Osteoporosis: serotonergic drugs may provide novel opportunities for therapeutic interventions

Posted on February 22, 2012 by Stone Hearth News

Scientists have long known that calcium leaches from the bones both during lactation and in certain types of cancer. The driver behind these phenomena is a molecule called parathyroid hormone related protein (PTHrP), which is secreted by the mammary glands. The signal that regulates the secretion of PTHrP, and where this other unknown molecule exerts its influence, has remained a mystery. Now, in a new study using cells and tissues from mice, cows, and people, a team of researchers at the University of Cincinnati have identified this mystery molecule as serotonin, a neurotransmitter most often recognized for its role in happiness and well-being. The scientists also identified the specific receptor that serotonin acts on in mammary tissue. Understanding these two findings more deeply could lead to better ways to combat bone loss, potentially by using drugs that affect serotonin signaling.

The study is entitled “Mammary Gland Serotonin Regulates Parathyroid Hormone-Related Protein and Other Bone-Related Signals” (http://bit.ly/yeB5uQ). It appears in the Articles in PresS section of the American Journal of Physiology – Endocrinology and Metabolism, published by the American Physiological Society (APS).

Methodology

The researchers first examined lactating mice with a genetic mutation that prevented them from making serotonin efficiently and compared the amount of PTHrP in these animals to that in lactating normal, healthy mice. Next, they treated mouse and cow mammary cells with serotonin to see if it could induce secretion of PTHrP. They then treated human breast cancer lines with serotonin to see if the neurotransmitter could change expression of PTHrP and a gene called Runx2, which is known to be involved in metastatic breast cancer and bone loss. Finally, they examined mice genetically modified to be missing a particular type of serotonin receptor, as well as mouse mammary cells, to determine which serotonin receptor might be responsible for influencing PTHrP secretion.

Results

The researchers found that lactating mice genetically modified to prevent them from making serotonin efficiently (tryptophan hydoxylase 1 mutation) had significantly less PTHrP in their mammary glands compared to lactating normal, healthy mice, suggesting that serotonin is pivotally important for producing PTHrP. Supporting these findings, mouse and cow mammary cells treated with serotonin increased their expression of the gene responsible for PTHrP production by 8- and 20-fold, respectively. Treating three human breast cancer cell lines with serotonin increased expression of the PTHrP gene by 20-fold, and also increased expression of Runx2 as well. Though previous studies have shown that a serotonin receptor known as 5-HT7 is important for some mammary gland functions, this current study suggests that a different receptor, known as 5-HT2, is the target responsible for stimulating PTHrP levels.

Importance of the Findings

These findings suggest that serotonin is a molecule that regulates PTHrP production, which in turn affects how calcium leaches from the bones during lactation and soft tissue cancer metastases. The authors suggest that this finding isn’t completely surprising, since many antidepressants that act on serotonin have bone loss as a side effect. Understanding the action of serotonin better could help researchers develop better ways to preserve bone, they say, potentially through the action of drugs that act on the serotonin system.

“The complexity of 5-HT (serotonin) signaling demands cautious interpretations and the testing of new hypotheses and additional model systems. With improved knowledge, serotonergic drugs may provide novel opportunities for therapeutic interventions,” the authors say.

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Study Team

The study was conducted by Nelson D. Horseman, Laura L. Hernandez and Karen A. Gregerson of the University of Cincinnati.

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HIV, Hep C drug interactions subject of European Medicines Agency alert

Posted on February 22, 2012 by Stone Hearth News

The European Medicines Agency has recommended updating the prescribing information for Victrelis (boceprevir) with information about drug interactions between this hepatitis C medicine and the ritonavir-boosted HIV protease inhibitors atazanavir, darunavir and lopinavir.

A drug interaction study in healthy volunteers carried out by Merck Sharp and Dohme, the marketing authorisation holder of Victrelis, found that blood levels of all three HIV medicines were markedly lower than expected when given with Victrelis. It also found that blood levels of Victrelis were markedly lower than expected when given with ritonavir-boosted darunavir or lopinavir, although this effect was not seen with ritonavir-boosted atazanavir.

The Agency’s Committee for Medicinal Products for Human Use (CHMP) concluded that the lower blood levels seen in the drug interaction study could mean that the medicines are less effective when given together to patients who are co-infected with hepatitis C and HIV. However, the Committee acknowledged that data from ongoing clinical studies in co-infected patients are needed to assess the clinical impact of these drug-interaction findings on these patients.

Studies on the efficacy and safety of Victrelis when used in patients co-infected with HIV and hepatitis C are ongoing. While data from these studies are awaited, the CHMP has recommended updating the product information to inform prescribers and patients of the findings as a precautionary measure.

