Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Antipsychotic drug exhibits cancer-fighting properties

10.01.2014
In zebrafish model, perphenazine activates therapeutic pathway for intractable leukemia, may hold promise for other tumors

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.

Irene Sege | EurekAlert!
Further information:
http://www.dana-farber.org/

More articles from Studies and Analyses:

nachricht Multi-year study finds 'hotspots' of ammonia over world's major agricultural areas
17.03.2017 | University of Maryland

nachricht Diabetes Drug May Improve Bone Fat-induced Defects of Fracture Healing
17.03.2017 | Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke

All articles from Studies and Analyses >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Argon is not the 'dope' for metallic hydrogen

24.03.2017 | Materials Sciences

Astronomers find unexpected, dust-obscured star formation in distant galaxy

24.03.2017 | Physics and Astronomy

Gravitational wave kicks monster black hole out of galactic core

24.03.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>