Cell Sugar Concentrations Affect Hyaluronan Production and Cancer Growth

Cell Sugar Concentrations Affect Hyaluronan Production and Cancer Growth

Feb. 27, 2013 — According to a recent University of Eastern Finland (UEF) study, elevated cell sugar concentrations increase the production of hyaluronan which, in turn, promotes cancer growth. Regulating the production of hyaluronan may be a way to prevent the spreading of cancer.

Hyaluronan is a long, linear carbohydrate polymer present in the human body. It forms a coating on the surface of many cells and plays a key role in fetal development and in the maintenance of normal tissue balance. Under normal circumstances, hyaluronan promotes tissue healing; however, it can also maintain inflammation and promote the growth of cancer cells. Due to its high water retention capacity, hyaluronan is widely used in cosmetics and also in the medical sector, for example in the treatment of osteoarthritis symptoms and in eye surgery. Hyaluronan injected into the human body for treatment purposes is not associated with cancer risk.
Cells produce hyaluronan with the help of three cell membrane enzymes (HAS1, HAS2 and HAS3), and the production process also needs glucose derivatives.. Hyaluronan synthase 1, i.e. the HAS1 enzyme, is the least well known of the hyaluronan-producing enzymes, and yet its role in cancer malignity seems to be greater than previously thought. Published in Journal of Biological Chemistry, the UEF study showed that HAS1 requires a higher sugar concentration for the production of hyaluronan than HAS2 and HAS3. This finding may be significant for fighting cancer, as cancer cells are known to thrive on blood glucose. Increased glucose levels can lead to increased production of hyaluronan which, in turn, promotes cancer growth. Increased hyaluronan levels have also been found in diabetics with increased blood sugar levels. Diabetics are known to have a higher risk for breast cancer.
HAS1 also plays a significant role in inflammation, because growth factors associated with inflammation mediation, e.g., interleukins, can increase its activeness. This finding constituted part of the doctoral study of Lic. Med. Hanna Siiskonen, which was recently examined at the University of Eastern Finland. By regulating hyaluronan levels, it may be possible to prevent the progression of cancer and other pathologies. The first clinical trials involving enzymes which break down hyaluronan have been able to slow down the growth and movement of cancer cells and to enhance the effectiveness of cancer drugs.

2012 Research Update – Dr. Dauchy

2012 Research Update – Dr. Dauchy
Since 2005 our research laboratory, under the direction of Dr. David E. Blask, Ph.D., M.D., has been actively involved in the study of leiomyosarcoma (LMS). As most of us are aware, LMS is primarily a disease of middle-aged people with the unique distinction of being difficult to treat with standard chemotherapy and radiation intervention, leaving surgical resection of the tumor as a primary alternative. From the beginning, it was clear to us that imaginative new strategies for treatment and/or prevention of LMS were needed.  Using a special technique developed in our lab for growing human LMS tumors in rats, we discovered that melatonin, the primary neurohormone produced by the pineal gland in our brain primarily at night, dramatically inhibits the growth of LMS.  In 2007 the National Leiomyosarcoma Foundation, while at Bassett Research Institute in Cooperstown, NY, awarded us a $70,000 grant to study melatonin’s LMS growth inhibitory effects. This led to the first basic research publication in 2009 in vivo describing the underlying mechanism behind melatonin’s potent anticancer effects. In 2011 the National Leiomyosarcoma Foundation awarded our team headed by Dr. Blask, and now including Dr. Lulu Mao, a molecular biologist, and myself, Bob Dauchy, a two-year $100,000 grant to continue our basic research efforts here at Tulane University in New Orleans, Louisiana. Over the past year, we have been attempting to determine the optimal effective dose of melatonin injested by human subjects that can suppress LMS tumor growth and metabolism and prevent metastasis. In studies now underway, blood samples from healthy female volunteers are collected following 1-hr administration of different doses of a commercially available melatonin supplement: 75 µg, 150 µg, 300 µg, or 1 mg.  Using our unique LMS tumor model, we then perfuse the human LMS tumors with the blood samples to determine what dose is most effective in inhibiting the tumor growth. We are very happy to announce, based on this recent work, that even low doses of melatonin (below 300 µg) administered to the subjects are remarkably effective in blocking the LMS cancer. At this time we would also like to inform everyone regarding some exciting recent developments in the life of one of our very own NLMSF members who has been working very closely with us. Our fellow member, whose name is held in confidence, has been on a regimen of 6 mg melatonin daily for nearly 1 ½  years. On January 1, 2012, our fellow member and dear friend informed us that the latest scan results just completed during the holidays showed no remaining tumor masses – LMS free for 1 year!

