 [PubMed - as supplied by publisher]

J Vet Sci. 2007 Mar;8(1):39-44.

Kim HJ, Kim MH, Byon YY, Park JW, Jee Y, Joo HG.

Department of Veterinary Medicine, College of Applied Life Sciences, Cheju National University, Jeju 690-756, Korea.

An acidic polysaccharide of Panax ginseng (APG), so called ginsan is known to have important immunomodulatory activities. It was recently reported that APG has radioprotective effects in mice but the detailed mechanism was not fully elucidated. This study examined the effects of APG on bone marrow cells (BMs). The phenotypical and functional changes in APG-treated BMs after gamma radiation were studied. The benefit of APG on BMs damaged by gamma radiation was determined by measuring the cell viability. Using 2 different assays, a pretreatment with APG significantly increased the viability of BMs against gamma radiation. APG-treated BMs had a significantly higher amount of IL-12, which is a major cytokine for immune responses, compared with the medium-treated BMs. The expression of MHC class II molecules of APG-treated BMs was also increased, and APG-treated BMs showed significantly higher levels of allogeneic CD4(+) T lymphocyte proliferation. Furthermore, APG-treated mice had a larger number of BMs after gamma radiation than the control mice, and the BMs of APG-treated mice were successfully cultured into dendritic cells, which are the representative antigenpresenting cells. Overall, this study shows that APG alters the phenotype of BMs, increases the viability and alloreactivity of BMs after gamma radiation both in vitro and in vivo. Therefore, APG may be a good candidate radioprotective agent for BMs.

PMID: 17322772 [PubMed - indexed for MEDLINE]

Radiat Res. 2009 Aug;172(2):175-86.

Wambi CO, Sanzari JK, Sayers CM, Nuth M, Zhou Z, Davis J, Finnberg N, Lewis-Wambi JS, Ware JH, El-Deiry WS, Kennedy AR.

Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

Abstract Dietary antioxidants have radioprotective effects after gamma-radiation exposure that limit hematopoietic cell depletion and improve animal survival. The purpose of this study was to determine whether a dietary supplement consisting of l-selenomethionine, vitamin C, vitamin E succinate, alpha-lipoic acid and N-acetyl cysteine could improve survival of mice after proton total-body irradiation (TBI). Antioxidants significantly increased 30-day survival of mice only when given after irradiation at a dose less than the calculated LD(50/30); for these data, the dose-modifying factor (DMF) was 1.6. Pretreatment of animals with antioxidants resulted in significantly higher serum total white blood cell, polymorphonuclear cell and lymphocyte cell counts at 4 h after 1 Gy but not 7.2 Gy proton TBI. Antioxidants significantly modulated plasma levels of the hematopoietic cytokines Flt-3L and TGFbeta1 and increased bone marrow cell counts and spleen mass after TBI. Maintenance of the antioxidant diet resulted in improved recovery of peripheral leukocytes and platelets after sublethal and potentially lethal TBI. Taken together, oral supplementation with antioxidants appears to be an effective approach for radioprotection of hematopoietic cells and improvement of animal survival after proton TBI.

PMID: 19630522 [PubMed - indexed for MEDLINE]

Altern Ther Health Med. 2007 Jan-Feb;13(1):22-8.

Simone CB 2nd, Simone NL, Simone V, Simone CB.

Simone Protective Cancer Institute in Lawrenceville, NJ, USA.

