Limits...
The Ketogenic Diet Does Not Affect Growth of Hedgehog Pathway Medulloblastoma in Mice.

Dang MT, Wehrli S, Dang CV, Curran T - PLoS ONE (2015)

Bottom Line: The altered metabolism of cancer cells has long been viewed as a potential target for therapeutic intervention.Serum insulin was significantly reduced in mice fed the ketogenic diet, but no alteration in PI3 kinase activity was observed.These findings indicate that while the ketogenic diet may be effective in inhibiting growth of other tumor types, it does not slow the growth of HH-medulloblastoma in mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.

ABSTRACT
The altered metabolism of cancer cells has long been viewed as a potential target for therapeutic intervention. In particular, brain tumors often display heightened glycolysis, even in the presence of oxygen. A subset of medulloblastoma, the most prevalent malignant brain tumor in children, arises as a consequence of activating mutations in the Hedgehog (HH) pathway, which has been shown to promote aerobic glycolysis. Therefore, we hypothesized that a low carbohydrate, high fat ketogenic diet would suppress tumor growth in a genetically engineered mouse model of medulloblastoma. However, we found that the ketogenic diet did not slow the growth of spontaneous tumors or allograft flank tumors, and it did not exhibit synergy with a small molecule inhibitor of Smoothened. Serum insulin was significantly reduced in mice fed the ketogenic diet, but no alteration in PI3 kinase activity was observed. These findings indicate that while the ketogenic diet may be effective in inhibiting growth of other tumor types, it does not slow the growth of HH-medulloblastoma in mice.

No MeSH data available.


Related in: MedlinePlus

The ketogenic diet does not slow growth of flank allograft tumors, and it does not affect tumor regression induced by GDC-0449.(A-C) Three distinct spontaneous medulloblastoma from Ptch1+/-Trp53-/- mice were used for these studies. Tumor volume differences were not statistically significant in two of the three trials. In the first trial, tumor volume was significantly lower at several time points (p = 0.001 to 0.048 on days 5 to 8; Student t-test). However, the difference was not evident when tumor volume was calculated as a percentage of total animal weight. Mice in all three trials lost approximately 9 to 13% of their body weight on the ketogenic diet whereas those on the standard diet maintained or marginally gained weight. (D) Glucose levels were significantly lower by day 7 (p = 0.027). (E) Ketone levels were significantly different between the standard and ketogenic diet groups (p = 0.0003 at 2 days; p = 0.013 at 7 days). (F) The ketogenic diet did not affect tumor regression induced by the SMO inhibitor GDC-0449. Tumor volumes regressed similarly on inhibitor treatment and had similar regrowth when removed from treatment.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4507880&req=5

pone.0133633.g002: The ketogenic diet does not slow growth of flank allograft tumors, and it does not affect tumor regression induced by GDC-0449.(A-C) Three distinct spontaneous medulloblastoma from Ptch1+/-Trp53-/- mice were used for these studies. Tumor volume differences were not statistically significant in two of the three trials. In the first trial, tumor volume was significantly lower at several time points (p = 0.001 to 0.048 on days 5 to 8; Student t-test). However, the difference was not evident when tumor volume was calculated as a percentage of total animal weight. Mice in all three trials lost approximately 9 to 13% of their body weight on the ketogenic diet whereas those on the standard diet maintained or marginally gained weight. (D) Glucose levels were significantly lower by day 7 (p = 0.027). (E) Ketone levels were significantly different between the standard and ketogenic diet groups (p = 0.0003 at 2 days; p = 0.013 at 7 days). (F) The ketogenic diet did not affect tumor regression induced by the SMO inhibitor GDC-0449. Tumor volumes regressed similarly on inhibitor treatment and had similar regrowth when removed from treatment.

Mentions: Next, we confirmed the results in an allograft model that allowed daily tumor volume measurements. For this study, we used a higher ratio ketogenic paste diet of 6:1. Three separate spontaneous MB from Ptch1+/-Trp53-/- mice were subcutaneously injected into the flanks of three groups of NOD SCID mice. Tumors were measurable between 3 to 5 days post-injection. Mice with tumors between 75mm3 to 100mm3 were paired; one was assigned to continue receiving the standard rodent pellet chow and the other to the 6:1 ketogenic paste. Each pair was euthanized when either mouse had a tumor >1000mm3. All mice appeared to have normal activity levels by observation and did not demonstrate signs of distress from tumor burden throughout the experiment. The ketogenic diet did not inhibit allograft tumor growth. In the first trial, the volume was significantly different at several time points (n = 5,5; p = 0.001 to 0.048 on days 5 to 8; Student t-test, Fig 2A–2C) but the difference was eliminated when tumor volume per mouse weight was analyzed. Mice in all three trials lost approximately 9 to 13% of their body weight on the ketogenic diet and those on the standard diet maintained or marginally gained weight.


