HOUSTON – Long-chain omega-3 fatty acids, primarily found in fish and seafood, may have a role in colorectal cancer prevention, according to results presented at the American Association for Cancer Research Frontiers in Cancer Prevention Research Conference, held Dec. 6-9, 2009, in Houston.

“Experimental data have shown benefits of long-chain omega-3 fatty acids in colorectal carcinogenesis, ranging from reduced tumor growth, suppression of angiogenesis and inhibition of metastasis,” said Sangmi Kim, Ph.D., a postdoctoral fellow at the National Institute of Environmental Health Sciences, Research Triangle Park, N.C. “Our finding of inverse association between dietary intakes of long-chain omega-3 fatty acids and distal large bowel cancer in white participants adds additional support to the hypothesis.”

Although experimental and clinical data suggest that long-chain omega-3 fatty acids possess anti-neoplastic properties in the colon, epidemiologic data to date has been inconclusive.

Kim and colleagues studied the link between polyunsaturated fatty acid intake and distal large bowel cancer using data from a population-based control study. They recruited 1,509 white participants (716 cancer cases and 787 controls) and 369 black participants (213 cancer cases and 156 controls) using the State Cancer Registry and Division of Motor Vehicles records.

Nineteen polyunsaturated fatty acids were assessed using a validated food frequency questionnaire, which included 124 questions on food items. The researchers used the questionnaire to collect information on the frequency and amount of foods typically consumed in the past 12 months.

Patients who consumed more long-chain omega-3 fatty acids had a reduced risk of distal large bowel cancer. Compared to the lowest quartile, fat intake in the highest quartile was linked with a 39 percent reduced risk of cancer.

The researchers detected these associations in white participants, but not in black participants.

“We were surprised that the association was not also observed among blacks,” Kim said. “We considered several possible explanations but were not able to account for this difference with the data we had. This finding warrants future study, but we should be careful about drawing conclusions about potential racial differences in the benefit from long-chain omega-3 fatty acids from this study.”

“An increase in dietary intake of long-chain omega-3 fatty acids, which mainly come from fish and seafood, may be beneficial in the prevention of distal large bowel cancer,” Kim said.

Commentary: And the list of health benefits of Omega-3 fatty acids continues to grow. I have been asked which product I use by several patients. I use Opti-EPA from Douglas Labs. They are enterically coated so they won’t give you indigestion. This product and others are available through my virtual dispensary. Please click here and use the access code “HEAL,” set-up an account and go shopping!

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Source: AACR Press Release, http://www.aacr.org/home/public–media/aacr-press-releases.aspx?d=1683

Edy Meiyanto 1), Rosita Melannisa 2) dan Muhammad Da’i 2)1) Faculty of Pharmacy Gadjah Mada University, Yogyakarta, 2) Faculty of Pharmacy Muhammadiyah Surakarta University

Abstract

Breast cancer is the most common cancer occurring in women after cervix cancer in Indonesia. Tumor metastasis is the major cause of mortality in breast cancer. For a tumor cell to metastasize effectively, it must induce angiogenesis. 17 β-estradiol has been shown to stimulate the proliferation and angiogenesis of breast cancer cells which express estrogen receptor (ER), T47D (human breast cancer cell line). In the present study Pentagamavunon-1 or PGV-1 [2,5-bis-(4'-hydroxy-3',5'-dimethylbenzylidene)- cyclopentanone], an analogue of curcumin [1,7-bis-(4'-hydroxy-3'-methoxyphenyl)-1,6-heptadiena-3,5-dion], were tested on their cytotoxicity and suppression effect on angiogenic factors (i.e. VEGF and COX-2) on the breast cancer cell lines (T47D) induced by 17 β-estradiol 10-8 M. The results showed that PGV-1 performed cytotoxicity effect againts T47D cells with IC50 values 3,16 µM. This was more potent than curcumin (IC50 = 19,05 µM). PGV-1 5 µM and curcumin 20 µM decrease VEGF and COX-2 expression. These results suggest both compounds possessed antiangio-genic potensial.

Keywords : PGV-1, curcumin, 17 β-estradiol, angiogenesis

NOTE – This blog entry is reprinted in its entirety from a New York Times guest-editorial by Bono, dated Jan. 2, 2010 – illustrations by Peter Arkle. Bono is much more than the U2 frontman. He has been a voice for many causes around the world, has been named Man of the Year by Time magazine, and been nominated for the Nobel Peace Prize.