PURPOSE: Some in the oncology community contend that patients undergoing chemotherapy and/or radiation therapy should not use food supplement antioxidants and other nutrients. Oncologists at an influential oncology institution contended that antioxidants interfere with radiation and some chemotherapies because those modalities kill by generating free radicals that are neutralized by antioxidants, and that folic acid interferes with methotrexate. This is despite the common use of amifostine and dexrazoxane, 2 prescription antioxidants, during chemotherapy and/or radiation therapy. DESIGN: To assess all evidence concerning antioxidant and other nutrients used concomitantly with chemotherapy and/or radiation therapy, the MEDLINE and CANCERLIT databases were searched from 1965 to November 2003 using the words vitamins, antioxidants, chemotherapy, and radiation therapy. Bibliographies of articles were searched. All studies reporting concomitant nutrient use with chemotherapy and/or radiation therapy (280 peer-reviewed articles including 62 in vitro and 218 in vivo) were indiscriminately included. RESULTS: Fifty human clinical randomized or observational trials have been conducted, involving 8,521 patients using beta-carotene; vitamins A, C, and E; selenium; cysteine; B vitamins; vitamin D3; vitamin K3; and glutathione as single agents or in combination. CONCLUSIONS: Since the 1970s, 280 peer-reviewed in vitro and in vivo studies, including 50 human studies involving 8,521 patients, 5,081 of whom were given nutrients, have consistently shown that non-prescription antioxidants and other nutrients do not interfere with therapeutic modalities for cancer. Furthermore, they enhance the killing of therapeutic modalities for cancer, decrease their side effects, and protect normal tissue. In 15 human studies, 3,738 patients who took non-prescription antioxidants and other nutrients actually had increased survival.

PMID: 17283738 [PubMed - indexed for MEDLINE]

Strahlenther Onkol. 2007 Jan;183(1):36-42.

Gehrisch A, Dörr W.

Department of Radiotherapy and Radiooncology, Medical Faculty Carl Gustav Carus, Technical University of Dresden, Dresden, Germany.

PURPOSE: To quantify the effect of sodium selenite (selenium) on radiation-induced oral mucositis (mouse) after subcutaneous or topical administration. MATERIAL AND METHODS: Mucosal ulceration of the lower epithelium of mouse tongue was analyzed. Selenium (5 mug) was applied subcutaneously (s.c.) or locally, 60 min or 30 min prior to irradiation, respectively. In combination with single-dose irradiation, a single selenium application was given. With daily fractionated irradiation (3 Gy/fraction) for 1 week (days 0-4), selenium was administered at all 5 days of irradiation. With ten fractions over 2 weeks, selenium was applied in week 1, week 2, or both. All fractionation protocols were terminated by graded test doses to generate full dose-effect curves. RESULTS: In a single-dose control experiment, the ED(50) (dose after which ulcer induction is expected in 50% of the mice) was 12.9 +/- 1.6 Gy. Selenium increased the ED(50) to 17.7 +/- 2.6 Gy (s.c.; p = 0.0003) and 16.3 +/- 3.0 Gy (local; p = 0.0104). The ED(50) for test irradiation after 5 x 3 Gy was 7.4 +/- 2.2 Gy. Subcutaneous administration of selenium resulted in an ED(50) of 11.5 +/- 2.0 Gy (p = 0.0015), local application yielded an ED(50) of 10.0 +/- 2.1 Gy (p = 0.0284). The ED(50) for test irradiation after 10 x 3 Gy/2 weeks was 8.0 +/- 1.7 Gy. Subcutaneous or local administration of selenium in week 1 yielded a significant increase in ED(50) to 10.5 +/- 1.0 Gy (p = 0.0069) and 10.7 +/- 1.0 Gy (p = 0.0039), respectively. By clear contrast, selenium administration in week 2 had no significant effect. Administration in both weeks resulted in an ED(50) of 9.1 +/- 2.0 Gy (s.c.; p = 0.2747) and 9.7 +/- 1.4 Gy (local; p = 0.0541). CONCLUSION: Administration of sodium selenite during clinically relevant fractionated irradiation protocols has a significant effect during the initial treatment phase, i.e., week 1 in the mouse. Therefore, in clinical radiotherapy, the latent time to manifestation of confluent mucositis may be significantly prolonged, and hence the burden for the patient clearly reduced by selenium.

PMID: 17225944 [PubMed - indexed for MEDLINE]

Molecules. 2009 Oct 12;14(10):3975-88.

Micke O, Schomburg L, Buentzel J, Kisters K, Muecke R.

Department of Radiotherapy and Radiation Oncology, Franziskus Hospital, Kiskerstrasse 26, D- 33615 Bielefeld, Germany.