Doctors treating patients co-infected with hepatitis C and HIV should be aware of the findings of the drug interaction study. They should not co-administer Victrelis with ritonavir-boosted darunavir or lopinavir in HIV and hepatitis C co-infected patients. Co-administration of Victrelis with ritonavir-boosted atazanavir may be considered on a case-by-case basis if deemed necessary in patients with suppressed HIV viral loads and with an HIV strain without any suspected resistance to the HIV regimen. Increased clinical and laboratory monitoring is warranted.

Patients should not stop taking any of their medicines without talking to their healthcare professional. Patients should contact their healthcare professional if they have any questions or concerns.

Healthcare professionals in the European Union will receive a letter in the coming days to inform them of the new drug interaction data and the CHMP’s recommendations while waiting for further data from ongoing studies in patients co-infected with HIV and hepatitis C.

Notes

The CHMP’s recommendation will be sent to the European Commission for the adoption of a decision.

Victrelis reduced mean trough concentrations of ritonavir-boosted atazanavir, lopinavir and darunavir by 49, 43 and 59 percent, respectively. Mean reductions of 34 to 44 percent and 25 to 36 percent were observed in area under the curve (AUC) and peak concentration (Cmax) of atazanavir, lopinavir and darunavir. Co-administration of ritonavir-boosted atazanavir with Victrelis did not significantly alter the exposure (AUC) of boceprevir, but co-administration of Victrelis with lopinavir/ritonavir or ritonavir-boosted darunavir decreased the AUC of boceprevir by 45 and 32 percent, respectively.

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Ovarian cancer treatment breakthrough at Penn State

Posted on February 22, 2012 by Stone Hearth News

Researchers at The Pennsylvania State University College of Medicine, Hershey, Pennsylvania have discovered that the presence and integrity of the opioid growth factor receptor (OGFr), which mediates the inhibitory action of opioid growth factor (OGF) on cell proliferation, is a key to understanding the progression and treatment of human ovarian cancer. Transplantation of human ovarian cancer cells that were molecularly engineered to have a reduced expression of OGFr, into immunocompromised mice resulted in ovarian tumors that grew rapidly. This discovery, reported in the February 2012 issue of Experimental Biology and Medicine, provides fresh new insights into the pathogenesis and therapy of a lethal cancer that is the fifth leading cause of cancer-related mortality among women in the USA, and has a death rate that is unchanged for over 75 years.

The OGF (also-termed [Met5]-enkephalin)-OGFr axis plays a fundamental role in cancer, development, and cellular renewal by regulating cell proliferation. An important question addressed in this study relates to the requirement of this peptide-receptor system for the progression of carcinogenesis. Human ovarian cancer cell lines that were genetically modified to underexpress OGFr grew far more rapidly in tissue culture than control (empty vector/wildtype) cell lines. Moreover, the addition of OGF to cultures of these genetically modified cells did not respond to the inhibitory peptide and change cell number, indicating that the loss of OGFr interfered with the function of the OGF-OGFr axis with respect to regulating cell proliferation. Immunocompromised mice injected with ovarian cancer cells that had a reduction in OGFr displayed tumors much earlier than controls, and these tumors grew faster than controls. Putting this information together with knowledge that the pathway for OGF-OGFr regulation of cell proliferation in ovarian cancer is by way of increasing the cyclin-dependent inhibitory kinase proteins p16 and p21, we now can understand that minimizing the quantity of OGFr results in an increase in the number of cells entering the G1/S phase of the cell cycle. This has the net effect of increasing the progression of tumorigenic events. These results reveal the critical nature of OGFr in human ovarian cancer, and that the receptor along with its ligand, OGF, is essential for determining the course of these neoplasias.