We are pleased to announce to all our members of the National Leiomyosarcoma Foundation that, to date, the LMS research conducted by our team has been presented in whole or in part in over 10 peer-reviewed publications – 5 since last year alone – and in over 50 published peer-reviewed abstracts, lectures, and presentations internationally, promoting continued awareness of LMS. Please know that your continued support and encouragement is so greatly appreciated. With each passing day our research team here at Tulane University continues to work diligently and unfalteringly on behalf of all our NLMSF membership and LMS patients everywhere in the eradication of this dreaded disease, – to Slay the Dragon.

LOW DOSE ANGIOPREVENTATIVE COCKTAIL for people who are NED (No Evidence of Disease)

for people who are NED (No Evidence of Disease)

1   500mg Acetyl-l-carnitine*  SW 1000 100 caps
1   600 mg Alpha lipoic acid*  SWU190 120 caps
1   325 mg. Aspirin
1   B 50 complex multi-vitamin with 500mg of C
1   900 mg Curcumin Complex * SWH084 60 caps
1   600 mg Green Tea Extract
1   250 mg Korean Ginseng * SW426 300 caps
3   3 mg Melantonin* SW502 120 caps
1   500 mg Milk Thistle *D7SW966          100 caps
2   600 mg N-acetylcysteine*  SW854 100 caps
1   1000 mg Omega three fish oil
1  30 mg Resveratrol Complex * SWU248 60 caps
1  100 mcg Selenium*  SW545 300 caps
1  550 mg Shark liver oil* SWU107 60 SFG
1  1,000 IU Vitamin D-3 * SW1030 250 caps
1  50 mg Zinc Gluconate* SW205 100 caps

*** Do not take Angio-preventative Cocktail ….
While healing…. (from surgery, fracture or other trauma)
While pregnant.

*Swanson Health Products 1(800) 437-4148   (low cost)
*For more information: www.pubmed.gov

Response to Jim Watson’s article about use of antioxidants for cancer

Most of Jim watsons’ article is spent attacking the use of antioxidants for cancer…

However in section 21 of Watson’s article… (see below), he writes about how effective metformin is against cancer. Metformin is a VERY strong ANTIOXIDANT. The fact that Jim dosen’t know this is beyond me. After the section by Watson…. I’ve included part of an article from Jefferson’s Kimmel Cancer Center on metformin and antioxidants…Bill

21. Metformin selectively targets (kills) mesenchymal cancer stem cells
Already we have at our disposal a relatively non-toxic, excessively well-tested drug that preferentially kills mesenchymal                     stem cells. In a still much unappreciated article published three years ago in Cancer Research, Kevin Struhl’s laboratory at Harvard Medical School first showed that metformin, a blocker of stage 2 oxidative phosphorylation,                     selectively targets stem cells. When so applied with chemotherapeutic agents to block xenographic tumour growth, it induces                     prolonged remission if not real cures [50,51]. But when metformin was left out of these experiments, subsequent multiplication of unkillable mesenchymal stem cells lets              these xenographs grow into life-threatening forms, showing that chemotherapy by itself does not kill stem cells. This most                     widely used anti-diabetic drug’s heightened ability to kill late-stage mesenchymal cancer cells probably explains why those                     humans who use it regularly have reduced incidences of many cancers.
Metformin is presently being added to a number of anti-cancer chemotherapeutic regimes to see whether it magnifies their effectiveness                     in humans. The fact that metformin works much more effectively against p53− − cells suggests that it may be most active against late-stage cancers, the vast majority of whose cells have lost both of           their p53 genes. By contrast, the highly chemo-radio-sensitive early-stage cancers against which most of anti-cancer drug development                     has focused might very well show little metformin effectiveness. By the end of 2013, we should know whether it radically improves                     any current therapies now in use. Highly focused new drug development should be initiated towards finding compounds beyond                     metformin that selectively kill stem cells. And the reason why metformin preferentially kills p53− − stem cells should be even more actively sought out.


(portion of) article from Jefferson’s Kimmel Cancer Cener RE: Metformin

…Both studies add to a growing body of laboratory and clinical evidence that the diabetes drug can play a role in cancer treatment and prevention.
“It provides additional clinical evidence that we should be treating patients with drugs that directly target mitochondrial metabolism in cancer cells, like metformin,” Michael Lisanti, MD, PhD, chair of the Department of Stem Cell Biology and Regenerative Medicine at Jefferson’s Kimmel Cancer Center, told HemOnc Today recently.
Dr. Lisanti, who has been studying metabolism in cancer cells and ways to target that activity for years, added, “we should focus on inhibiting cancer cell mitochondria, which are the powerhouse of the cell.”
His research could help explain why the drug has such an impact on cancer cells.
Dr. Lisanti has shown that the cancer cell mitochondria are the powerhouse and unsuspecting “Achilles’ heel” of tumor growth. To stop that growth, he says, we need to cut off the “fuel supply” from neighboring tissue to the cancer cells with antioxidants.
Metformin, which has an antioxidant effect, can interfere with that activity and prevent cancer cells from using their mitochondria to grow and spread throughout the body, several of Dr. Lisanti’s recent studies suggest.