When I read this piece, I wanted more people to read it. See if you find any ideas that give you hope for the future…

Ten for the Next Ten

By BONO

An Equal Right to Pollute (and the Polluter-Pays Principle)

In the recent climate talks in Copenhagen, it was no surprise that developing countries objected to taking their feet off the pedal of their own carbon-paced growth; after all, they played little part in building the congested eight-lane highway of a problem that the world faces now. One smart suggestion I’ve heard, sort of a riff on cap-and-trade, is that each person has an equal right to pollute and that there might somehow be a way to monetize this. By this accounting, your average Ethiopian can sell her underpolluting ways (people in Ethiopia emit about 0.1 ton of carbon a year) to the average American (about 20 tons a year) and use the proceeds to deal with the effects of climate change (like drought), educate her kids and send them to university. (Trust in capitalism — we’ll find a way.) As a mild green, I like the idea, though it’s controversial in militant, khaki-green quarters. And yes, real economists would prefer to tax carbon at the source, but so far the political will is not there. If it were me, I’d close the deal before the rising nations want it backdated.

A Person (Dr. William Li) and a Word (Angiogenesis)

Angiogenesis is the process by which new blood vessels grow. This is good — except when it’s very bad, as in the case of cancerous tumors. Blood vessels are their supply lines. Dr. William Li of the Angiogenesis Foundation has called research in this realm the “first medical revolution of the 21st century,” and he should know. (I shouldn’t, given my lack of a medical pedigree, but I learned about it from my bandmate the Edge, who supports Dr. Li’s foundation.) Work on angiogenesis inhibitors is at the vanguard. In a world worrying about whether it can afford health care, advances in prevention are at a premium. Factoid: Cancers start as tiny nests of malignant cells that do not enlarge until they recruit new vessels to deliver oxygen and nutrients; then a cancer can expand 16,000 times in only two weeks.

Matter Doesn’t Matter

God, it appears, is a Trekkie. (God help us.) Dr. Anton Zeilinger, an Austrian physicist, is becoming a rock star of science for his work in quantum teleportation, which I know very little about but which I think I may have achieved backstage one night in Berlin in the early 1990s. At any rate, it seems to have something to do with teleporting properties or bits of information, not physical objects; even though Dr. Zeilinger plays down the possibility of a “Star Trek” moment, his breakthroughs are catching the attention of the nonscientific world for their metaphysical implications. His own version of E=mc2 ends in a cosmic punch line: that when it comes to the origin of the universe, information matters more than matter. Could it be that God is a nerd?

Festival of Abraham

Here’s something that could never have happened in the Naughts but will maybe be possible in the Tweens or Teens — if there’s a breakthrough in the Mideast peace process. The idea is an arts festival that celebrates the origin of the three Abrahamic religions: Judaism, Christianity and Islam. Every year it could be held in a different location; Jerusalem would obviously be the best place to start.In Ireland, at the height of the “Troubles,” it was said that the only solution for rabid sectarianism was to let 1,000 punk-rock bands bloom: music helped create a free space for dialogue (of a high-volume variety). So no politicians allowed. Artists only.

People Power and the Upside-Down Pyramid

Dr. Thomas Witzig, Dr. Matthew Drake, and Dr. James Cerhan discuss a new study that found the amount of vitamin D in patients being treated for diffuse large B-cell lymphoma was strongly associated with cancer progression and overall survival. The results were presented at the 2009 annual meeting of the American Society of Hematology .

ABSTRACT
Background: Vitamin D is a naturally occurring steroid hormone. In addition to its well established role in maintaining serum calcium homeostasis, vitamin D has effects on cellular differentiation, proliferation, apoptosis, and angiogenesis. Vitamin D3 is naturally produced in skin in response ultraviolet-B (UVB) radiation from the sun. Several recent studies, however, have shown that a high proportion of community-dwelling subjects in both tropical and temperate climates are deficient in vitamin D, and that subjects in northern latitudes often require dietary supplementation to maintain vitamin D sufficiency. Further, several reports now suggest that vitamin D sufficiency is protective against the development of several cancers, including non-Hodgkin lymphoma (NHL). However, it is not known whether vitamin D impacts prognosis in diffuse large B-cell lymphoma (DLBCL), the most common NHL subtype.

