By Jenny C Leary
In the November 14 issue of the Journal of the American Medical Association (JAMA), medical clinicians and researchers advocate for new techniques to fight drug overdoses. Alexander Walley, MD, MSc, assistant professor at Boston University School of Medicine, co-authored the article with Leo Beletsky, JD, MPH, assistant professor at Northeastern University School of Law and Bouvé College of Health Sciences, who served as the paper’s lead author, and Josiah Rich, MD, MPH, professor at Brown Medical School.
The article specifically focuses on the national problem of fatal overdoses from opioid drugs, which include the street drug heroin and prescription drugs such as oxycodone. According to the article, opioid overdose kills 16,000 Americans annually and affects all sectors of society. The article calls for federal, state and local authorities to act in concordance to improve awareness about drug overdose and increase availability of the life saving drug, naloxone.
Naloxone is a critical medication that acts to quickly to reverse the effects opioid overdose. However, the authors describe several barriers impeding more effective use of naloxone. For example, although naloxone is generic, there is a critical supply shortage, making the drug expensive. Furthermore, many doctors are fearful of increased liability if they prescribe naloxone and worry about facilitating risky behavior.
In order to increase supply, the authors call for the federal government to streamline naloxone importation. They ask for the U.S. Food and Drug Administration to facilitate the clearance of easier to administer forms of the drug, such as a nasal spray or an “epi-pen” like auto injector instead of the current method, which utilizes unwieldy needles. They also call for clinicians to be educated about the benefits of naloxone for their patients. Additionally, the authors call on state and local authorities to increase awareness and offer patient education about drug overdose and naloxone therapy.
“Community-based overdose prevention programs that include overdose education and naloxone access could help avert unnecessary, preventable death,” said Walley, who also is a physician at Boston Medical Center.
-Written by David Mosbach, MD
The Boston University School of Medicine (BUSM) Division of Graduate Medical Sciences Office of Postdoctoral Affairs is celebrating National Postdoc Appreciation Week (NPAW) Sept. 17-21. This is the second year that events will be held on the medical campus. The activities held during Appreciation Week will help increase awareness of postdocs and recognize the contributions they make to research at BUMC.
Three special events are being held celebrating the contributions and achievements of BUMC postdocs:
Careers in Communicating Science: Journals, Blogs, Netcasts and Tweets
- Monday, Sept. 17
- 3- 4:30 p.m.
- Room L-201/203
- 72 East Concord St.
Ice Cream Social
- Tuesday, Sept. 18
- 1-3:20 p.m.
- Talbot Green
- (Rain location: Hiebert Lounge 14th Floor, 72 East Concord St.)
Film Screening: Losing Control
- Thursday, Sept. 20
- 5:30-7:50 p.m.
- Keefer Auditorium
- 72 East Concord St.
The Appreciation Week evolved out of National Postdoc Appreciation Day and has become the nation’s largest celebration of postdoctoral scholars. In 2010, NPAW culminated with the passage of H.RES. 1545 by the U.S. House of Representatives on Sept. 24, 2010, which nationally recognizes NPAW.
Since 2009 participation for the event has grown: in 2011, 171 events were hosted at 89 institutions in 30 states and Canada. Past events have included wine and cheese receptions, postdoc picnics, professional development workshops, and networking events.
BUMC NPAW is coordinated by Yolanta Kovalko, Administrative Manager, Office of Postdoctoral Affairs (OPA). Contact Yolanta at Yolanta@bu.edu
For more information about BUMC OPA and to RSVP for the Careers in Communicating Science: Journals, Blogs, Netcasts and Tweets Talk, email: Yolanta@bu.edu
To RSVP for the Ice Cream Social, visit http://www.bumc.bu.edu/gms/gateway/post-doc/professional-development/upcoming-events/rsvp-ice-cream-social/
To RSVP for the Movie, Losing Control and Panel Discussion, visit http://www.bumc.bu.edu/gms/gateway/post-doc/professional-development/upcoming-events/movie-losing-control/
Accountable care organizations, supported by federal health care reform, are enough of an improvement over the failed capitation arrangements of the 1990s to make them a “worthy experiment,” but they are not a cure-all for controlling health care costs, according to an analysis co-authored by a researcher from the BU Schools of Medicine and Public Health.