The essential trace element selenium, which is a crucial cofactor in the most important endogenous antioxidative systems of the human body, is attracting more and more the attention of both laypersons and expert groups. The interest of oncologists mainly focuses in the following clinical aspects: radioprotection of normal tissues, radiosensitizing in malignant tumors, antiedematous effect, prognostic impact of selenium, and effects in primary and secondary cancer prevention. Selenium is a constituent of the small group of selenocysteine-containing selenoproteins and elicits important structural and enzymatic functions. Selenium deficiency has been linked to increased infection risk and adverse mood states. It has been shown to possess cancer-preventive and cytoprotective activities in both animal models and humans. It is well established that Se has a key role in redox regulation and antioxidant function, and hence in membrane integrity, energy metabolism and protection against DNA damage. Recent clinical trials have shown the importance of selenium in clinical oncology. Our own clinical study involving 48 patients suggest that selenium has a positive effect on radiation-associated secondary lymphedema in patients with limb edemas, as well as in the head and neck region, including endolaryngeal edema. Another randomized phase III study of our group was performed to examine the cytoprotective properties of selenium in radiation oncology. The aim was to evaluate whether sodium selenite is able to compensate a preexisting selenium deficiency and to prevent radiation induced diarrhea in adjuvant radiotherapy for pelvic gynecologic malignancies. Through this study, the significant benefits of sodium selenite supplementation with regards to selenium deficiency and radiotherapy induced diarrhea in patients with cervical and uterine cancer has been shown for the first time in a prospective randomized trial. Survival data imply that supplementation with selenium does not interfere with the positive biological effects of radiation treatment and might constitute a valuable adjuvant therapy option especially in marginally supplied individuals. More recently there were emerging concerns coming up from two large clinical prevention trials (NPC, SELECT), that selenium increases the possible risk of developing diabetes type II. Despite obvious flaws of both studies and good counterarguments, a controversial debate remains on the possible advantage and risks of selenium in cancer prevention. However, in the light of the recent clinical trials the potential benefits of selenium supplementation in tumor patients are undeniable, even if further research is needed.

PMID: 19924043 [PubMed - indexed for MEDLINE]

Cancer Prev Res (Phila Pa). 2009 Nov;2(11):931-41.

Tsao AS, Liu D, Martin J, Tang XM, Lee JJ, El-Naggar AK, Wistuba I, Culotta KS, Mao L, Gillenwater A, Sagesaka YM, Hong WK, Papadimitrakopoulou V.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.

Comment in: Cancer Prev Res (Phila Pa). 2009 Nov;2(11):919-21.

Epidemiologic and preclinical data support the oral cancer prevention potential of green tea extract (GTE). We randomly assigned patients with high-risk oral premalignant lesions (OPL) to receive GTE at 500, 750, or 1,000 mg/m(2) or placebo thrice daily for 12 weeks, evaluating biomarkers in baseline and 12-week biopsies. The OPL clinical response rate was higher in all GTE arms (n = 28; 50%) versus placebo (n = 11; 18.2%; P = 0.09) but did not reach statistical significance. However, the two higher-dose GTE arms [58.8% (750 and 1,000 mg/m(2)), 36.4% (500 mg/m(2)), and 18.2% (placebo); P = 0.03] had higher responses, suggesting a dose-response effect. GTE treatment also improved histology (21.4% versus 9.1%; P = 0.65), although not statistically significant. GTE was well tolerated, although higher doses increased insomnia/nervousness but produced no grade 4 toxicity. Higher mean baseline stromal vascular endothelial growth factor (VEGF) correlated with a clinical (P = 0.04) but not histologic response. Baseline scores of other biomarkers (epithelial VEGF, p53, Ki-67, cyclin D1, and p16 promoter methylation) were not associated with a response or survival. Baseline p16 promoter methylation (n = 5) was associated with a shorter cancer-free survival. Stromal VEGF and cyclin D1 expression were downregulated in clinically responsive GTE patients and upregulated in nonresponsive patients at 12 weeks (versus at baseline). An extended (median, 27.5 months) follow-up showed a median time to oral cancer of 46.4 months. GTE may suppress OPLs, in part through reducing angiogenic stimulus (stromal VEGF). Higher doses of GTE may improve short-term (12-week) OPL outcome. The present results support longer-term clinical testing of GTE for oral cancer prevention.

PMID: 19892663 [PubMed - indexed for MEDLINE]

Radiat Res. 2008 Apr;169(4):384-96.