Methods: We evaluated serum vitamin D concentrations in two cohorts of DLBCL patients. The first cohort consisted of 374 patients newly diagnosed from September 2002-February 2008 who were prospectively enrolled in the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource, an observational study in which neither therapeutic nor diagnostic management is prescribed. All serum was obtained within 120 days of diagnosis, and was prior to treatment in 221 (59%). In the second study, 62 patients newly diagnosed from February 2006-August 2007 were enrolled on NCCTG clinical trial N0489, and all serum was obtained before the first course of therapy. Central pathology review was performed on all patients to confirm the diagnosis of DLBCL. Serum 25-hydroxyvitamin (25-OH-VitD) levels were measured by the gold standard method for vitamin D determination: liquid chromatography tandem mass spectroscopy (LC-MS/MS). Vitamin D deficiency was defined as total serum 25-OH-VitD < 25 ng/mL (62.5 nmol/L). SPORE patients were followed per a standard protocol for event-free (progression, retreatment, or death due to any cause) and overall survival (EFS and OS, respectively); N0489 patients were followed in a similar way per the clinical trial protocol. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CI).

Results: SPORE patients were primarily treated with immunochemotherapy (83%); all N0489 patients were treated with epratuzumab + R-CHOP21. The median age at diagnosis was 62 years (range, 19-93) for SPORE patients and 61 years (range, 21-82) for N0489 patients. Median follow-up for SPORE patients was 36 months (range, 1-77) with 95 deaths and 131 events; median follow-up for N0489 patients was 24 months (range, 7-39) with 13 deaths and 18 events. Vitamin D deficiency was identified in 188 SPORE patients (50%) and 15 N0489 patients (24%). There were no differences in the prevalence of vitamin D deficiency by age, IPI, or whether serum was obtained prior to starting treatment (all p > 0.28). Vitamin D deficiency was associated with inferior overall (HR=2.33, 95% CI 1.53-3.57, logrank p =0.0001) and event-free survival (HR=1.71, 95% CI 1.20-2.44, logrank p = 0.003) in the SPORE cohort. These associations remained significant after adjusting for IPI and treatment: OS HR=1.97, 95% CI 1.27-3.07; EFS HR=1.47, 95% CI 1.02-2.21. These results were similar for the subset of SPORE patients who were treated with R-CHOP. The HRs for vitamin D deficiency and event-free survival were consistent in the N0489 patients (HR=1.63, 95% CI 0.61-4.35, IPI adjusted HR=1.43, 95% CI 0.53-3.85), although these results lacked precision due to a smaller sample size. We were unable to evaluate OS in N0489 due to the small number of deaths.

Conclusions: Approximately 50% of all DLBCL patients in this northern US latitude population are vitamin D deficient at the time of diagnosis and treatment. Vitamin D deficient patients have an inferior event-free and overall survival compared to patients with vitamin D levels within the normal range. Vitamin D supplementation during treatment of DLBCL patients with vitamin D deficiency should be evaluated in a clinical trial setting.

Authors
Matthew T Drake, MD, PhD1*, Matthew J Maurer, MS1*, Brian K Link, MD2*, Ivana N Micallef, MD1*, Thomas M Habermann, MD1, Jennifer L Kelly, PhD, MPH3, William R Macon, MD1*,
Daniel Nikcevich, MD4*, Joseph P Colgan, MD1*, Cristine Allmer, BS1*, Susan L Slager, PhD1*, George J Weiner, MD2, Thomas E Witzig, MD1* and James R Cerhan, MD, PhD1
1Mayo Clinic, Rochester, MN; 2University of Iowa, Iowa City, IA;
3University of Rochester, Rochester, NY; 4St. Mary’s Duluth Clinic, Duluth, MN

PHILADELPHIA – Pancreatic cancer remains one of the deadliest and hardest to treat cancers. After diagnosis, patients tend to live only six months and less than 5 percent survive to five years.

“In terms of a patient population, there is very little we can do for them once we find the cancer,” said Craig Thompson, M.D., director of the Abramson Cancer Center at the University of Pennsylvania.

The currently available treatment is gemcitabine, which is sold as Gemzar by Eli Lilly and Company, but the response rate with this treatment is typically only 5 percent. Researchers are working to develop new ways of treating pancreatic cancer and early scientific studies are showing promise.

As part of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, Thompson moderated a press conference on emerging treatments in pancreatic cancer on Tuesday, Nov. 17, 2009, in Room 202 of the Hynes Convention Center in Boston, Mass., from 1:00 p.m. to 2:00 p.m. ET.

