Compounds could be new class of cancer drugs

February 04, 2009

A team of Vanderbilt University Medical Center investigators has developed a group of chemical compounds that could represent a new class of drugs for treating cancer.

The compounds are the first selective inhibitors of the protein phospholipase D (PLD), an enzyme that has been implicated in multiple human cancers including breast, renal, gastric and colorectal.

The new inhibitors, reported in the February issue of Nature Chemical Biology, block the invasive migration of breast cancer cells, supporting their further development as antimetastatic agents. They will also be useful tools for understanding the complex roles of PLD in cellular physiology, said H. Alex Brown, Ph.D., professor of Pharmacology and one of the team leaders.

"PLD is associated with many fundamental cellular processes like secretion, migration, growth and proliferation. But the absence of selective inhibitors has really interfered with the ability of biologists to study this important enzyme," Brown said.

There are two related "isoforms" of PLD: PLD1 and PLD2. Both PLD enzymes produce phosphatidic acid, a key lipid metabolic and signaling molecule. But whether the two PLDs have different roles is an open question, one that the new isoform-selective inhibitors can now be used to address.

Brown and colleagues had discovered that PLD was important to the invasive migration of breast cancer cells in culture using a genetic tool called small interfering RNA (siRNA).

"When we had evidence from siRNA and other methods that blocking PLD resulted in dramatic effects of blocking metastatic invasion of breast cancer cells, we were highly motivated to attempt to make isoform-selective inhibitors," Brown said.

Craig Lindsley, Ph.D., a medicinal chemist who joined the Vanderbilt faculty after five years at Merck Research Laboratories, and his group used a previously described PLD inhibitor as a starting point for a chemistry process called diversity-oriented synthesis. The team screened resulting compounds for activity against PLD1 and PLD2 using in vitro and cell-based screening tools developed in Brown's laboratory.

"Without these high quality screening assays and rapid turnaround, this process wouldn't have worked," said Lindsley, associate professor of Pharmacology and Chemistry. The researchers were able to generate compounds that selectively inhibited PLD1 or PLD2, and other compounds that inhibited both isoforms.

"With the compounds we've made, we can almost choose the range at which we'd like to inhibit the different isoforms, something that's never before been possible," Lindsley said.

The researchers demonstrated that the compounds act directly on the PLD enzymes (using purified proteins), and they showed that they blocked the invasive migration behavior of three different breast cancer cell lines.

"These inhibitors are the key tools we need to really probe the biology, and we're obviously hoping to develop them for therapeutic applications too," Brown added. "Not only is Craig an excellent chemist, but he really knows about making compounds that have the potential to become drugs, and that has had a very positive influence on this collaboration."

In focusing on PLD, Brown, Lindsley and their colleagues are carrying the torch forward for an enzyme that was famously characterized at Vanderbilt. John Exton, M.D., Ph.D., professor of Molecular Physiology & Biophysics and Pharmacology, was elected to the National Academy of Sciences for his work on PLDs.

The researchers will now optimize their new compounds for in vivo studies and to give them characteristics compatible with being good medications. They are also expanding their research into other areas of biology - in addition to studying the inhibitors in breast cancer models, they will explore how they work in cell systems that model brain tumors, rheumatoid arthritis and viral infections.