Wambi C, Sanzari J, Wan XS, Nuth M, Davis J, Ko YH, Sayers CM, Baran M, Ware JH, Kennedy AR.

Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

The purpose of this study was to determine whether a dietary supplement consisting of L-selenomethionine, vitamin C, vitamin E succinate, alpha-lipoic acid and N-acetyl cysteine could improve the survival of mice after total-body irradiation. Antioxidants significantly increased the 30-day survival of mice after exposure to a potentially lethal dose of X rays when given prior to or after animal irradiation. Pretreatment of animals with antioxidants resulted in significantly higher total white blood cell and neutrophil counts in peripheral blood at 4 and 24 h after 1 Gy and 8 Gy. Antioxidants were effective in preventing peripheral lymphopenia only after low-dose irradiation. Antioxidant supplementation was also associated with increased bone marrow cell counts after irradiation. Supplementation with antioxidants was associated with increased Bcl2 and decreased Bax, caspase 9 and TGF-beta1 mRNA expression in the bone marrow after irradiation. Maintenance of the antioxidant diet was associated with improved recovery of the bone marrow after sublethal or potentially lethal irradiation. Taken together, oral supplementation with antioxidants appears to be an effective approach for radioprotection of hematopoietic cells and improvement of animal survival, and modulation of apoptosis is implicated as a mechanism for the radioprotection of the hematopoietic system by antioxidants.

PMID: 18363433 [PubMed - indexed for MEDLINE]

Cancer Lett. 2008 Oct 8;269(2):352-62. Epub 2008 May 9.

Ramasamy K, Agarwal R.

Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, 4200 East Ninth Street, Box C238, Denver, CO 80262, USA.

Silymarin, a flavonolignan from milk thistle (Silybum marianum) plant, is used for the protection against various liver conditions in both clinical settings and experimental models. In this review, we summarize the recent investigations and mechanistic studies regarding possible molecular targets of silymarin for cancer prevention. Number of studies has established the cancer chemopreventive role of silymarin in both in vivo and in vitro models. Silymarin modulates imbalance between cell survival and apoptosis through interference with the expressions of cell cycle regulators and proteins involved in apoptosis. In addition, silymarin also showed anti-inflammatory as well as anti-metastatic activity. Further, the protective effects of silymarin and its major active constituent, silibinin, studied in various tissues, suggest a clinical application in cancer patients as an adjunct to established therapies, to prevent or reduce chemotherapy as well as radiotherapy-induced toxicity. This review focuses on the chemistry and analogues of silymarin, multiple possible molecular mechanisms, in vitro as well as in vivo anti-cancer activities, and studies on human clinical trials.

PMID: 18472213 [PubMed - indexed for MEDLINE]

Biochem Biophys Res Commun. 2009 Dec 4;390(1):71-6. Epub 2009 Sep 22.

Jung HJ, Park JW, Lee JS, Lee SR, Jang BC, Suh SI, Suh MH, Baek WK.

Chronic Disease Research Center, School of Medicine, Keimyung University, Daegu 700-712, Republic of Korea.

Silibinin is a polyphenolic flavonoid isolated from the milk thistle (Silybum marianum) and is reported to exhibit anticancer properties. Recently, it has been reported that silibinin inhibits hypoxia-inducible factor-1alpha (HIF-1alpha) expression in cancer cells. However, the precise mechanism by which silibinin decreases HIF-1 expression is not fully understood. In this study, silibinin inhibited basal and hypoxia induced expression levels of HIF-1alpha protein in LNCaP and PC-3 prostate cancer cells, while the rate of HIF-1alpha protein degradation and mRNA levels were not affected. We found that the decrease in HIF-1 protein by silibinin correlated with suppression of de novo synthesis of HIF-1alpha protein. Silibinin inhibited global protein synthesis coincided with reduction of eIF4F complex formation and induction of phosphorylation of the translation initiation factor 2alpha (eIF-2alpha) which can cause inhibition of general protein synthesis. These results suggest that silibinin's activity to inhibit HIF-1alpha protein expression is associated with the suppression of global protein translation.

PMID: 19778521 [PubMed - indexed for MEDLINE]

Oncogene. 2009 Jan 22;28(3):313-24. Epub 2008 Nov 3.

García-Maceira P, Mateo J.