Researchers presented new data on nanotechnology methods of delivering therapies, angiogenesis, microRNA and the tumor microenvironment.

“Successful treatment of pancreatic cancer is going to require new and creative thinking from the scientific community, and the research being presented at this meeting is a good example of that,” said Thompson.

The following abstracts were presented at the press conference:

# A2. Targeting intracellular VEGF using nanotechnology for sub-cellular delivery of bevacizumab improves efficacy of combination therapy against pancreatic cancer

New nanotechnology-based delivery of a common anti-angiogenesis agent improved efficacy in models of pancreatic cancer, suggesting a possible therapy for this hard to treat disease.

Researchers at Massachusetts General Hospital used bevacizumab, sold under the brand name Avastin by Genentech, which is an anti-angiogenesis drug designed to starve cancerous tumors of the blood they need to grow. The Food and Drug Administration (FDA) has approved the agent for several cancers (including breast and colorectal cancers) and oncologists use it to treat other cancers as well.

Avastin works by removing vascular endothelial growth factor (VEGF), which is a protein that stimulates new blood vessel growth in tumors. However, as administered currently, it has had limited efficacy because it can only remove some of the VEGF on the outside of the tumor cell. VEGF can still thrive inside the cell where it is made and continues to be secreted outside, long after the injected Avastin has disappeared and thus contributes to tumor growth.

“In order for these agents to work you have to deliver them at the right place at the right time. While Avastin is able to partially mop up VEGF outside a tumor cell, this is the first time we have been able to show that it can effectively be delivered and work inside the cell as well,” said Tayyaba Hasan, Ph.D., professor of dermatology at Harvard Medical School and Massachusetts General Hospital.

Hasan and colleagues designed a nanotechnology-based delivery device to simultaneously deliver Avastin along with an FDA approved light-activated chemical within the tumor of mouse models of pancreatic cancer. In a previous small study, photodynamic therapy, a light activated therapy, enhanced the treatment outcome in pancreatic cancer. However, in clinical trials where standard chemotherapy for pancreatic cancer was combined with bevacizumab, there was no benefit to survival.

Their results showed that the nanotechnology successfully delivered Avastin to the interior of a pancreatic cancer cell and improved the acute treatment response in mice treated with the nanotechnology compared with those treated with Avastin alone. The combination with photodynamic therapy was associated with even greater improvements.

Absent the nanotechnology delivery, at the low doses of agents used, neither Avastin nor photodynamic therapy significantly improved the acute treatment effect of Avastin. The researchers also noted that Avastin delivered by nanotechnology caused at least a two-fold reduction in metastasis to the liver, lungs and lymph nodes.

“This finding represents a new paradigm for Avastin-based treatment that could be delivered with greater effectiveness and with less toxicity,” said Hasan.

# C246. Nab-paclitaxel targets tumor stroma and results, combined with gemcitabine, in high efficacy against pancreatic cancer models

Treatment with nab-paclitaxel appears to weaken the stroma, or protective wall, surrounding a pancreatic tumor and increase the potency of gemcitabine, the most commonly used agent for pancreatic cancer, when the two drugs are used in combination.

“What we are seeing here is a real paradigm shift, because it shows that effective treatment does not necessarily require a fancy new molecular therapy but just the smart combination of what is already available,” said Anirban Maitra, M.D., associate professor of pathology and oncology at the Johns Hopkins University School of Medicine.

Both gemcitabine, sold as Gemzar by Eli Lilly and Company, and nab-paclitaxel, sold as Abraxane by Abraxis Bioscience, are clinically available treatments. Researchers at TGen in Arizona and other clinical centers in the United States have already tested the combination in humans and reported preliminary results earlier this year demonstrating a median survival of 10.3 months, as compared to the previously reported 5.7 months survival seen with gemcitabine alone.

Maitra and colleagues sought to determine the mechanism behind that dramatic finding in 11 freshly generated pancreatic cancer mouse xenografts from Johns Hopkins laboratories.

Replicating the human trial, the researchers found the response rate of the combination in mice was almost double of what was seen with either agent alone.

A further evaluation by histology at the cellular level showed that nab-paclitaxel depleted the stroma surrounding pancreatic tumors and thus was able to facilitate delivery of gemcitabine more effectively. Those treated with the combination had a gemcitabine concentration in tumors that was 3.7-fold higher than what was seen with gemcitabine alone.