In the September issue of Health Affairs, Austin Frakt, a health economist who is an assistant professor of health policy and management at BUSPH and assistant professor of psychiatry at BUSM, and co-author Rick Mayes, an associate professor of political science at the University of Richmond, examine the lessons learned during the failed cost-capitation effort of the 1990s. The rise and fall of capitation payments — a fixed lump-sum per patient paid to health care providers to cover all care — offers a stark example of how difficult it is for providers to assume “meaningful financial responsibility” for patient care, Frakt and Mayes argue.
They say that while capitation offered some advantages for payers and providers, such as more control over the provision of the care, it also had limitations, such as a greater financial risk for providers who could not offer medical care for less than the lump sum, as well as incentives to “stint” on care. After an increase in popularity, the lump-sum payment system was largely abandoned, with most providers returning to the traditional fee-for-service model, meaning they are paid for whatever services they render.
Frakt and Mayes note that policy makers “have again turned their attention toward new methods to control volume, including exhibiting renewed interest in shifting cost risk to providers, as capitation did in the 1990s.” Yet, they write, “the capitated arrangements of that era proved unsustainable. Is history doomed to repeat itself?”
Not necessarily, the duo says. They see some promise in the newest attempts to shift financial risk onto providers by creating accountable care organizations (ACOs) — networks of providers responsible for the care of a defined group of patients and, in part, for the cost and quality of that care. ACOs have the goal of providing financial incentives for coordinated and judicious provision of appropriate, high-quality health care. The organizations can secure bonuses if their spending on patients falls below a designated benchmark and they meet quality targets.
Frakt and Mayes say some of the lessons of capitation appear to have informed the new ACO models, which don’t put providers at the same high degree of risk for health care costs that capitation did. If ACOs fail to meet benchmarks, the financial penalties — if any– are relatively modest. And because most ACOs have relatively large patient bases, they may be better able to spread risk.
“Accountable care organizations offer an opportunity to increase quality and reduce spending, while potentially avoiding some of the larger dangers that doomed capitation,” the analysis says. “Nevertheless, they are not without their own limitations and challenges.”
Frakt and Mayes note that some experts are skeptical that the newer models can save significant amounts of money, arguing that only full capitation or similar models will work. Yet, Frakt and Mayes say, policy makers and stakeholders “are justifiably wary of repeating the failed capitation experiment. It is not yet evident how to resolve this Catch-22. Full capitation did not succeed, but models that fall short of it might not, either.
“The United States remains in the same situation it has been in for decades: unsure of how to bend the cost curve while maintaining or improving the quality of care,” they conclude. “With accountable care organizations, the search for the’ sweet spot’ between provider and payer risk continues.”
The full article is available here: http://content.healthaffairs.org/content/31/9/1951.full
-By Lisa Chedekel
Two Boston University School of Medicine (BUSM) faculty members have been named to a consortium that will investigate better ways to treat and diagnose post-traumatic stress disorder (PTSD).
- Ann Rasmusson, MD, associate professor of psychiatry at BUSM and psychiatrist and neuroendocrinologist at the Veterans Affairs (VA) Boston Healthcare System and National Center for PTSD
- Jennifer Vasterling, PhD, professor of psychiatry at BUSM, clinical investigator and chief of psychology at the VA Boston Healthcare System and National Center for PTSD
Draper Laboratory formed this consortium of nationally-recognized PTSD experts to improve diagnostic tools and treatment outcomes for the disorder. Bringing together experts from a variety of disciplines and institutions has several advantages, including the ability to look at the full spectrum of factors from neuroimaging to gene expression, and conduct human and animal studies in parallel, thus accelerating knowledge and development of solutions.
The consortium plans to develop solutions based on objective, clinical decision making by using sophisticated algorithms to integrate data from a spectrum of biomarkers including neuroimaging, psychophysiology, chemical assays and gene expression. The resulting diagnostic and treatment protocols will be more objective and personalized, complementing today’s primarily subjective means of evaluation and treatment selection.
Vasterling will lead the effort to integrate neurocognitive data, which includes measures such as memory, attention and other thinking skills that pertain to brain functioning. She will also help with the integration of psychometric measures (i.e., normed self-report measures and structured clinical interviews pertaining to psychosocial functioning and mental health diagnoses) with the biomarker information.
Rasmusson will lead the selection and development of methods for testing and measuring biomarkers from blood, cerebrospinal fluid, or other sources that characterize the function of an individual’s stress response system both at rest and when activated by general or trauma-related stressors. The aim is to identify stress system factors best addressed and treated on an individual basis—to prevent PTSD or aid recovery from extreme stress and prevent its long-term downstream medical and psychiatric consequences.