Department of Regenerative Cardiology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.

The hypoxia-inducible factor 1 (HIF-1) plays a critical role for tumour adaptation to microenvironmental hypoxia, and represents an appealing chemotherapeutic target. Silibinin is a nontoxic flavonoid reported to exhibit anticancer properties. However, the mechanisms by which silibinin inhibits tumour growth are not fully understood. In this study, silibinin was found to inhibit hypoxia-induced HIF-1alpha accumulation and HIF-1 transcriptional activity in human cervical (HeLa) and hepatoma (Hep3B) cells. Neither HIF-1alpha protein degradation rate nor HIF-1alpha steady-state mRNA level was affected by silibinin. Rather, we found that suppression of HIF-1alpha accumulation by silibinin correlated with strong dephosphorylation of mammalian target of rapamycin (mTOR) and its effectors ribosomal protein S6 kinase (p70S6K) and eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), a pathway known to regulate HIF-1alpha expression at the translational level. Silibinin also activated Akt, a mechanistic feature exhibited by established mTOR inhibitors in many tumour cells. Moreover, silibinin reduced hypoxia-induced vascular endothelial growth factor (VEGF) release by HeLa and Hep3B cells, and this effect was potentiated by the PI3K/Akt inhibitor LY294002. Finally, silibinin was found to be a potent inhibitor of cell proliferation. These results show that silibinin is an effective inhibitor of HIF-1 and provide new perspectives into the mechanism of its anticancer activity.

PMID: 18978810 [PubMed - indexed for MEDLINE]

Int J Radiat Oncol Biol Phys. 2004 Jan 1;58(1):167-74.

Ertekin MV, Koç M, Karslioglu I, Sezen O.

Department of Radiation Oncology, Atatürk University Faculty of Medicine, Erzurum, Turkey. mvertekin@hotmail.com

PURPOSE: To determine the effect of oral zinc sulphate supplementation on radiation-induced oropharyngeal mucositis in patients with head-and-neck cancer. MATERIALS AND METHODS: Thirty patients with head-and-neck cancer were randomly assigned to receive either zinc sulfate or placebo. Primary tumors were localized in the larynx in 14 patients, in the nasopharynx in 4, in the oral cavity in 4, in a salivary gland in 1, in the maxillary sinus in 1, in neck nodes (lymphoma presenting primarily) in 3 and in neck metastases from an unknown primary in 3. In the placebo group, 3 patients were excluded; 1 patient died during treatment, 1 left the study, and 1 did not come to the 6 week control visit. The patients were treated with telecobalt radiotherapy at conventional fractionation (2 Gy/fraction, five fractions weekly, for 20-35 fractions within 4-7 weeks). The median radiation dose was 6400 cGy (4000-7000 cGy). Oral mucositis was assessed by two independent physicians, experts in radiation oncology, using the Radiation Therapy Oncology Group Acute Radiation Morbidity Scoring criteria. RESULTS: In the zinc sulfate group, Grade 3-4 mucositis was not detected in any patient; Grade 0 mucositis was detected in 2, and Grade 1 in 8, and Grade 2 in 5 patients. In the placebo group, Grade 2 mucositis was detected in 4 and Grade 3 in 8 patients. We observed that the degree of mucositis in the patients in the zinc sulfate group was significantly lower than that in the placebo group (p < 0.05). Confluent mucositis developed earlier in the placebo group than in the zinc sulfate group after the onset of treatment (p < 0.05) and started to improve sooner in the zinc sulfate group than in the placebo group (p < 0.05). CONCLUSIONS: Zinc sulfate is beneficial in decreasing the severity of radiation-induced mucositis and oral discomfort. These results should be confirmed by additional evaluation in randomized studies with a larger number of patients.

PMID: 14697435 [PubMed - indexed for MEDLINE]

J Am Coll Nutr. 1998 Oct;17(5):409-18.

Prasad AS, Beck FW, Doerr TD, Shamsa FH, Penny HS, Marks SC, Kaplan J, Kucuk O, Mathog RH.

Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan, USA.