“What we have done is effectively make gemcitabine-resistant tumors into gemcitabine-sensitive tumors with the added punch of nab-paclitaxel, so we’re getting synergy of the two-drug combination and better delivery of gemcitabine where it needs to be,” said Maitra.

# A127. Combination therapy targeting EGFR/MET crosstalk using nanotechnology improves photodynamic therapy treatment of pancreatic cancer

Simultaneous inhibition of the epidermal growth factor receptor (EGFR) and MET signaling pathways significantly reduced pancreatic tumor burden and toxicity when inhibitors were delivered using nanotechnology, according to research conducted at Massachusetts General Hospital.

“These pathways are key to the growth of pancreatic tumors, and the fact that we were able to deliver these inhibitors in combination represents a significant step forward,” said Prakash Rai, Ph.D., a research fellow working in the Tayyaba Hasan, Ph.D., laboratory at Massachusetts General Hospital.

Cell growth pathway inhibition is a recognized therapy for cancer, and current treatment regimens typically deliver large molecules such as antibodies outside of a cell, whereas the smaller molecules that are readily delivered inside the cell are often associated with high toxicity. In this report, nanotechnology appears to overcome these problems; it was able to simultaneously deliver an antibody and a small molecule inside the cell while reducing the toxicity of the small molecule.

To target EGFR, researchers used C225, a receptor antibody that has shown no survival benefit in patients with pancreatic cancer. Because different cancer growth pathways have “cross talk” capabilities, combinations that simultaneously target these “cross-talking” pathways may have better outcomes. For the current study, Rai and colleagues simultaneously targeted the EGFR and the MET pathways by combining C225 with the small molecule inhibitor PHA-665752 in a nano-construct.

“Combination pathway inhibition is extremely important because if you just inhibit one pathway, the cancer cells are smart enough to grow using the other signaling pathway, so you have to attack both at once,” said Rai.

These two therapies were further enhanced by a light-activated treatment, photodynamic therapy, which by itself was reported to have improved median survival in pancreatic cancer patients in a small study. Nanotechnology-based delivery of the two agents successfully positioned the therapy on the inside of a tumor cell and reduced the local tumor burden.

The researchers are continuing their studies to determine if there is any effect on metastasis and long-term survival.

# A53. Tumor suppressor microRNA miR-34 inhibits human pancreatic and gastric cancer stem cells

Treatment with miR-34, a microRNA, significantly reduced pancreatic and gastric cancer stem cells, which suggests the molecule may be a potential therapeutic agent in these cancers.

Cancer stem cells are the tumor cells left over after chemotherapy that, in nearly all cases, lead to regrowth of the tumor. Typically, these cells are resistant to conventional treatments. Researchers are looking to microRNAs, which are proteins that regulate gene expression, as potentially therapeutic and they have already demonstrated some benefit in liver cancer.

“MiR-34 may be a new player in treatment for these very aggressive tumors because it acts as a tumor suppressor and can be delivered effectively,” said Liang Xu, Ph.D., M.D., assistant professor of radiation oncology at the University of Michigan.

Xu and colleagues examined the role of miR-34 in p53-mutant human pancreatic and gastric cancer cell lines. They found that restoration of miR-34 inhibited tumor cell growth, increased cell death and sensitized the cancer cells to chemotherapy and radiation.

Significantly, restoration of miR-34 reduced the number of tumor initiating cells, or cancer stem cells.

Xu is currently leading a research team that will investigate miR-34 as a potential therapeutic agent delivered by patented nanotechnology, which is funded by a grant from the National Institutes of Health.

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# # #

The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, the AACR is the world’s oldest and largest professional organization dedicated to advancing cancer research. The membership includes 30,000 basic, translational and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and nearly 90 other countries. The AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants, research fellowship and career development awards. The AACR Annual Meeting attracts more than 16,000 participants who share the latest discoveries and developments in the field. Special conferences throughout the year present novel data across a wide variety of topics in cancer research, treatment and patient care. The AACR publishes six major peer-reviewed journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; Cancer Epidemiology, Biomarkers & Prevention; and Cancer Prevention Research. The AACR also publishes CR, a magazine for cancer survivors and their families, patient advocates, physicians and scientists. CR provides a forum for sharing essential, evidence-based information and perspectives on progress in cancer research, survivorship and advocacy.

