New screen shows obesity drug is tumour blocker
scientists to identify active targets and simultaneously screen for
their inhibitors. The screening technique has already revealed that
orlistat, an anti-obesity drug, has an additional benefit as a
treatment for prostate cancer, writes Wai Lang Chu.
Led by Dr Jeffrey Smith, the team from the Burnham Institute in the US designed a proteomics screen based on monitoring the activity of a family of enzymes - serine hydrolases - involved in metabolism. Orlistat was one of a number of pharmaceutical drugs involved in the enzyme screen.
Dr Smith, associate scientific director at The Burnham Institute said: "Initially we were experimenting with the serine proteases that we knew were involved in prostate cancer. The chemical probe allowed us to discover the serine hydrolases and their relation to fatty acid synthase (FAS)."
Prostate cancer cells are characterised by an increased activity of FAS, an enzyme that converts dietary carbohydrate to fat that has become a useful market for prostate cancer, but until now the role of serine hydrolases in this pathway was not known.
Meanwhile, the identification of orlistat's ability to inhibit the thioesterase domain of FAS, a catalyst in one of the biochemical steps in the conversion of carbohydrates into fat, was achieved by comparing normal prostate cells with prostate cancer cells.
"The new proteomics screening will give us really good insights into the mechanism, and we anticipate that's going to reveal additional drug targets along this pathway," said Dr Smith.
The activity-based proteomics screening technique's ability to compile a comprehensive profile of a potential drug's activities, revealing unintended and intended behaviours offers a systematic way to simulate how a drug will work, before it is actually tested in animals and humans.
Recent emphasis on global profiling strategies, including gene expression profiling and non-activity based proteomics are limited as these profiling technologies measure abundance, not function, falling short of making it possible to screen drugs against a plethora of targets.
Dr Smith said: "The activity-based proteomics screening technique can be applied pretty widely. As well as the serine hydrolases we discovered probes that could be applied to the cystine hydrolase group and the kinase enzyme group."
"I would say the technique is not widely used at the moment but is getting popular. The data and discoveries we have made using this method would not have been possible with other techniques as this experimental procedure is one of a kind."
Treatment of tomorrow
"One future use I can envisage is the segregation of cancer patients according to their unique enzymic profile. Treatment could then be tailored to the patient," Dr Smith added.