In this review, we provide evidence based on our studies, for zinc deficiency and cell mediated immune disorders, and the effects of protein and zinc status on clinical morbidities in patients with head and neck cancer. We investigated subjects with newly diagnosed squamous cell carcinoma of the oral cavity, oropharynx, larynx, and hypopharynx. Patients with metastatic disease and with severe co-morbidity were excluded. Nutritional assessment included dietary history, body composition, and prognostic nutritional index (PNI) determination. Zinc status was determined by zinc assay in plasma, lymphocytes, and granulocytes. Pretreatment zinc status and nutritional status were correlated with clinical outcomes in 47 patients. Assessment of immune functions included production of TH1 and TH2 cytokines, T cell subpopulations and cutaneous delayed hypersensitivity reaction to common antigens. At baseline approximately 50% of our subjects were zinc-deficient based on cellular zinc criteria and had decreased production of TH1 cytokines but not TH2 cytokines, decreased NK cell lytic activity and decreased proportion of CD4+ CD45RA+ cells in the peripheral blood. The tumor size and overall stage of the disease correlated with baseline zinc status but not with PNI, alcohol intake, or smoking. Zinc deficiency was associated with increased unplanned hospitalizations. The disease-free interval was highest for the group which had both zinc sufficient and nutrition sufficient status. Zinc deficiency and cell mediated immune dysfunctions were frequently present in patients with head and neck cancer when seen initially. Zinc deficiency resulted in an imbalance of TH1 and TH2 functions. Zinc deficiency was associated with increased tumor size, overall stage of the cancer and increased unplanned hospitalizations. These observations have broad implications in the management of patients with head and neck cancer.

PMID: 9791836 [PubMed - indexed for MEDLINE]

Oral Dis. 2009 Aug 4. [Epub ahead of print]

Gómez-Moreno G, Guardia J, Ferrera MJ, Cutando A, Reiter RJ.

School of Dentistry, University of Granada, Granada, Spain.

Oral Diseases (2009) doi: 10.1111/j.1601-0825.2009.01610.xBackground: Melatonin is the principal secretory product of the pineal gland. It has immunomodulatory and antioxidant activities, stimulates the proliferation of collagen and osseous tissue and acts as a protector against cellular degeneration associated with aging and toxin exposure. Arising out of its antioxidant actions, melatonin protects against inflammatory processes and cellular damage caused by the toxic derivates of oxygen. As a result of these actions, melatonin may be useful as a co-adjuvant in the treatment of certain conditions of the oral cavity. Methods: An extensive review of the scientific literature was carried out using PubMed, Science Direct, ISI Web of Knowledge and the Cochrane base. Results: Melatonin, which is released into the saliva, may have important implications for oral diseases. Melatonin may have beneficial effects in certain oral pathologies including periodontal diseases, herpes viral infections and Candida, local inflammatory rocesses, xerostomia, oral ulcers and oral cancer. Conclusions: Melatonin may play a role in protecting the oral cavity from tissue damage caused by oxidative stress. The experimental evidence suggests that melatonin may have utility in the treatment of several common diseases of the oral cavity. However, more specific studies are necessary to extend the therapeutic possibilities to other oral diseases.

PMID: 19682319 [PubMed - as supplied by publisher]

Laryngoscope. 2007 Aug;117(8):1381-8.

Janus SC, Weurtz B, Ondrey FG.

Department of Otolaryngology, University of Minnesota, Minneapolis, Minnesota 55455, USA. janu0003@umn.edu