About NCI
The National Cancer Institute (NCI) leads the National Cancer Program and the NIH effort to dramatically reduce the burden of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI Web site at http://www.cancer.gov or call NCI’s Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

About EORTC
The European Organisation for Research and Treatment of Cancer (EORTC) is an international association under Belgian law created in 1962.

The aims of the EORTC are to develop, conduct, coordinate, and stimulate translational and clinical cancer research in Europe to improve the management of cancer and related problems by increasing both survival and patient quality of life. The ultimate goal of the EORTC is to establish state-of-the-art cancer treatment to improve survival rate, quality of life and quality of care for all patients with cancer.

The EORTC is primarily devoted to high-quality clinical research to establish optimal therapeutic strategies via large multi-center clinical studies in a multidisciplinary approach leading to state-of-the-art treatment.

In line with the increasingly important role of functional imaging in trials involving translational research and having endpoints linked to biological markers, the EORTC Board has decided to establish an Imaging Group to drive the development of treatment strategies tailored to the biological characteristics of a particular tumor.

EORTC Headquarters has instituted quality assurance in radiotherapy (QART), and these measures have resulted in measurably significant improvement in treatment delivery and patient outcome in radiotherapy.

The EORTC has initiated a European tumor bank project to improve and harmonize the histological review and to promote translational research in EORTC trials.

The EORTC Headquarters’ Early Project Optimization Department (EPOD) lends support and methodological expertise to the EORTC groups for all new projects.

A Network of Core Institutions (NOCI) has been formed as part of the overall EORTC strategy. NOCI is based on core recruiting academic centers across Europe, specifically apt to develop projects with important translational research components.

EORTC Headquarters comprises about 160 staff members (15 nationalities) including medical doctors, statisticians, Ph.D.’s, quality of life specialists, scientific and administrative staff, computer specialists, and research fellows.

All EORTC research projects and clinical studies are peer reviewed and have to be approved by the relevant EORTC Committees.

An Academic Research Fund has been created to allocate support for clinical trials of excellence submitted to the Board.

Over 6,000 new patients are treated each year according to EORTC protocols.

For further information see: www.eortc.be

Media Contact:
Jeremy Moore
(267) 646-0557
jeremy.moore@aacr.org
In Boston, Nov. 15-19:
(617) 954-3042

An engineered transcription factor which activates VEGF-A enhances recovery after spinal cord injury.

Liu Y, Figley S, Spratt SK, Lee G, Ando D, Surosky R, Fehlings MG.

Neurobiol Dis. 2009 Oct 28. [Epub ahead of print] doi:10.1016/j.nbd.2009.10.018

Spinal cord injury (SCI) leads to local vascular disruption and progressive ischemia, which contribute to secondary degeneration. Enhancing angiogenesis through the induction of vascular endothelial growth factor (VEGF)-A expression therefore constitutes an attractive therapeutic approach. Moreover, emerging evidence suggests that VEGF-A may also exhibit neurotrophic, neuroprotective, and neuroproliferative effects. Building on this previous work, we seek to examine the potential therapeutic benefits of an engineered zinc finger protein (ZFP) transcription factor designed to activate expression of all isoforms of endogenous VEGF-A (ZFP-VEGF). Administration of ZFP-VEGF resulted in increased VEGF-A mRNA and protein levels, an attenuation of axonal degradation, a significant increase in vascularity and decreased levels of apoptosis. Furthermore, ZFP-VEGF treated animals showed significant improvements in tissue preservation and neurobehavioural outcomes. These data suggest that activation of VEGF-A via the administration of an engineered ZFP transcription factor holds promise as a therapy for SCI and potentially other forms of neurotrauma.

Stimulatory effects of thyroid hormone on brain angiogenesis in vivo and in vitro.

Zhang L, Cooper-Kuhn CM, Nannmark U, Blomgren K, Kuhn HG.