The Ketogenic Diet Does Not Affect Growth of Hedgehog Pathway Medulloblastoma in Mice.

Dang MT, Wehrli S, Dang CV, Curran T - PLoS ONE (2015)

The ketogenic diet does not slow growth of flank allograft tumors, and it does not affect tumor regression induced by GDC-0449.(A-C) Three distinct spontaneous medulloblastoma from Ptch1+/-Trp53-/- mice were used for these studies. Tumor volume differences were not statistically significant in two of the three trials. In the first trial, tumor volume was significantly lower at several time points (p = 0.001 to 0.048 on days 5 to 8; Student t-test). However, the difference was not evident when tumor volume was calculated as a percentage of total animal weight. Mice in all three trials lost approximately 9 to 13% of their body weight on the ketogenic diet whereas those on the standard diet maintained or marginally gained weight. (D) Glucose levels were significantly lower by day 7 (p = 0.027). (E) Ketone levels were significantly different between the standard and ketogenic diet groups (p = 0.0003 at 2 days; p = 0.013 at 7 days). (F) The ketogenic diet did not affect tumor regression induced by the SMO inhibitor GDC-0449. Tumor volumes regressed similarly on inhibitor treatment and had similar regrowth when removed from treatment.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4507880&req=5

pone.0133633.g002: The ketogenic diet does not slow growth of flank allograft tumors, and it does not affect tumor regression induced by GDC-0449.(A-C) Three distinct spontaneous medulloblastoma from Ptch1+/-Trp53-/- mice were used for these studies. Tumor volume differences were not statistically significant in two of the three trials. In the first trial, tumor volume was significantly lower at several time points (p = 0.001 to 0.048 on days 5 to 8; Student t-test). However, the difference was not evident when tumor volume was calculated as a percentage of total animal weight. Mice in all three trials lost approximately 9 to 13% of their body weight on the ketogenic diet whereas those on the standard diet maintained or marginally gained weight. (D) Glucose levels were significantly lower by day 7 (p = 0.027). (E) Ketone levels were significantly different between the standard and ketogenic diet groups (p = 0.0003 at 2 days; p = 0.013 at 7 days). (F) The ketogenic diet did not affect tumor regression induced by the SMO inhibitor GDC-0449. Tumor volumes regressed similarly on inhibitor treatment and had similar regrowth when removed from treatment.
Mentions: Next, we confirmed the results in an allograft model that allowed daily tumor volume measurements. For this study, we used a higher ratio ketogenic paste diet of 6:1. Three separate spontaneous MB from Ptch1+/-Trp53-/- mice were subcutaneously injected into the flanks of three groups of NOD SCID mice. Tumors were measurable between 3 to 5 days post-injection. Mice with tumors between 75mm3 to 100mm3 were paired; one was assigned to continue receiving the standard rodent pellet chow and the other to the 6:1 ketogenic paste. Each pair was euthanized when either mouse had a tumor >1000mm3. All mice appeared to have normal activity levels by observation and did not demonstrate signs of distress from tumor burden throughout the experiment. The ketogenic diet did not inhibit allograft tumor growth. In the first trial, the volume was significantly different at several time points (n = 5,5; p = 0.001 to 0.048 on days 5 to 8; Student t-test, Fig 2A–2C) but the difference was eliminated when tumor volume per mouse weight was analyzed. Mice in all three trials lost approximately 9 to 13% of their body weight on the ketogenic diet and those on the standard diet maintained or marginally gained weight.

Bottom Line: The altered metabolism of cancer cells has long been viewed as a potential target for therapeutic intervention.Serum insulin was significantly reduced in mice fed the ketogenic diet, but no alteration in PI3 kinase activity was observed.These findings indicate that while the ketogenic diet may be effective in inhibiting growth of other tumor types, it does not slow the growth of HH-medulloblastoma in mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.

ABSTRACT
The altered metabolism of cancer cells has long been viewed as a potential target for therapeutic intervention. In particular, brain tumors often display heightened glycolysis, even in the presence of oxygen. A subset of medulloblastoma, the most prevalent malignant brain tumor in children, arises as a consequence of activating mutations in the Hedgehog (HH) pathway, which has been shown to promote aerobic glycolysis. Therefore, we hypothesized that a low carbohydrate, high fat ketogenic diet would suppress tumor growth in a genetically engineered mouse model of medulloblastoma. However, we found that the ketogenic diet did not slow the growth of spontaneous tumors or allograft flank tumors, and it did not exhibit synergy with a small molecule inhibitor of Smoothened. Serum insulin was significantly reduced in mice fed the ketogenic diet, but no alteration in PI3 kinase activity was observed. These findings indicate that while the ketogenic diet may be effective in inhibiting growth of other tumor types, it does not slow the growth of HH-medulloblastoma in mice.

No MeSH data available.


Related in: MedlinePlus