By Régis Gasper and Erik Goormaghtigh, Université Libre de Bruxelles
Mechanism of action of anticancer compounds on cells could be accurately characterized by their infrared fingerprint thereby improving objective decision for the selection of new molecules.
The main problem with this approach is that little information is revealed about how original the product is compared with current therapies. As a consequence, the number of anticancer drugs that fail to bring innovative therapies far outweighs those that were initially considered effective, mainly because compared with drugs already present on the market they are too similar or not notably better. This huge failure rate leads to high innovation costs for the pharmaceutical industry (about US$800 million per drug that reaches the market).
A selection system based on the biological effects of potential new drugs could allow immediate rejection of a large number of substances that have similar effects to drugs that are already available.
We have developed a new screening method based on infrared (IR) spectroscopy applied to cancer cells. Infrared spectroscopy produces a ‘fingerprint’ of the types and numbers of all chemical bonds present in any sample. The technique is already being used as a means of classifying bacteria accurately and it is now being developed to identify pathogens in food. It can also be used in medical science to discriminate between healthy tissues and tumours.
Our laboratory recently discovered that the chemical changes produced in cells by an antitumour drug candidate can be identified as an IR fingerprint. This gives us a way of classifying how potential new drugs works and has led to an in-depth study on several promising anticancer candidate compounds called cardiotonic steroids. These compounds have been used in traditional medicine for more than 200 years to treat heart failure but recently researchers have reported promising effects in cancer prevention. For example, one study found that women with breast cancer were nearly ten times less likely to have a recurrence after 5 years of treatment with digitalis, a widely used cardiotonic steroid, compared with patients who did not take digitalis.
Our study considered four cardiotonic steroids; two were natural compounds isolated from plants and the other two were chemically modified in order to improve their toxicity against cancer cells. We recorded the IR fingerprint of the modifications these cardiotonic steroids induced in cancer cells. From our analysis, we identified three distinct effects on the cells. The two natural compounds had an identical effect on the cancer cells while both hemi-synthetic compounds altered the cells’ metabolism in different ways. As all four molecules have similar global chemical structure the differences between their effects on cancer cells are very subtle. Nevertheless, our approach revealed that different biochemical pathways were affected. The sensitivity of this classification system based on cells’ molecular vibrations is astonishing. In addition to the standard drug discovery methods, IR spectroscopy might become a tool of choice for the fine selection of new drugs with unique mechanisms of action. Besides, it has a low cost and its results are highly reproducible (i.e. reliable). The advantage for the pharmaceutical industry could be a significant reduction of the R&D cost and accordingly contribute to reducing treatment costs.
Régis Gasper and Erik Goormaghtigh
Université Libre de Bruxelles
www.atomiumculture.eu
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