PTSD has been diagnosed in more than 200,000 troops returning from combat in Iraq and Afghanistan, but it is also commonly found in civilians who have been involved in an accident or assault, or have suffered the unexpected loss of a loved one. Approximately 8 percent of the U.S. population will suffer from PTSD at some point in their lives, which can lead to panic attacks, substance abuse, depression, suicide, and a host of serious medical complications, most notably, cardiovascular disorders.
The current state of the art in PTSD diagnosis is based on clinical interviews, so doctors have to rely on patients’ subjective reports. Although the clinical history is a good start, PTSD diagnosis and treatment selection would be better informed if reliable biomarkers of the condition were available, as is the case in many other areas of medicine.
Draper Laboratory is a not-for-profit, engineering research and development organization dedicated to solving critical national problems in national security, space systems, biomedical systems, and energy.
Researchers from Boston University School of Medicine (BUSM) and Veterans Affairs (VA) Boston Healthcare System have demonstrated that the effects on white matter brain volume from long-term alcohol abuse are different for men and women. The study, which is published online in Alcoholism: Clinical and Experimental Research, also suggests that with abstinence, women recover their white matter brain volume more quickly than men.
The study was led by Susan Mosher Ruiz, PhD, postdoctoral research scientist in the Laboratory for Neuropsychology at BUSM and research scientist at the VA Boston Healthcare System, and Marlene Oscar Berman, PhD, professor of psychiatry, neurology and anatomy and neurobiology at BUSM and research career scientist at the VA Boston Healthcare System.
In previous research, alcoholism has been associated with white matter pathology. White matter forms the connections between neurons, allowing communication between different areas of the brain. While previous neuroimaging studies have shown an association between alcoholism and white matter reduction, this study furthered the understanding of this effect by examining gender differences and utilizing a novel region-of-interest approach.
The research team employed structural magnetic resonance imaging (MRI) to determine the effects of drinking history and gender on white matter volume. They examined brain images from 42 abstinent alcoholic men and women who drank heavily for more than five years and 42 nonalcoholic control men and women. Looking at the correlation between years of alcohol abuse and white matter volume, the researchers found that a greater number of years of alcohol abuse was associated with smaller white matter volumes in the abstinent alcoholic men and women. In the men, the decrease was observed in the corpus callosum while in women, this effect was observed in cortical white matter regions.
“We believe that many of the cognitive and emotional deficits observed in people with chronic alcoholism, including memory problems and flat affect, are related to disconnections that result from a loss of white matter,” said Mosher Ruiz.
The researchers also examined if the average number of drinks consumed per day was associated with reduced white matter volume. They found that the number of daily drinks did have a strong impact on alcoholic women, and the volume loss was one and a half to two percent for each additional daily drink. Additionally, there was an eight to 10 percent increase in the size of the brain ventricles, which are areas filled with cerebrospinal fluid (CSF) that play a protective role in the brain. When white matter dies, CSF produced in the ventricles fills the ventricular space.
Recovery of white matter brain volume also was examined. They found that, in men, the corpus callosum recovered at a rate of one percent per year for each additional year of abstinence. For people who abstained less than a year, the researchers found evidence of increased white matter volume and decreased ventricular volume in women, but not at all in men. However, for people in recovery for more than a year, those signs of recovery disappeared in women and became apparent in men.
“These findings preliminarily suggest that restoration and recovery of the brain’s white matter among alcoholics occurs later in abstinence for men than for women,” said Mosher Ruiz. “We hope that additional research in this area can help lead to improved treatment methods that include educating both alcoholic men and women about the harmful effects of excessive drinking and the potential for recovery with sustained abstinence.”
This research was supported by the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health under award numbers R01-AA07112 and K05-AA00219, the US Department of Veterans Affairs Medical Research Service and the Center for Functional Neuroimaging Technologies (award number P41RR14075).
Investigators at Boston University School of Medicine (BUSM) and Veterans Affairs (VA) Boston Healthcare System have identified a new gene linked to post-traumatic stress disorder (PTSD). The findings, published online in Molecular Psychiatry, indicate that a gene known to play a role in protecting brain cells from the damaging effects of stress may also be involved in the development of PTSD.
The article reports the first positive results of a genome-wide association study (GWAS) of PTSD and suggests that variations in the retinoid-related orphan receptor alpha (RORA) gene are linked to the development of PTSD.