OBJECTIVES/HYPOTHESIS: Nuclear factor (NF)-kappaB is an early response gene that has been associated with head and neck squamous cell cancer (HNSCC) progression. NF-kappaB activation is induced by some chemotherapy agents, including paclitaxel. The activation of this gene can be correlated with apoptosis resistance. Inositol hexaphosphate (IP6) is a naturally occurring polyphosphorylated carbohydrate. NF-kappaB levels were evaluated in oral cavity HNSCC lines after treatment with paclitaxel and IP6, alone and in combination. Resulting levels of cell death and apoptosis were assessed, and conclusions are drawn regarding a possible synergistic relationship between paclitaxel and IP6. METHODS: NF-kappaB activation in cancer cells treated with paclitaxel and IP6, alone and in combination, was measured by transient transfection, and results were interpreted by luminometry. Cell proliferation of treated cells was measured by MTT assay. Cell viability and apoptosis of cancer cells treated with paclitaxel and IP6 combinations were quantitated by trypan blue staining and Caspase-Glo 3/7 assay, respectively. RESULTS: IP6 was observed to significantly downregulate NF-kappaB activation in both NA and CA-9-22 oral cavity HNSCC cell lines. Paclitaxel treatments caused increased NF-kappaB activation in the same cell lines. IP6 was observed to mitigate paclitaxel-induced NF-kappaB activation in the CA-9-22 cell line. IP6, when combined with paclitaxel, reduces CA-9-22 cell proliferation, increases cell death, and increases apoptosis, when compared with treatment with paclitaxel alone. CONCLUSIONS: IP6 reduces paclitaxel induced NF-kappaB activation and increases paclitaxel-mediated cell killing and apoptosis. As a well-tolerated and safe supplement, IP6 deserves further study in the treatment of oral cavity squamous cell carcinoma.

PMID: 17607147 [PubMed - indexed for MEDLINE]

Oral Oncol. 2005 Apr;41(4):383-9.

Kim KS, Rhee KH, Yoon JH, Lee JG, Lee JH, Yoo JB.

Department of Otorhinolaryngology, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemoon-gu, Seoul, Korea. ydrhinol@yumc.yonsei.ac.kr

We have investigated whether Ginkgo biloba extract (EGb 761) induces apoptosis of oral cavity cancer cells and attempted to characterize the apoptotic pathway activated by EGb 761. The inhibition of SCC 1483 oral cavity cancer cells proliferation was noted from 250 micro/ml of EGb 761. Apoptosis was observed after 24 h of incubation with 250 microg/ml EGb 761 and occurred in a time- and dose-dependent manner. Apoptosis was confirmed by DNA fragmentation and PARP cleavage. Co-treatment with the caspase inhibitor (z-VAD-fmk) inhibited apoptosis and PARP cleavage induced by EGb 761. Caspase-3 activity was upregulated by EGb 761 but reduced to the control level by co-treating with z-VAD-fmk. In summary, EGb 761 induces apoptosis of oral cavity cancer cells and caspase-3 is activated in this apoptosis. Therefore, EGb 761 may be considered as a possible chemopreventive agent against oral cavity cancer.

PMID: 15792610 [PubMed - indexed for MEDLINE]

Cancer Biol Ther. 2009 Nov;8(21):1994-2001. Epub 2009 Nov 3.

Karar J, Maity A.

Department of Radiation Oncology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.

Radiosensitivity can be influenced both by factors intrinsic and extrinsic to the cancer cell. One of the factors in the tumor microenvironment (TME) extrinsic to the cancer cell that can affect radiosensitivity is oxygenation. Severely hypoxic cells require a 2-3 fold higher dose of radiation to achieve the same level of cell killing as do well-oxygenated cells. Other elements in the microenvironment that may influence tumor radiosensitivity are the response of stromal cells to radiation and the expression of factors such as vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1 (HIF-1). There are currently several classes of agents that may increase tumor radiosensitivity by modulating the TME. Pre-clinical evidence indicates that inhibition of VEGF may increase local control after radiation. Several mechanisms have been postulated to explain this including radiosensitization of tumor endothelial cells, prevention of the establishment of new vasculature post-radiation, and increased oxygenation secondary to vascular normalization. Agents targeting HIF-1 also increase local control after radiation in pre-clinical models. This may occur via indirect inhibition of VEGF, which is a downstream target of HIF-1, or by VEGF-independent means. When combined with radiation, the EGFR inhibitor cetuximab improves local control and survival in patients with head and neck cancer. Pre-clinical data indicate that EGFR inhibitors can increase the intrinsic radiosensitivity of cancer cells. They can also improve tumor blood flow and oxygenation, which may increase extrinsic radiosensitivity. One of the pathways downstream of EGFR that may contribute to this effect is the PI3K/Akt pathway. Agents that directly inhibit this pathway improve blood flow and increase tumor oxygenation in pre-clinical models. The challenge remains to obtain clinical data from patients showing that modulation of the TME is an important mechanism by which biological agents can radiosensitize tumors and then to utilize this information to optimize therapy.

PMID: 19823031 [PubMed - in process]

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