Vanderbilt University Medical Center

---

---

	Balance SSRI benefits with risks for children.(Behavioral Pediatrics)(selective serotonin reuptake inhibitors ): An article from: Pediatric News by Kerri Wachter (Author) This digital document is an article from Pediatric News, published by International Medical News Group on April 1, 2005. The length of the article is 849 words. The page length shown above is based on a typical 300-word page. The article is delivered in HTML format and is available in your Amazon.com Digital Locker immediately after purchase. You can view it with any web browser. Citation Details Title: Balance SSRI benefits with risks for children.(Behavioral Pediatrics)(selective serotonin reuptake inhibitors ) Author: Kerri Wachter Publication: Pediatric News (Magazine/Journal) Date: April 1, 2005 Publisher: International Medical News Group Volume: 39 Issue: 4 Page: 23(1) Distributed by Thomson...
	Weighing new evidence on SSRI use.(Selective serotonin reuptake inhibitors)(Drug overview): An article from: Internal Medicine News by Lee S. Cohen (Author) This digital document is an article from Internal Medicine News, published by Thomson Gale on July 15, 2006. The length of the article is 803 words. The page length shown above is based on a typical 300-word page. The article is delivered in HTML format and is available in your Amazon.com Digital Locker immediately after purchase. You can view it with any web browser. Citation Details Title: Weighing new evidence on SSRI use.(Selective serotonin reuptake inhibitors)(Drug overview) Author: Lee S. Cohen Publication: Internal Medicine News (Magazine/Journal) Date: July 15, 2006 Publisher: Thomson Gale Volume: 39 Issue: 14 Page: 35(1) Article Type: Drug overview Distributed by Thomson...
	Use of Selective Serotonin Reuptake Inhibitors During Pregnancy and Risk of Major and Cardiovascular Malformations: An Update (Postgraduate Medicine) by JTE Multimedia Abstract: General consensus exists about the need to avoid drug intake as much as possible during pregnancy due to the lack of thorough evidence about the safety of pharmacologic treatments during gestation for both mothers and fetuses. In this respect, the overall safety profile of selective serotonin reuptake inhibitors (SSRIs) in pregnancy remains unclear. This article reviews current evidence about the safety of each SSRI during pregnancy in order to describe their specific teratogenic potential, with a particular focus on major and cardiovascular malformations, and to verify whether such toxicity can be considered as a class effect. The literature review included controlled studies and meta-analyses (retrieved using PsychINFO, EMBASE, and Medline from January 1966 to May 2010) from...
	Cancer and the Search for Selective Biochemical Inhibitors, Second Edition by E.J. Hoffman (Author) The world of medicine has become splintered into two factions, that of orthodoxy and its counterpart, alternative or complementary medicine. A problem with alternative medicine is, of course, that of anecdote and hearsay. The solution: the disclosure, in an unassailable fashion, of the underlying biochemical principles for alternative cancer therapies. Cancer and the Search for Selective Biochemical Inhibitors, Second Edition delineates the underlying biochemical principles for alternative cancer therapies. Completely revised and updated, this edition includes coverage of the link between concepts and practices of alternative and conventional medicine. The author examines anticancer plant substances and other alternatives such as Vitamin C, essiac tea, shark cartilage, and cat’s claw....
	Selective 5-Ht Reuptake Inhibitors: Novel or Commonplace Agents? (Advances in Biological Psychiatry) by M. Gastpar (Author), J. S. Wakelin (Editor)
	Selective Serotonin Re-Uptake Inhibitors: The Clinical Use of Citalopram, Fluoxetine, Fluvoxamine, Paroxetine, and Sertraline (Perspectives in Psychiatry) by J. P. Feighner (Author), W. F. Boyer (Author) With a minimum of side effects, low toxicity in overdose and a broad range of clinical applications, selective serotonin re-uptake inhibitors have found widespread and increasing use in psychiatry worldwide. Here is the most comprehensive reference source available on these important drugs. Beginning with examinations of the drugs' pharmacology their effects on serotonergic function and the central role of serotonin in many psychiatric disorders, the book moves on to reviews of clinical trials in many psychiatric conditions. Finally, an important chapter discusses clinical issues in the use of these agents.
	Selective Serotonin Re-Uptake Inhibitors: Advances in Basic Research and Clinical Practice (Perspectives in Psychiatry) by J. P. Feighner (Editor), W. F. Boyer (Editor) Interest in Selective Serotonin Re-Uptake Inhibitors has grown considerably in recent years, particularly as their therapeutic profile is expanding to the treatment of other types of psychiatric disorder besides depression. It is therefore timely that the authors of Selective Serotonin Re-Uptake Inhibitors should now provide a second edition. Reorganised and updated to include additional chapters which greatly extend the scope of the book, this edition gives an excellent review of the biochemical, pharmacological and clinical aspects of this important group of drugs. Written by an array of outstanding, authoritative, international scientists and clinicians this invaluable reference provides a wealth of knowledge and an extensive source of up-to-date references on a subject that is...
	Cancer and the Search for Selective Biochemical Inhibitors by E.J. Hoffman (Author) Cancer and the Search for Selective Biochemical Inhibitors examines the nonorthodox methods-particularly plant and herbal possibilities-for treating cancer. This book explores the theory of why and how alternative treatments of cancer should work, with an emphasis on the role of enzyme inhibitors, the basis for most modern drug therapy, including those which may be selective for cancer cell metabolism.
	Natalizumab may quell Crohn's disease, MS: selective adhesion-molecule inhibitor.(Clinical Rounds): An article from: Family Practice News by Kerri Wachter (Author) This digital document is an article from Family Practice News, published by Thomson Gale on September 15, 2003. The length of the article is 604 words. The page length shown above is based on a typical 300-word page. The article is delivered in HTML format and is available in your Amazon.com Digital Locker immediately after purchase. You can view it with any web browser. Citation Details Title: Natalizumab may quell Crohn's disease, MS: selective adhesion-molecule inhibitor.(Clinical Rounds) Author: Kerri Wachter Publication: Family Practice News (Magazine/Journal) Date: September 15, 2003 Publisher: Thomson Gale Volume: 33 Issue: 18 Page: 18(1) Distributed by Thomson...
	Selective COX-2 Inhibitors: Pharmacology, Clinical Effects and Therapeutic Potential by Sir John R. Vane (Editor), Jack H. Botting (Editor) This volume is the proceedings of the William Harvey Research Conference held in Cannes, France, on the 20th and 21st March, 1997. It describes the present knowledge of the structures of the cyclooxygenase isoforms and the experimental and clinical effects of selective inhibitors of cyclooxygenase-2. The pathophysiological significance of the cyclooxygenase enzymes in tumorigenesis, programmed cell death, vascular disease and asthma is also covered.