March 25, 2013 | 1
Apoptosis or programmed cell death is one of the great truths of cellular life, an essential process that’s not only required to make way for new cells but to prevent old cells from going haywire. When cells circumvent this great truth they start dividing uncontrollably and contribute to cancer. Our knowledge of cancer over the last three decades has confirmed the central role that a breakdown in the usual mechanisms of apoptosis plays in pushing a cell across the tipping point into a cancerous state. Of the many strategies to fight cancer, one consists of trying to find drugs that force cells to regain their normal balance of apoptosis. Now this effort may have found an unlikely ally.
Chlorhexidine is an antibacterial and plaque-fighting compound that is a common component of mouthwash, usually present as a 0.1% or 0.2% solution. In a paper published in the journal Angewandte Chemie, scientists in Germany report an unexpected effect of chlorhexidine and its related cousin alexidine: they inhibit cancer cells in the mouth by blocking an important protein-protein interaction. This research opens up new directions in investigating this class of compounds as anticancer agents and also sheds light on the value of finding novel potential uses for everyday chemical compounds. One of the great advantages in this endeavor is that the “repurposed” compounds have already run the gauntlet of safety tests required by the FDA, potentially shortening the period of approval for their new uses.
Protein-protein interactions (PPIs) are often considered the next frontier in drug discovery. They are involved in almost every important molecular-level event in health and disease. Traditional drugs work by blocking the action of single proteins (typically fitting into them like a key fits into a lock) but since there are many more protein-protein interactions than single proteins, there is enormous potential in developing drugs that disrupt these interactions, many of which are upregulated in diseases like cancer. Unfortunately targeting PPIs is difficult because of a variety of reasons; they have large, spread-out interfaces which makes it difficult for small organic molecules to span their surface area, and typically the ones which do are too big to satisfy the many qualities of an ideal drug, such as an ability to get inside cells in the first place.
One of the most well studied PPIs is the interaction between a family of pro-apoptotic and anti-apoptotic proteins called the Bcl-2 family. These proteins are present in all our cells. As their name indicates, one group of proteins speeds up apoptosis while the other group inhibits it. In a normal cell there is a usually a precise balance between these two activities engineered by the two sets of proteins binding to each other and regulating each other’s function. It’s a delicate dance which ensures that the cells are active only when needed and any cells gone haywire are eliminated. In cancer this precise balance is disrupted and the anti-apoptotic proteins are over-expressed and become dominant. One anti-apoptotic protein named Bcl-Xl in particular keeps its usually equipotent pro-apoptotic protein partner named Bak bound up and prevents the cell from committing suicide; this molecular-level feud leads to uncontrolled cell division. Over the years researchers have tried to find many druglike molecules and peptides which could block Bcl-Xl and free up the Bak protein. But none of the attempts have resulted in a clinically marketed drug.
What the researchers in Germany did was to screen about 4000 everyday chemical compounds to look for ones that might block the Bcl-Xl protein. They found two which, surprisingly, had very different uses. Chlorhexidine and alexidine are common components of mouthwash. Both compounds were found to inhibit the Bcl-Xl – Bak interaction at a concentration that’s much lower than that found in mouthwash. Surface-exposed oral cells in the mouth are thus bathed in a rather potent concentration of small molecules that prevent at least one important mechanism involved in cancer from manifesting itself. The researchers also did further experiments, including computer modeling, that localized the site of binding of the two compounds on the Bcl-Xl protein. This site was the same as that occupied by the Bak protein, further supporting the blocking interaction of the mouthwash components with the anti-apoptotic protein.
Finally the researchers tested these two compounds against cancerous cells from the tongue and the pharynx. Both compounds were found to significantly reduce the degree of apoptosis suppression in these cells, connecting the molecular level interaction of the molecules to actual anticancer effects.
This study is interesting for several reasons. It directly leads to a new class of compounds that may have promising anticancer activities; very likely the compounds’ structures would have to be modified by chemists to improve their properties, but this is what chemists have always done best. The therapeutic concentration that’s required for inhibiting the proteins is already exceeded in your garden variety mouthwash; this may also indicate a healthy margin of safety. A more intriguing question to ask is whether the use of mouthwash correlates with lower incidence of oral cancer. The literature on the relationship between mouthwash and oral cancer has been confusing and there don’t seem to be large-scale studies investigating a possible connection. By suggesting a possible mechanism of cancer prevention, this study provides a strong motivation to gather epidemiological data about possible anticancer effects of mouthwash and its components. It’s too early to start dousing your mouth with mouthwash though since these compounds only target one kind of interaction and we don’t have enough data on higher concentrations and long-term effects. But it’s definitely a promising start that points the way to interesting experiments, and that’s what science is best at doing.
Most tantalizingly though, the study asks what other kinds of therapeutic effects may be hidden in everyday chemical products, in our bathroom and kitchen closets. Nature is much more interesting than we think and molecules often lead double lives. Contemplate this the next time you brush your teeth or wash your dishes.