Mark W. Miller, PhD, associate professor at BUSM and a clinical research psychologist in the National Center for PTSD at VA Boston Healthcare System was the study’s principal investigator. Mark Logue, PhD, research assistant professor at BUSM and Boston University School of Public Health and Clinton Baldwin, PhD, professor at BUSM, were co-first authors of the paper.
PTSD is a psychiatric disorder defined by serious changes in cognitive, emotional, behavioral and psychological functioning that can occur in response to a psychologically traumatic event. Previous studies have estimated that approximately eight percent of the U.S. population will develop PTSD in their lifetime. That number is significantly greater among combat veterans where as many as one out of five suffer symptoms of the disorder.
Previous GWAS studies have linked the RORA gene to other psychiatric conditions, including attention-deficit hyperactivity disorder, bipolar disorder, autism and depression.
“Like PTSD, all of these conditions have been linked to alterations in brain functioning, so it is particularly interesting that one of the primary functions of RORA is to protect brain cells from the damaging effects of oxidative stress, hypoxia and inflammation,” said Miller.
Participants in the study were approximately 500 male and female veterans and their intimate partners, all of whom had experienced trauma and approximately half of whom had PTSD. The majority of the veterans had been exposed to trauma related to their military experience whereas their intimate partners had experienced trauma related to other experiences, such as sexual or physical assault, serious accidents, or the sudden death of a loved one. Each participant was interviewed by a trained clinician, and DNA was extracted from samples of their blood.
The DNA analysis examined approximately 1.5 million genetic markers for signs of association with PTSD and revealed a highly significant association with a variant (rs8042149) in the RORA gene. The researchers then looked for evidence of replication using data from the Detroit Neighborhood Health Study where they also found a significant, though weaker, association between RORA and PTSD.
“These results suggest that individuals with the RORA risk variant are more likely to develop PTSD following trauma exposure and point to a new avenue for research on how the brain responds to trauma,” said Miller.
This study was supported by the National Institute on Mental Health of the National Institutes of Health under award number R01 MH079806 and a grant from the Department of Veterans Affairs.
BUSM Study Identifies Adenosine Receptor’s Role in Regulating High Fat Diet-Induced Obesity and Type 2 Diabetes
A recent study led by Boston University School of Medicine (BUSM) demonstrates that the A2b-type adenosine receptor, A2bAR, plays a significant role in the regulation of high fat, high cholesterol diet-induced symptoms of type 2 diabetes. The findings, which are published online in PLoS ONE, also identify A2bAR as a potential target for the treatment of type 2 diabetes.
Katya Ravid, DSc/PhD, professor of medicine and biochemistry and director of the Evans Center for Interdisciplinary Biomedical Research at BUSM, led this study. Colleagues from Ravid’s lab who collaborated on this research include Hillary Johnston-Cox, BSc (MD/PhD, 2014) and Milka Koupenova-Zamor, PhD. Noyan Gokce, MD, associate professor of medicine at BUSM, and Melissa Farb, PhD, a postdoctoral fellow at BUSM, also collaborated on the study.
Diets that are high in fat and cholesterol induce changes in how the body regulates blood glucose levels. Exercise induces an increased production adenosine, a metabolite produced naturally by cells. A2bAR, a naturally occurring protein receptor found in the cell membrane, is activated by adenosine. This receptor is known to play an important role in regulating inflammation, which is associated with type 2 diabetes and obesity.
To examine the association of A2bAR activation with a diet high in fat and cholesterol, the researchers used an experimental model that lacked A2bAR and compared the results with a control group. When the experimental model group was given a diet high in fat and cholesterol, there was an increase in the development of obesity and signs of type 2 diabetes. The signs demonstrated in the study included elevated blood glucose levels and increased in insulin levels. When the control group was given the same diet, however, the levels of A2bAR increased, resulting in decreased insulin and glucose levels and obesity.
A novel link also was identified between the expression of A2bAR, insulin receptor substrate 2 (IRS-2) and insulin signaling. The results showed that the level of IRS-2, a protein that has previously been shown to mediate the effect of insulin, was impaired in tissues of the experimental model lacking A2bAR, causing higher concentrations of blood glucose. When A2bAR was activated in the control group using a pharmacologic agent with a diet high in fat and cholesterol, the level of IRS-2 was upregulated, lowering blood glucose.
“The pharmacologic activation of A2bAR demonstrated its newly identified role in signaling down to regulate the levels of IRS-2, which then improved the signs of high fat diet-induced type 2 diabetes,” said Ravid.