The research team was comprised of Dr. Ian S. Zagon, Distinguished University Professor, and Dr. Patricia J. McLaughlin, Professor, along with Dr. Renee N. Donahue in the Department of Neural & Behavioral Sciences. Drs. Zagon and McLaughlin discovered that endogenous opioids serve as growth factors, and have been pioneers in translating their findings from the bench to the bedside. Dr. Zagon states that “Over 75% of women are initially diagnosed with advanced ovarian cancer. Despite excellent initial response to cytoreductive surgery and adjuvant chemotherapy, 65% of these patients relapse within two years. However, only palliative care is available for these patients. With evidence from Phase I and II clinical trials as to the success of OGF for the treatment of advanced pancreatic cancer and knowledge presented herein that the OGF-OGFr axis is a critical determinant of the course of ovarian neoplasia, the present study raises the possibility of using this information to modulate the OGF-OGFr pathway with i) exogenous OGF, ii) imiquimod to upregulate OGFr, and/or iii) low dose naltrexone (LDN) to increase OGF and OGFr, as a therapeutic strategy for ovarian carcinoma.” Co-author Dr. McLaughlin adds that “A major problem in ovarian cancer is the need for diagnostic markers – both for early diagnosis and to monitor treatment modalities. Since some of the signaling pathways for OGF-OGFr are known (e.g., karyopherin β, Ran, p16, p21), the components of this system would represent a worthwhile focus in designing diagnostic assays.” Dr. Donahue, who conducted the ovarian cancer studies and its relationship to the OGF-OGFr axis for her doctoral dissertation, states that “Ovarian cancers frequently have a methylation of p16 that is associated with an increased progression of ovarian cancer and a loss of OGFr in ovarian tumors. The diminished expression of OGFr and its repercussions on tumorigenesis, only adds to the concern about the need for information concerning genetic and epigenetic changes that may impact the course of disease and its treatment. Our findings also hold potentially ominous overtones for those individuals taking naltrexone for addictive disorders. The dosage used for treatment of addiction blocks opioid receptors continually. The present findings that diminishing the OGF-OGFr axis by depleting the receptor exacerbates tumorigenesis, could place these patients using naltrexone at risk for accelerating disease processes that involve cell proliferation.”

Dr. Steven R. Goodman, Editor-in-Chief of Experimental Biology and Medicine, said “This compelling evidence confirms the absolute requirement for OGFr (and OGF) as a tonically active inhibitory regulatory mechanism in ovarian cancer. As a corollary, amplifying the OGF-OGFr pathway is a novel and highly effective biotherapeutic strategy to suppress the progression of these deadly cancers.”

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Experimental Biology and Medicine is the journal of the Society of Experimental Biology and Medicine. To learn about the benefits of society membership visit www.sebm.org. If you are interested in publishing in the journal please visit http://ebm.rsmjournals.com/.

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How stress ages cells and, therefore, us: new research

Posted on February 22, 2012 by Stone Hearth News

The ability to anticipate future events allows us to plan and exert control over our lives, but it may also contribute to stress-related increased risk for the diseases of aging, according to a study by UCSF researchers.

In a study of 50 women, about half of them caring for relatives with dementia, the psychologists found that those most threatened by the anticipation of stressful tasks in the laboratory and through public speaking and solving math problems, looked older at the cellular level. The researchers assessed cellular age by measuring telomeres, which are the protective caps on the ends of chromosomes. Short telomeres index older cellular age and are associated with increased risk for a host of chronic diseases of aging, including cancer, heart disease and stroke.

“We are getting closer to understanding how chronic stress translates into the present moment,” said Elissa Epel, PhD, an associate professor in the UCSF Department of Psychiatry and a lead investigator on the study. “As stress researchers, we try to examine the psychological process of how people respond to a stressful event and how that impacts their neurobiology and cellular health. And we’re making some strides in that.”

The researchers also found evidence that caregivers anticipated more threat than non-caregivers when told that they would be asked to perform the same public speaking and math tasks. This tendency to anticipate more threat put them at increased risk for short telomeres. Based on that, the researchers propose that higher levels of anticipated threat in daily life may promote cellular aging in chronically stressed individuals.

“How you respond to a brief stressful experience in the laboratory may reveal a lot about how you respond to stressful experiences in your daily life,” said Aoife O’Donovan, PhD, a Society in Science: Branco Weiss Fellow at UCSF and the study’s lead author. “Our findings are preliminary for now, but they suggest that the major forms of stress in your life may influence how your respond to more minor forms of stress, such as losing your keys, getting stuck in traffic or leading a meeting at work. Our goal is to gain better understanding of how psychological stress promotes biological aging so that we can design targeted interventions that reduce risk for disease in stressed individuals. We now have preliminary evidence that higher anticipatory threat perception may be one such mechanism.”

The study will be published in the May issue of the journal Brain, Behavior and Immunity.

Research on telomeres, and the enzyme that makes them, was pioneered by three Americans, including UCSF molecular biologist and co-author on this manuscript Elizabeth Blackburn, PhD, who co-discovered the telomerase enzyme in 1985. The scientists received the Nobel Prize in Physiology or Medicine in 2009 for this work.

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The research related to anticipation was funded by grants from the Division of Behavioral and Social Research at the National Institute of Aging/National Institutes of Health and Bernard and Barbro Foundation as well as by a Society in Science: Branco Weiss Fellowship.

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