New study below .
Anyone here suffer from angina? Ranolazine might really improve PCa therapy.
I have mentioned a few times that PCa cells do not switch to glucose for energy, but continue to favor fatty acids, particularly palmitic acid.
"We have found that deficient lipid oxidation via carnitine palmitoyltransferase (CPT1) results in decreased growth and invasion, underscoring the role of lipid oxidation to fuel PCa growth. ... we have found that ... CPT1A ... is abundant in PCa compared to benign tissue ... especially in those with high-grade tumors."
"... we have evaluated the synergistic effects of combining CPT1A inhibition and anti-androgen therapy."
"This results in increased androgen receptor (AR) action and increased sensitivity to the anti-androgen enzalutamide."
I suppose that means synergy?
Would be good with Casodex too?
See the ScienceDaily story .
Oncotarget. 2017 Apr 21. doi: 10.18632/oncotarget.17359. [Epub ahead of print]
Lipid catabolism inhibition sensitizes prostate cancer cells to antiandrogen blockade.
Flaig TW1, Salzmann-Sullivan M1, Su LJ1, Zhang Z, Joshi M2, Gijón MA2, Kim J1, Arcaroli JJ1, Van Bokhoven A3, Lucia MS3, La Rosa FG3, Schlaepfer IR1.
Prostate cancer (PCa) is the most common malignancy among Western men and the second leading-cause of cancer related deaths. For men who develop metastatic castration resistant PCa (mCRPC), survival is limited, making the identification of novel therapies for mCRPC critical. We have found that deficient lipid oxidation via carnitine palmitoyltransferase (CPT1) results in decreased growth and invasion, underscoring the role of lipid oxidation to fuel PCa growth. Using immunohistochemistry we have found that the CPT1A isoform is abundant in PCa compared to benign tissue (n=39, p<0.001) especially in those with high-grade tumors. Since lipid oxidation is stimulated by androgens, we have evaluated the synergistic effects of combining CPT1A inhibition and anti-androgen therapy. Mechanistically, we have found that decreased CPT1A expression is associated with decreased AKT content and activation, likely driven by a breakdown of membrane phospholipids and activation of the INPP5K phosphatase. This results in increased androgen receptor (AR) action and increased sensitivity to the anti-androgen enzalutamide. To better understand the clinical implications of these findings, we have evaluated fat oxidation inhibitors (etomoxir, ranolazine and perhexiline) in combination with enzalutamide in PCa cell models. We have observed a robust growth inhibitory effect of the combinations, including in enzalutamide-resistant cells and mouse TRAMPC1 cells, a more neuroendocrine PCa model. Lastly, using a xenograft mouse model, we have observed decreased tumor growth with a systemic combination treatment of enzalutamide and ranolazine. In conclusion, our results show that improved anti-cancer efficacy can be achieved by co-targeting the AR axis and fat oxidation via CPT1A, which may have clinical implications, especially in the mCRPC setting.
CPT1A; INPP5K; enzalutamide; prostate cancer; ranolazine
PMID: 28473655 DOI: 10.18632/oncotarget.17359