(Press-News.org) Contact information: Irene Sege
irene.sege@childrens.harvard.edu
617-919-3110
Dana-Farber Cancer Institute
Antipsychotic drug exhibits cancer-fighting properties
In zebrafish model, perphenazine activates therapeutic pathway for intractable leukemia, may hold promise for other tumors
BOSTON, Jan. 9, 2014 - In a prime example of finding new uses for older drugs, studies in zebrafish show that a 50-year-old antipsychotic medication called perphenazine can actively combat the cells of a difficult-to-treat form of acute lymphoblastic leukemia (ALL). The drug works by turning on a cancer-suppressing enzyme called PP2A and causing malignant tumor cells to self-destruct.
The findings suggest that developing medications that activate PP2A, while avoiding perphenazine's psychotropic effects, could help clinicians make much-needed headway against T-cell ALL, and perhaps other tumors as well.
A study team led by Alejandro Gutierrez, MD, and A. Thomas Look, MD, of Dana-Farber/Boston Children's Cancer and Blood Disorders Center, and Jon Aster, MD, PhD, of Dana-Farber Cancer Institute and Brigham and Women's Hospital, reported the results Jan. 9 in the Journal of Clinical Investigation.
T-ALL is rarer and more aggressive than the B-cell form of ALL, and it has a relatively poor prognosis. Despite improvements in the treatments available, 20 percent of children and more than 50 percent of adults diagnosed with T-ALL succumb to it.
To identify possible new treatment options, Gutierrez, Look and their collaborators screened a library of 4,880 compounds—including FDA-approved drugs whose patents had expired, small molecules and natural products—in a model of T-ALL engineered using zebrafish.
Strategies that identify new uses for existing drugs have grown in popularity in recent years as a way of quickly developing new disease therapies. Zebrafish models are cost-effective platforms for rapidly conducting drug screens, as well as basic stem cell, genetic, cancer and developmental research.
"We wanted to see if there were drugs or known bioactive molecules that are active against T-ALL that hadn't been tested yet," Look explained. "There may be drugs available for other indications that could be readily repurposed if we can show activity."
One of the strongest hits in the zebrafish screen was the drug perphenazine. It is a member of the phenothiazines, a family of antipsychotic medications used for 50 years, because they can block dopamine receptors.
The team verified perphenazine's anti-leukemic potential in vitro in several mouse and human T-ALL cell lines. Biochemical studies indicated that perphenazine's anti-tumor activity is independent of its psychotropic activity, and that it attacks T-ALL cells by turning on PP2A.
The fact that perphenazine works by reactivating a protein shut down in cancer cells is itself novel in the drug development field.
"We rarely find potential drug molecules that activate an enzyme," Gutierrez explained. "Most new drugs deactivate some protein or signal that the cancer cell requires to survive. But, here, perphenazine is restoring the activity of PP2A in the T-ALL cell."
Gutierrez and Look, along with their collaborators, are now working to better understand the interactions between PP2A and perphenazine. They also want to search for or develop molecules that bind to and activate the enzyme more tightly and specifically to avoid perphenazine's psychiatric effects.
"The challenge is to use medicinal chemistry to develop new PP2A inhibitors similar to perphenazine and the other phenothiazines, but to dial down dopamine interactions and accentuate those with PP2A," Look said.
The researchers see future PP2A inhibitors not as magic bullets but as potentially important additions to the oncologist's arsenal when treating patients with T-ALL.
" T-ALL patients are often on the borderline between a long remission and a cure," Look said. "If we can push the leukemia cells a little harder, we may get more patients who are actually cured. In this way, PP2A inhibitors may, in combination with other drugs, make a real difference for patients."
It may be that the benefits of PP2A-activating drugs could extend beyond T-ALL. "The proteins that PP2A suppresses, such as Myc and Akt, are involved in many tumors," Look noted. "We are optimistic that PP2A activators will have quite broad activity against different kinds of cancer, and we're anxious to study the pathway in other malignancies as well."
###
This study was supported by the National Cancer Institute (grant numbers K08CA133103 and P01CA109901), the Leukemia and Lymphoma Society, the William Lawrence Blanche Hughes Foundation, the Bear Necessities Foundation, the Ligue Nationale contre le Cancer, Association Laurette Fugain, Institut National du Cancer (INCA), Universités Paris Diderot and Paris Sud, INSERM, CEA and Canceropole Ile de France, European Union's Seventh Framework Programme and the American Society of Hematology.
The Dana-Farber/Boston Children's Cancer and Blood Disorders Center brings together two internationally known research and teaching institutions that have provided comprehensive care for pediatric oncology and hematology patients since 1947. The Harvard Medical School affiliates share a clinical staff that delivers inpatient care at Boston Children's Hospital and outpatient care at the Dana-Farber Cancer Institute's Jimmy Fund Clinic. Dana-Farber/Boston Children's brings the results of its pioneering research and clinical trials to patients' bedsides through five clinical centers: the Blood Disorders Center, the Brain Tumor Center, the Hematologic Malignancies Center, the Solid Tumors Center, and the Stem Cell Transplant Center.
Antipsychotic drug exhibits cancer-fighting properties
In zebrafish model, perphenazine activates therapeutic pathway for intractable leukemia, may hold promise for other tumors
2014-01-10
ELSE PRESS RELEASES FROM THIS DATE:
Some motor proteins cooperate better than others
2014-01-10
Some motor proteins cooperate better than others
Rice University researchers view competition, cooperation among motors in live cells
HOUSTON - (Jan. 9, 2014) - Rice University researchers have engineered cells to characterize how sensitively altering the cooperative functions of ...
