Pharma R&D Today
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Getting the message across
Posted on April 1st, 2016 by Joanna Aldred in Chemistry
If you ever get out of the laboratory or office onto the street, look around and you can be certain that most people you see will not be concentrating on where they are walking (or, here in the Netherlands, where they are cycling) but at their smartphones. Mobile telephones have developed a long way since they first provided parents with the possibility of keeping track on their errant child: so much so that errant children wishing to avoid parental contact who fail to respond to a telephone call will be bombarded by one or several messaging systems (of course, there is still the “the phone battery is empty” excuse…) and, if all else fails, followed by the social media trail of their friends.
Some cells are like errant children and try to avoid messages sent to them. When the message is something along the lines of “it is time to die” you can imagine why this might be, but these messages are a regular occurrence in living organisms. The programmed death of cells (apoptosis) is the mechanism by which a healthy organism get rids of damaged or unwanted cells. Unfortunately, cells sometimes become resistant to messages. Cells which are most likely to resist this “self-destruct” message are often ones which lead to diseases such as cancer.
Treating cancer by forcing the cancerous cells to obey the call to destroy themselves must certainly be a path worth exploring. The B-cell lymphoma 2 (Bcl-2) family of proteins play a part in passing on the apopotosis message and their roles have been explored in detail, as discussed in a review paper in Bioorganic & Medicinal Chemistry Letters by Edward J. Hennessy.
“Family” is a good word to describe this group of proteins: they are like a group of squabbling children who can never agree. Some Bcl-2 family proteins work to increase the sensitivity of the cell to the messages to die (proapoptotic), while others decrease the sensitivity to the message (antiapoptotic). The balance of these proteins decides the fate of each cell. One way to stop the Bcl-2 proteins from repressing apopotosis is to bind on an appropriate protein from the family. Depending on which proteins are linked together the proapoptotic message or the antiapoptotic message can be enhanced. So, to find a way to encourage the cancer cells to die, it is necessary that the proapoptotic proteins are linked to other family members that make them stronger while the antiapoptotic proteins need to be linked to family members that make their message weaker. Research has concentrated on linking the correct proapoptotic proteins together to make sure that the cancer cells understand that their time has come. There are already some medicines at the clinical trial stage, which is good news. This treatment appears to be particularly effective for cancers such as chronic lymphocytic leukemia and non-Hodgkin’s lymphoma. However, there are serious side-effects which have to be considered: these proteins can also encourage non-cancerous cells to die. Also, genetic variability seems to be important as well. In vitro tests have shown that means that some cells are more sensitive to apopotosis than others with a different gene coding.
This paper gives a really good description of how taking one step along the path to drug discovery leads into other areas, some of which offer improvements and others which cause new problems. As with most things in life, a combination of hard work and good luck offer the best chance of success!
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