Cimetidine: an anticancer drug?

Eur J Pharm Sci. 2011 Apr 18;42(5):439-44. doi: 10.1016/j.ejps.2011.02.004. Epub  2011 Feb 15.
Cimetidine: an anticancer drug?
Kubecova M, Kolostova K, Pinterova D, Kacprzak G, Bobek V.

Department of Radiotherapy and Oncology, Charles University in Prague, Third Faculty of Medicine and Faculty Hospital Kralovske Vinohrady, Czech Republic.


Cimetidine, H(2) receptor antagonists, is commonly prescribed for gastric and duodenal ulcer disease. Additionally, cimetidine has been shown to have anticancer effects. This review describes the mechanism of antitumor action of cimetidine including its ability to interfere with tumor cell adhesion, angiogenesis and proliferation; its effect on the immune system; as well as inhibition of postoperative immunosuppression. Its anticancer effect is also compared to that of the other H(2) receptor antagonists as well as outcomes of cimetidine in clinical studies in cancer patients.
Copyright © 2011 Elsevier B.V. All rights reserved.



[PubMed – indexed for MEDLINE]

Drug-induced gynecomastia

Pharmacotherapy. 2012 Dec;32(12):1123-40. doi: 10.1002/phar.1138. Epub  2012 Nov 16.
Drug-induced gynecomastia.
Bowman JD, Kim H, Bustamante JJ.

Department of Pharmacy Practice, Rangel College of Pharmacy, Texas A&M Health Science Center, Kingsville, TX 78363-8202, USA. bowman@pharmacy.tamhsc.edu


Drugs account for about 20% of gynecomastia cases in men. As a number of factors can alter the estrogen:androgen ratio, several pathophysiologic mechanisms are associated with drugs causing this disorder. Antiandrogens, protease inhibitors, and nucleoside reverse transcriptase inhibitors are the most common drug causes of gynecomastia, whereas first-generation antipsychotics, spironolactone, verapamil, and cimetidine are less common causes. Other drugs have been reported rarely as causes. Treatment may involve switching to an alternative agent or may require surgery or irradiation if the causative agent cannot be discontinued. We reviewed the literature on drug-induced gynecomastia and provided another perspective by reviewing data from the United States Food and Drug Administration’s Adverse Event Reporting System. Epidemiologic studies are needed to provide a more accurate description of the frequency of drug-induced gynecomastia.
© 2012 Pharmacotherapy Publications, Inc.



[PubMed – in process]

Mediterr J Hematol Infect Dis. 2009 Nov 15;1(2):e2009012. The importance of epigenetic alterations in the development of epstein-barr virus-related lymphomas.

Mediterr J Hematol Infect Dis. 2009 Nov 15;1(2):e2009012.
The importance of epigenetic alterations in the development of epstein-barr virus-related lymphomas.

Division of Virology, National Center for Epidemiology, H-1097 Budapest, Gyali út 2-6, Hungary.

Epstein-Barr virus (EBV), a human gammaherpesvirus, is associated with a series of malignant tumors. These include lymphomas (Burkitt’s lymphoma, Hodgkin’s disease, T/NK-cell lymphoma, post-transplant lymphoproliferative disease, AIDS-associated lymphoma, X-linked lymphoproliferative syndrome), carcinomas (nasopharyngeal carcinoma, gastric carcinoma, carcinomas of major salivary glands, thymic carcinoma, mammary carcinoma) and a sarcoma (leiomyosarcoma). The latent EBV genomes persist in the tumor cells as circular episomes, co-replicating with the cellular DNA once per cell cycle. The expression of latent EBV genes is cell type specific due to the strict epigenetic control of their promoters. DNA methylation, histone modifications and binding of key cellular regulatory proteins contribute to the regulation of alternative promoters for transcripts encoding the nuclear antigens EBNA1 to 6 and affect the activity of promoters for transcripts encoding transmembrane proteins (LMP1, LMP2A, LMP2B). In addition to genes transcribed by RNA polymerase II, there are also two RNA polymerase III transcribed genes in the EBV genome (EBER 1 and 2). The 5′ and internal regulatory sequences of EBER 1 and 2 transcription units are invariably unmethylated. The highly abundant EBER 1 and 2 RNAs are not translated to protein. Based on the cell type specific epigenetic marks associated with latent EBV genomes one can distinguish between viral epigenotypes that differ in transcriptional activity in spite of having an identical (or nearly identical) DNA sequence. Whereas latent EBV genomes are regularly targeted by epigenetic control mechanisms in different cell types, EBV encoded proteins may, in turn, affect the activity of a set of cellular promoters by interacting with the very same epigenetic regulatory machinery. There are EBNA1 binding sites in the human genome. Because high affinity binding of EBNA1 to its recognition sites is known to specify sites of DNA demethylation, we suggest that binding of EBNA1 to its cellular target sites may elicit local demethylation and contribute thereby to the activation of silent cellular promoters. EBNA2 interacts with histone acetyltransferases, and EBNALP (EBNA5) coactivates transcription by displacing histone deacetylase 4 from EBNA2-bound promoter sites. EBNA3C (EBNA6) seems to be associated both with histone acetylases and deacetylases, although in separate complexes. LMP1, a transmembrane protein involved in malignant transformation, can affect both alternative systems of epigenetic memory, DNA methylation and the Polycomb-trithorax group of protein complexes. In epithelial cells LMP1 can up-regulate DNA methyltransferases and, in Hodgkin lymphoma cells, induce the Polycomb group protein Bmi-1. In addition, LMP1 can also modulate cellular gene expression programs by affecting, via the NF-κB pathway, levels of cellular microRNAs miR-146a and miR-155. These interactions may result in epigenetic dysregulation and subsequent cellular dysfunctions that may manifest in or contribute to the development of pathological changes (e.g. initiation and progression of malignant neoplasms, autoimmune phenomena, immunodeficiency). Thus, Epstein-Barr virus, similarly to other viruses and certain bacteria, may induce pathological changes by epigenetic reprogramming of host cells. Elucidation of the epigenetic consequences of EBV-host interactions (within the framework of the emerging new field of patho-epigenetics) may have important implications for therapy and disease prevention, because epigenetic processes are reversible and continuous silencing of EBV genes contributing to patho-epigenetic changes may prevent disease development.