The prevalence of type 2 diabetes and obesity continues to increase in developed countries and both factors are known to contribute to the development of cardiovascular disease. According to the World Health Organization, 346 million people worldwide have diabetes and 90 percent of those people have type 2 diabetes.
To correlate these results in humans, the researchers then examined fat tissue samples from obese individuals. The results showed that A2bAR expression is high in fat from obese individuals, marked by inflammation, compared to lean ones, and is strongly correlated with IRS-2 expression.
“Our study suggests the important role of A2bAR in maintaining the level of IRS-2, a regulator of glucose and insulin homeostasis,” added Ravid.
This study was funded in part by the National Heart, Lung and Blood Institute under award numbers HL93149 (Katya Ravid) and HL084213 (Noyan Gokce). Click on the following link to view the study online: http://dx.plos.org/10.1371/journal.pone.0040584
A research study led by Boston University School of Medicine (BUSM) and the University of Exeter in the United Kingdom, in collaboration with a global consortium, has identified genetic markers that influence a protein involved in regulating estrogen and testosterone levels in the bloodstream. The results, published online in PLoS Genetics, also reveal that some of the genetic markers for this protein are near genes related to liver function, metabolism and type 2 diabetes, demonstrating an important genetic connection between the metabolic and reproductive systems in men and women.
Andrea D. Coviello, MD, assistant professor of medicine at BUSM and an endocrinologist at Boston Medical Center, is one of the paper’s lead authors. This study was done in collaboration with the Framingham Heart Study and investigators from 15 international epidemiologic studies participating in the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) consortium.
Sex hormone-binding globulin (SHBG) is the key protein that carries testosterone and estrogen in the bloodstream in both men and women. As the main carrier of these sex hormones, SHBG helps to regulate their effects in different tissues and organs in the body. In addition to effects on reproduction in men and women through regulation of sex hormones, SHBG has been linked to many chronic diseases including type 2 diabetes and hormone-sensitive cancers such as breast and prostate.
Previous family studies have demonstrated that approximately 50 percent of the variation in SHBG concentrations in the bloodstream is inherited from parents, suggesting that SHBG levels are under significant genetic control. However, little has been known about the specific genes that influence SHBG levels.
Investigators examined human genomes from 21,791 men and women to determine which genes influence SHBG levels and validated the results from this genome-wide association study (GWAS) in an additional 7,046 men and women. They identified 12 single-nucleotide polymorphisms (SNPs), or DNA sequence variations, associated with the concentration of SHBG circulating in the bloodstream. However, these SNPs combined explain only 16 percent of the variation of SHBG in men and eight percent in women, respectively, indicating that SHBG levels are affected by many other factors as well.
The results also showed that the SNPs that influence SHBG levels are near genes related to liver function, fat and carbohydrate metabolism and type 2 diabetes. In addition, there were genes that had stronger effects in one sex compared to the other.
“These findings underscore the connection between the reproductive system and metabolism in both men and women, and may help explain sex differences observed in some metabolic diseases, particularly type 2 diabetes,” said Coviello.
Funding for this study was provided by multiple sources. For complete information, go to http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1002805.
A recent study led by researchers at Boston University School of Medicine (BUSM) revealed that the FOXO1 gene may play an important role in the pathological mechanisms of Parkinson’s disease. These findings are published online in PLoS Genetics, a peer-reviewed open-access journal published by the Public Library of Science.
The study was led by Alexandra Dumitriu, PhD, a postdoctoral associate in the department of neurology at BUSM. Richard Myers, PhD, professor of neurology at BUSM, is the study’s senior author.
According to the Parkinson’s Disease Foundation, 60,000 Americans are diagnosed with Parkinson’s disease each year and approximately one million Americans are currently living with the disease.
Parkinson’s disease is a complex neurodegenerative disorder characterized by a buildup of proteins in nerve cells that lead to their inability to communicate with one another, causing motor function issues, including tremors and slowness in movement, as well as dementia. The substantia nigra is an area of the midbrain that helps control movement, and previous research has shown that this area of the brain loses neurons as Parkinson’s disease progresses.
