Sulindac: An Old Anti-Inflammatory Drug With Newly Identified Anti-Cancer Properties
Sulindac is a very old general cox enzyme inhibitor. It's an inexpensive prescription drug that has been shown to both prevent and treat colon cancers. Sulindac's anti-cancer properties have little (but not nothing) to do with its ability to inhibit cox-1/2 enzymes.
The National Cancer Institute conducted a series of clinical trials using sulindac to treat colon cancer. After some initial success, the subjects became resistant to the anti-cancer properties of sulindac. I believe all further studies were abandoned.
Sulindac has been referred to as a histone deacetylase inhibitor in some scientific papers, but I haven't been able to find a confirming study that proves this. Nevertheless, sulindac does share biochemical properties with known HDAC inhibitors.
First and foremost, HDAC inhibitors stimulate the synthesis of the p21Waf1 inhibitor protein. This protein inhibits the activity of enzymes that promote the cell cycle. If p21Waf1 synthesis is enhanced, the cells stop dividing and accumulate in the G0/G1 phase of the cell cycle. Eventually, they die.
Sulindac also promotes the synthesis of p21Waf1.
If the p21Waf1 gene is methylated at the DNA level, therefore becoming inactive, sulindac loses its ability to inhibit tumor formation.
Clearly, sulindac has anti-cancer properties that transcend its ability to inhibit the cox1/2 enzymes.
Let's "assume" that sulindac is indeed a true blue histone deacetylase inhibitor. This would be very very good news.
Interestingly, as with other HDAC inhibitors (discussed in the previous blog), the cancer killing affects of sulindac are inhibited by activation of the PI-3K/AKT pathway.
However, and this is very exciting, sulindac can directly inhibit the AKT kinase (protein kinase B). Actually, a metabolite of sulindac, sulindac sulfide, is the AKT inhibitor. It appears that sulindac metabolites inactivate AKT by two different pathways. The first pathway degrades AKT by the caspase-8 enzyme. The second pathway decreases phosphorylation of the AKT kinase.
In a previous essay, we learned that histone deacetylase inhibitors sensitized cells to TRAIL by activating expression of the TRAIL DR5 receptor.
We also learned that HDAC inhibitors activated caspase-8 activity by inhibiting the synthesis of c-FLIP, the caspase-8 inhibitor. Caspase-8, an enzyme, is critically involved in "chewing up" cellular proteins during the process of apoptosis.
As further proof that sulindac is a true histone deacetylase inhibitor, this NSAID drug induces apoptosis in colon and prostate cancer cells by activating the synthesis of TRAIL receptor D5 and increasing the activity of caspase-8 (no doubt through the inhibition of c-FLIP).
Finally, sulindac is a direct inhibitor of the NF-kappaB pathway. Both sulindac and aspirin inhibit an enzyme that activates the NF-kappaB pathway. As an inhibitor of histone deacetylases, sulindac would be expected to activate the acetylation of NF-kappaB subunits and promote its activity in the nucleus. However, sulindac is not a pure histone deacetylase inhibitor. It is also an NSAID drug that binds directly to the IkB kinase, thereby inactivating it and preventing excessive NF-kappaB activation. As an NF-kappaB inhibitor, sulindac enhances the cancer cell killing properties of TNF, TRAIL and FAS death pathways.
Does it get much better than this???
Sulindac will absolutely be added to the cytotoxic phase of our general cancer treatment protocol. Ibuprofen will be removed.
Consider the anti-cancer properties of sulindac.
1. It is a histone deacetylase inhibitor and all this implies.
2. It is a general cox1/2 enzyme inhibitor.
3. It is a AKT enzyme inhibitor.
4. It is a direct NF-kappaB inhibitor.
NO other molecule has these properties.
How can we enhance the cancer killing properties of sulindac? Vitamin A, retinoic acid, baby!
Stay tuned...
Grouppe Kurosawa, Medicine in the Public Interest
http://www.grouppekurosawa.com
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