Introduction: The essential vitamin folate is an important component of cellular proliferation through its contribution to nucleotide synthesis and methylation reactions. To combat neural tube defects that were a result of folate deficiency, the FDA approved folic acid fortification in select processed foods which yielded a dramatic reduction in these conditions. This non-targeted fortification, however, also resulted in an increase of folate uptake in groups that were not at risk of folate deficiency with potential unintended consequences. It has been shown that increased folic acid supplementation and high serum folate levels can contribute to more aggressive prostate cancer, but its role in other cancers is less well established. For instance, the role of folic acid supplementation on renal cancer risk have been inconclusive with only very small correlations. Using an in vivo mouse model, we sought to determine whether dietary folate intake intervention could decrease renal tumor growth as well as increase the sensitivity to treatment .
Methods: To test this, SN12c renal cancer cells were injected subcutaneously in the flanks of nude mice. These mice were then place on folate-defined diets consisting of 0mg/kg folate, 2mg/kg folate, 5mg/kg folate, and 10mg/kg folate. Additionally, a subset of the 2mg/kg and 10mg/kg diet mice were treated by daily gavage with either vehicle or 20mg/kg of the chemotherapeutic agent Sorafenib. Tumors were measured and immunohistochemical analysis was performed on sections of tumor.
Results: At the end of the experiment, we found that the red blood cells folate levels were significantly different between the diets. This change in dietary folate intake had no impact on growth or size of renal tumors. The 10mg/kg diet, however, sensitized tumors to sorafenib treatment, resulting in slower growth and smaller tumors. This was in contrast to the 2mg/kg diet that showed no significant reduction in tumor size with sorafenib treatment. CD34 staining revealed that high folic acid in conjunction with sorafenib decreased the microvessel density indicating disruption of angiogenesis as a potential mechanism for this reduction in tumor growth.
Conclusions: Sorafenib is a tyrosine kinase inhibitor that is known to target the VEGF pathway. Sorafenib is no longer used often in clinical use due to its high toxicity in patients. This study highlights a potential role and mechanism of folic acid in increasing the effectiveness of sorafenib in renal cell carcinoma patients through dietary intervention. Source of
Funding: This work was funded by the Morrison Trust Foundation
Keith Ashcraft is a SABER-IRACDA K12 Scholar supported by K12GM111726
