The ketogenic diet is not feasible as a therapy in a CD-1 nu/nu mouse model of renal cell carcinoma with features of Stauffer's syndrome

Abstract

The ketogenic diet (KD), a high-fat low-carbohydrate diet, has shown some efficacy in the treatment of certain types of tumors such as brain tumors and neuroblastoma. These tumors are characterized by the Warburg effect. Because renal cell carcinoma (RCC) presents similar energetic features as neuroblastoma, KD might also be effective in the treatment of RCC. To test this, we established xenografts with RCC 786-O cells in CD-1 nu/nu mice and then randomized them to a control diet or to KDs with different triglyceride contents. Although the KDs tended to reduce tumor growth, mouse survival was dramatically reduced due to massive weight loss. A possible explanation comes from observations of human RCC patients, who often experience secondary non-metastatic hepatic dysfunction due to secretion of high levels of inflammatory cytokines by the RCCs. Measurement of the mRNA levels of tumor necrosis factor alpha (TNFα) and interleukin-6 revealed high expression in the RCC xenografts compared to the original 786-O cells. The expression of TNFα, interleukin-6 and C-reactive protein were all increased in the livers of tumor-bearing mice, and KD significantly boosted their expression. KDs did not cause weight loss or liver inflammation in healthy mice, suggesting that KDs are per se safe, but might be contraindicated in the treatment of RCC patients presenting with Stauffer's syndrome, because they potentially worsen the associated hepatic dysfunction.

Untargeted Metabolomics Reveals Molecular Effects of Ketogenic Diet on Healthy and Tumor Xenograft Mouse Models

“…LCT-MCT8 diet significantly increased the concentration of blood ketone bodies in the mice already after five days of treatment (for breast cancer bearing mice see Supplementary Figure S1c; for healthy mice see Supplementary Figure S1d in [42]). In contrast, average blood glucose levels did not show any diet specific change and remained mostly unchanged until termination of the experiment after 80 days (Supplementary Figure S1d).…”

A ketogenic diet supplemented with medium-chain triglycerides enhances the anti-tumor and anti-angiogenic efficacy of chemotherapy on neuroblastoma xenografts in a CD1-nu mouse model

“…In addition, Liśkiewicz et al also observed that long-term KD (79% fat content) increased renal tumor growth in a rat model of Tuberous Sclerosis [ 73 ]. Furthermore, we recently reported that KD is not feasible as a therapy in a CD-1 nu/nu mouse model of renal cell carcinoma with features of Stauffer’s syndrome [ 74 ]. Therefore, it is of utmost importance to evaluate the effect of KDs in preclinical studies on specific types of tumors and also to take into account the different genetic alterations before considering clinical studies, as differences in the response of tumor growth to dietary intervention between mice and humans cannot be excluded.…”

Ketogenic diet in cancer therapy

“…In contrast to the safe application of KDs reported in various cancer models, our research group recently reported that mice bearing renal cell carcinoma xenografts and with signs of Stauffer’s syndrome experienced dramatic weight loss and liver dysfunction when treated with a KD [ 4 ]. Another study investigating the effect of long-term KD treatment on kidney cancer described a pro-tumor effect of the KD in a rat model of tuberous sclerosis complex [ 5 ].…”