ORNL-UT researchers invent 'sideways' approach to 2-D hybrid
2014-01-10
ORNL-UT researchers invent 'sideways' approach to 2-D hybrid
OAK RIDGE, Tenn., Jan. 9, 2014 -- Researchers at the Department of Energy's Oak Ridge National Laboratory and the University of Tennessee, Knoxville have pioneered a new technique for forming ...
Hubble probes interior of Tarantula Nebula
2014-01-10
Hubble probes interior of Tarantula Nebula
Like lifting a giant veil, the near-infrared vision of NASA's Hubble Space Telescope uncovers a dazzling new view deep inside the Tarantula Nebula. Hubble reveals a glittering treasure trove of more than ...
Hubble views stellar genesis in the Southern Pinwheel
2014-01-10
Hubble views stellar genesis in the Southern Pinwheel
A photogenic and favorite target for amateur astronomers, the full beauty of nearby barred spiral galaxy M83 is unveiled in all of its glory in this Hubble Space Telescope mosaic image. The ...
Novel biomarker approach suggests new avenues to improve schizophrenia disease management
2014-01-10
Novel biomarker approach suggests new avenues to improve schizophrenia disease management
Environmental effects of events such as oxygen deprivation and infections may be preserved as markers in blood that are associated to schizophrenia, according to an ...
Stem cells injected into nerve guide tubes repair injured peripheral nerve
2014-01-10
Stem cells injected into nerve guide tubes repair injured peripheral nerve
Putnam Valley, NY. (Jan. 9, 2014) – Using skin-derived stem cells (SDSCs) and a previously developed collagen tube designed to successfully bridge gaps in injured ...
Are you listening? Kids' ear infections cost health care system nearly $3 billion a year
2014-01-10
Are you listening? Kids' ear infections cost health care system nearly $3 billion a year
Acute otitis media, or ear infection, is the most common ailment among kids of preschool age and younger in the U.S., primarily because these children ...
NIH-created toxin can kill HIV-infected cells that persist despite treatment
2014-01-10
NIH-created toxin can kill HIV-infected cells that persist despite treatment
Approach could potentially be part of future HIV cure strategy
A team including University of North Carolina and NIH scientists has demonstrated in ...
Researchers develop tool to determine individual risk of prostate cancer overdiagnosis
2014-01-10
Researchers develop tool to determine individual risk of prostate cancer overdiagnosis
Nomogram aims to enable informed decision-making and personalized treatment
SEATTLE - Studies have found that prostate cancer is overdiagnosed in up to 42 percent ...
Study: Athlete's first reaction in victory is dominance
2014-01-10
Study: Athlete's first reaction in victory is dominance
Body language, also called 'triumph,' stronger in victors from cultures that emphasize hierarchy
SAN FRANCISCO -- Upon victory, an athlete's initial and instinctive reaction is one that displays dominance ...
LAST 30 PRESS RELEASES:
Exercise as an anti-ageing intervention to avoid detrimental impact of mental fatigue
UMass Amherst Nursing Professor Emerita honored as ‘Living Legend’
New guidelines aim to improve cystic fibrosis screening
Picky eaters by day, buffet by night: Butterfly, moth diets sync to plant aromas
Pennington Biomedical’s Dr. Leanne Redman honored with the E. V. McCollum Award from the American Society for Nutrition
CCNY physicists uncover electronic interactions mediated via spin waves
Researchers’ 3D-printing formula may transform future of foam
Nurture more important than nature for robotic hand
Drug-delivering aptamers target leukemia stem cells for one-two knockout punch
New study finds that over 95% of sponsored influencer posts on Twitter were not disclosed
New sea grant report helps great lakes fish farmers navigate aquaculture regulations
Strain “trick” improves perovskite solar cells’ efficiency
How GPS helps older drivers stay on the roads
Estrogen and progesterone stimulate the body to make opioids
Dancing with the cells – how acoustically levitating a diamond led to a breakthrough in biotech automation
Machine learning helps construct an evolutionary timeline of bacteria
Cellular regulator of mRNA vaccine revealed... offering new therapeutic options
Animal behavioral diversity at risk in the face of declining biodiversity
Finding their way: GPS ignites independence in older adult drivers
Antibiotic resistance among key bacterial species plateaus over time
‘Some insects are declining but what’s happening to the other 99%?’
Powerful new software platform could reshape biomedical research by making data analysis more accessible
Revealing capillaries and cells in living organs with ultrasound
American College of Physicians awards $260,000 in grants to address equity challenges in obesity care
Researchers from MARE ULisboa discover that the European catfish, an invasive species in Portugal, has a prolonged breeding season, enhancing its invasive potential
Rakesh K. Jain, PhD, FAACR, honored with the 2025 AACR Award for Lifetime Achievement in Cancer Research
Solar cells made of moon dust could power future space exploration
Deporting immigrants may further shrink the health care workforce
Border region emergency medical services in migrant emergency care
Resident physician intentions regarding unionization
[Press-News.org] Antipsychotic drug exhibits cancer-fighting propertiesIn zebrafish model, perphenazine activates therapeutic pathway for intractable leukemia, may hold promise for other tumors