The researchers analyzed gene expression differences in brain tissue between 27 samples with known Parkinson’s disease and 26 samples from neurologically healthy controls. This data set represents the largest number of brain samples used in a whole-genome expression study of Parkinson’s disease to date. The novel aspect of this study is represented by the researchers’ emphasis on removing possible sources of variation by minimizing the differences among samples. They used only male brain tissue samples that showed no significant marks of Alzheimer’s disease pathology, one of the frequently co-occurring neurological diseases in Parkinson’s disease patients. The samples also had similar tissue quality and were from the brain’s prefrontal cortex, one of the less studied areas for the disease. The prefrontal cortex does not show neuronal death to the same extent as the substantia nigra, although it displays molecular and pathological modifications during the disease process, while also being responsible for the dementia present in a large proportion of Parkinson’s disease patients.
Results of the expression experiment showed that the gene FOXO1 had increased expression in the brain tissue samples with known Parkinson’s disease. FOXO1 is a transcriptional regulator that can modify the expression of other genes. Further examination of the FOXO1 gene showed that two single-nucleotide polymorphisms (SNPs), or DNA sequence variations, were significantly associated with age at onset of Parkinson’s disease.
“Our hypothesis is that FOXO1 acts in a protective manner by activating genes and pathways that fight the neurodegeneration processes,” said Dumitriu. “If this is correct, there could be potential to explore FOXO1 as a therapeutic drug target for Parkinson’s disease.”
Research reported in this publication was supported in part by the National Institute of Neurological Disorders and Stroke under award number 1R01NS076843-01, the Cogan Family Foundation, the Robert P. & Judith N. Goldberg Foundation and the William N. and Bernice E. Bumpus Foundation.
A study conducted at Boston University School of Medicine (BUSM) demonstrates an effective combination therapy for breast cancer cells in vitro. The findings, published in the July 2012 issue of Anticancer Research, raise the possibility of using this type of combination therapy for different forms of breast cancer, including those that develop resistance to chemotherapy and other treatments.
The study was led by researchers at the Boston University Cancer Center. Sibaji Sarkar, PhD, adjunct instructor of medicine at BUSM, is the study’s corresponding author.
According to the Centers for Disease Control and Prevention, breast cancer is the most common cancer among women in the United States aside from non-melanoma skin cancer. Breast cancer also is one of the leading causes of cancer death among women of all races and Hispanic origin populations.
Triple negative breast cancer, which accounts for approximately 14 to 20 percent of all breast cancer cases, is a type of the disease that occurs when the cancer cells lack hormone receptors, including the receptor called HER-2, and typically will not respond to hormone and herceptin-based therapies. Triple negative breast cancer occurs more often in African-American women and is considered to be a more aggressive form of the disease with higher rates of recurrence and mortality than other forms of breast cancer.
“Cancer is like a car without brakes. Cell growth speeds up and it doesn’t stop,” said Sarkar. “When expressed, tumor suppressor genes, which work in a protective way to limit tumor growth, function as the brakes. They are not expressed in most cancers, causing the cancer to grow and potentially metastasize.”
A major focus in the area of anti-cancer drug development is to find a way to re-express tumor suppressor genes so that they can help inhibit cancer cell growth. Some tumor suppressor genes are imprinted, meaning that from the two genes inherited from the mother and father, only one of the genes is functional. In cancer, both imprinted tumor suppressor genes may become non-functional and unable to stop tumor growth.
The researchers tested, in vitro, a combination therapy of an epigenetic drug with a protease inhibitor on breast cancer cell lines that are hormone responsive and breast cancer lines, like triple negative, that are not hormone responsive. They utilized histone deacetylases inhibitors (HDACi) and calpeptin, which inhibits calpain, a protein involved in the regulation of signaling proteins. Calpain inhibition is being studied as a potential treatment model for blood clots and other neurological diseases.
In this study, they found that the combination therapy both inhibited cell growth and increased cell death in both cancer cell lines by inducing cell cycle arrest and cell death. However, the mechanism of how the combination therapy stops the cells from growing was different. Cells in the hormone responsive line stopped the cell cycle in an earlier phase compared to the non-hormone responsive cells. In the triple negative breast cancer cell line, the inhibitors allowed an imprinted tumor suppressing gene, ARHI, to re-express, which helped stop the growth of the cancer cells and led to cancer cell death.
“The study data demonstrates that HDACi’s bring back the brakes of the car, halting cell growth and promoting cell death,” added Sarkar, who also is a faculty member at the Genome Science Institute at Boston University. “These results provide a model to investigate the re-expression of tumor suppressor genes, including imprinted genes, in many forms of breast cancer.”
This study needs further investigation but raises the possibility of using this type of combination therapy for diverse types of breast cancers including those that are hormone refractory and develop drug resistance to conventional chemotherapy.
This study was funded by the American Cancer Society.