Saturday, June 7, 2014

Cholesterol and Cancer Inhibition

For our project, Matt and I focused on cholesterol and its metabolite’s promoting effects on breast cancer.  However, as Matt mentioned in our presentation, there is a tumor suppressing metabolite of cholesterol.  It is still very much in the works, but research seems to support the suppression of this metabolite, called Dendrogenin A (DDA).  This molecule is an amino-oxysterol metabolite that “arises from cholesterol-5,6-epoxides and histamine in mammals” (Silvente-Poirot).  Very little is actually known about this molecule and its inhibitive abilities, and a Google search turned up this study and one other that identified DDA as a product of cholesterol.  It has recently been discovered to be a natural metabolite occurring in mammals, having been previously synthesized synthetically.  The fact that this molecule may be a successful inhibitor of cancer makes it very exciting.  The fact that it is naturally occurring makes it even better.

What was very cool about this molecule is that in vitro, DDA was able to induce cell differentiation and eventually death(Medina).  As a result, the researchers decided to test this result in mice.  They took mice with functioning immune systems and infected(grafred) them with either mammary tumors, or melanoma.  The same day they were treated with DDA or the vehicle control(Medina).  The results were incredible.  In Figure 1 A,C,E, and F, we can see that the tumor suppression brought about by DDA are great.  Each treatment with DDA shows the least amount of growth in the differing systems (which mainly meant the type of cells used to grow the tumors were different).  When analyzing the two Kaplin-meyer plots, we see that the mice injected with DDA show a greater mean survival rate, doing considerably better than those treated with the vehicle (Figure 1 B and D).  Also, those mice injected with 0.37 ug/kg of DDA did a little better than those injected with 0.037 ug/kg DDA, a seemingly minor point that will lead to eventual dosing calculations.  Later on in the paper, they discuss how this may be due to the immune response to cells containing higher levels of DDA.  They believe this is the result of DDA somehow allowing the immune system to recognize the tumors better and eradicate them from the body (Medina).     
An external file that holds a picture, illustration, etc.
Object name is ncomms2835-f4.jpg
Figure 1: DDA inhibited the growth of B16F10 melanoma and TS/A mammary tumours implanted into immunocompetent mice and enhanced animal survival.
Immunocompetent mice were implanted s.c. with (a) B16F10 cells or (b,c) TS/A cells and animals (n=10 mice per group) were treated every 5 days starting on the day of tumour implantation with the indicated doses of either dacarbazine (intraperitoneally (i.p.)), DDA (s.c.), C17 (s.c.), vehicle (s.c.) or Tam (i.p.). Animals were monitored for tumour growth (a,c), *P<0.05; **P<0.01 (analysis of variance (ANOVA), Dunnett’s post test), and survival (b,d), *P<0.05; ***P<0.0001 (log-rank tests). Immunocompetent mice were implanted s.c. with (e) B16F10 cells or (f) TS/A cells, and when the tumour reached a volume of 50–100 mm3, animals (n=10 mice per group) were treated once per day with the indicated doses of dacarbazine (i.p.), DDA (s.c.), C17 (s.c.), vehicle (s.c.) or Tam (i.p.) and were monitored over time for tumour growth, *P<0.05; **P<0.01 (ANOVA, Dunnett’s post tests). The mean tumour volume±s.e.m is shown. The data are representative of three independent experiments.
Now this information is very interesting, but the best part of this development is its usefulness to the treatment of all cancers.  The anti-tumor abilities have already been applied to two very different cancers, showing inhibiting effects.  This gives researchers great hope that this may help in many different cancers as well.  And the fact that it is naturally occurring is very big as well.  So now the research will focus on finding a way to boost the levels of DDA in the tumor cells safely and effectively.  Then they have to see if these changes in body chemistry happen to cause any adverse side effects.  With the many side effects of the current treatments, it seems as though it is a possibility.  However, I feel that the fact that it naturally occurs in the body, it would not have as many side effects as seen by other drugs.  If this is able to be done, theoretically it could help to treat many different forms of cancer.  This research is very new and is still only in the early stages of mouse testing.  I feel that in a couple of years, we will see this DDA research being applied to clinical trials.  The multi-cancer treatability of this molecule will make it a goldmine for drug companies.  It is the treatment of the future.   

Works Cited
1.  Medina, Philippe De, Michael R. Paillasse, Gregory Segala, Maud Voisin, Loubna Mhamdi, Florence Dalenc, Magali Lacroix-Triki, Thomas Filleron, Frederic Pont, Talal Al Saati, Christophe Morisseau, Bruce D. Hammock, Sandrine Silvente-Poirot, and Marc Poirot. "Dendrogenin A Arises from Cholesterol and Histamine Metabolism and Shows Cell Differentiation and Anti-tumour Properties." Nature Communications 4 (2013): 1840. Web.

2.    Silvente-Poirot, S., and M. Poirot. "Cholesterol and Cancer, in the Balance." Science 343.6178 (2014): 1445-446. Web.