Free PMC Article

Caffeine Induces Apoptosis of Osteosarcoma Cells by Inhibiting AKT/mTOR/S6K, NF-κB and MAPK Pathways Anticancer Research, 09/21/2012

Caffeine Induces Apoptosis of Osteosarcoma Cells by Inhibiting AKT/mTOR/S6K,  NF-κB and MAPK Pathways
Anticancer Research,  09/21/2012

Miwa S et al. – Caffeine inhibited proliferation of HOS cells and suppressed  nuclear factor kappa–light–chain–enhancer of activated B cells (NF–κB), AKT,  mTOR/S6K and ERK activities. The results support those from previous studies  relating to the use of caffeine in the treatment of osteosarcoma.

Read more: http://www.mdlinx.com/orthopedics/news-article.cfm/4217629/osteosarcoma#ixzz2EOp76ZI2

Cancer. 2012 Dec 1;118(23):5878-87. doi: 10.1002/cncr.27614. Epub  2012 May 30.
Alterations of the p53 and PIK3CA/AKT/mTOR pathways in angiosarcomas: A pattern distinct from other sarcomas with complex genomics.
Italiano A, Chen CL, Thomas R, Breen M, Bonnet F, Sevenet N, Longy M, Maki RG, Coindre JM, Antonescu CR.

Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York; Department of Medical Oncology, Bergonie Institute, Bordeaux, France.italiano@bergonie.org.

The p53 and phosphoinositide-3-kinase, catalytic, alpha polypeptide/v-akt murine thymoma viral oncogene homolog/mechanistic target of rapamycin (PIK3CA/AKT/mTOR) pathways frequently are altered in sarcoma with complex genomics, such as leiomyosarcoma (LMS) or undifferentiated pleomorphic sarcoma (UPS). The scale of genetic abnormalities in these pathways remains unknown in angiosarcoma (AS).
The authors investigated the status of critical genes involved in the p53 and PIK3CA/AKT/mTOR pathways in a series of 62 AS.
The mutation and deletion rates of tumor protein 53 (TP53) were 4% and 0%, respectively. Overexpression of p53 was detected by immunohistochemistry in 49% of patients and was associated with inferior disease-free survival. Although p14 inactivation or overexpression of the human murine double minute homolog (HDM2) were frequent in LMS and UPS and could substitute for TP53 mutation or deletion, such alterations were rare in angiosarcomas. Phosphorylated ribosomal protein S6 kinase (p-S6K) and/or phosphorylated eukaryotic translation initiation factor 4E binding protein 1 (p-4eBP1) overexpression was observed in 42% of patients, suggesting frequent activation of the PIK3CA/AKT/mTOR pathway in angiosarcomas. Activation was not related to intragenic deletion of phosphatase and tensin homolog (PTEN), an aberration that is frequent in LMS and UPS but absent in angiosarcomas.
The current results indicated that angiosarcomas constitute a distinct subgroup among sarcomas with complex genomics. Although TP53 mutation and PTEN deletion are frequent in LMS and UPS, these aberrations are rarely involved in the pathogenesis of angiosarcoma. Cancer 2012. © 2012 American Cancer Society.
Copyright © 2012 American Cancer Society.