Journal of Cerebral Blood Flow & Metabolism advance online publication, 28 October 2009; doi:10.1038/jcbfm.2009.216

Thyroid hormone is critical for the proper development of the central nervous system. However, the specific role of thyroid hormone on brain angiogenesis remains poorly understood. Treatment of rats from birth to postnatal day 21 (P21) with propylthiouracil (PTU), a reversible blocker of triiodothyronine (T3) synthesis, resulted in decreased brain angiogenesis, as indicated by reduced complexity and density of microvessels. However, when PTU was withdrawn at P22, these parameters were fully recovered by P90. These changes were paralleled by an altered expression of vascular endothelial growth factor A (Vegfa) and basic fibroblast growth factor (Fgf2). Physiologic concentrations of T3 and thyroxine (T4) stimulated proliferation and tubulogenesis of rat brain-derived endothelial (RBE4) cells in vitro. Protein and mRNA levels of VEGF-A and FGF-2 increased after T3 stimulation of RBE4 cells. The thyroid hormone receptor blocker NH-3 abolished T3-induced Fgf2 and Vegfa upregulation, indicating a receptor-mediated effect. Thyroid hormone inhibited the apoptosis in RBE4 cells and altered mRNA levels of apoptosis-related genes, namely Bcl2 and Bad. The present results show that thyroid hormone has a substantial impact on vasculature development in the brain. Pathologically altered vascularization could, therefore, be a contributing factor to the neurologic deficits induced by thyroid hormone deficiency.

Notch signal is sufficient to direct an endothelial conversion from non-endothelial somitic cells conveyed to the aortic region by CXCR4

Emi Ohata, Ryosuke Tadokoro, Yuki Sato, Daisuke Saito and Yoshiko Takahashi

Developmental Biology Volume 335, Issue 1, 1 November 2009, Pages 33-42 doi:10.1016/j.ydbio.2009.08.010

During the early formation of the dorsal aorta, the first-forming embryonic vessel in amniotes, a subset of somitic cells selected as presumptive angioblasts, migrates toward the dorsal aorta, where they eventually differentiate into endothelial cells. We have recently shown that these processes are controlled by Notch signals (Sato, Y., Watanabe, T., Saito, D., Takahashi, T., Yoshida, S., Kohyama, J., Ohata, E., Okano, H., and Takahashi, Y., 2008. Notch mediates the segmental specification of angioblasts in somites and their directed migration toward the dorsal aorta in avian embryos. Dev. Cell 14, 890–901.). Here, we studied a possible link between Notch and chemokine signals, SDF1/CXCR4, the latter found to be dominantly expressed in developing aorta/somites. Although CXCR4 overexpression caused a directed migration of somitic cells to the aortic region in a manner similar to Notch, no positive epistatic relationships between Notch and SDF1/CXCR4 were detected. After reaching the aortic region, the CXCR4-electroporated cells exhibited no endothelial character. Importantly, however, once provided with Notch activity, they could successfully be incorporated into developing vessels as endothelial cells. These findings were obtained combining the tetracycline-inducible gene expression method with the transposon-mediated stable gene transfer technique. We conclude that Notch activation is sufficient to direct naïve mesenchymal cells to differentiate into endothelial cells once the cells are conveyed to the aortic region.

Nurulita, N.A 1) and Meiyanto, E. 2)

1) Faculty of Pharmacy Muhammadiyah University of Purwokerto
2) Faculty of Pharmacy Gadjah Mada University

Abstract

Pentagamavunon-0 or PGV-0 [2,5-bis-(4'-hydroxy-3'-methoxy-benzylidene)-cyclopentanone], was determined on its cytotoxicity, antiproliferative, and antiangiogenesis effects in comparation to the effect of its analogue, curcumin (1,7-bis-(4′-hydroxy-3′-methoxyphenyl)-1,6-heptadiena-3,5-dion) against 17-β-estradiol (E2) induced human breast cancer cells T47D.
MTT assay was used for measuring the cytotoxic and antiproliferative effects. Apoptotic effect of T47D cells as a result of PGV-0 and curcumin treatments could be seen by ethidium bromide-acrydin orange doublestainning method. Immunocytochemistry method was used to determine p53, Bcl-2, Bax, VEGF, and COX-2 proteins expression.
The results showed that PGV-0 and curcumin possessed cytotoxicity effect againsts T47D cells with IC50 6,85 μM and 19,83 μM, respectively. Both compounds showed an antiproliferative properties as indicated by the prolongation of the doubling time. PGV-0 had cytotoxic and antiproliferative properties better than curcumin. PGV-0 induced apoptosis at lower concentration than that of curcumin, as showed with ethidium bromide-acrydin orange doublestainning. The increasing of p53 and Bax and decreasing of Bcl-2 expressions, might have a relationship with apoptosis. PGV-0 had antiangiogenesis properties stronger than curcumin. It was showed by dereasing of VEGF and COX-2 expressions.

Keywords: PGV-0, curcumin, T47D, 17-b-estradiol, antiproliferative, apoptosis, angiogenesis