Abstract
Since cancer cells depend on glucose more than normal cells, we compared the effects of low carbohydrate (CHO) diets to a Western diet on the growth rate of tumors in mice. To avoid caloric restriction-induced effects, we designed the low CHO diets isocaloric with the Western diet by increasing protein rather than fat levels because of the reported tumor-promoting effects of high fat and the immune-stimulating effects of high protein. We found that both murine and human carcinomas grew slower in mice on diets containing low amylose CHO and high protein compared with a Western diet characterized by relatively high CHO and low protein. There was no weight difference between the tumor-bearing mice on the low CHO or Western diets. Additionally, the low CHO-fed mice exhibited lower blood glucose, insulin, and lactate levels. Additive antitumor effects with the low CHO diets were observed with the mTOR inhibitor CCI-779 and especially with the COX-2 inhibitor Celebrex, a potent anti-inflammatory drug. Strikingly, in a genetically engineered mouse model of HER-2/neu-induced mammary cancer, tumor penetrance in mice on a Western diet was nearly 50% by the age of 1 year whereas no tumors were detected in mice on the low CHO diet. This difference was associated with weight gains in mice on the Western diet not observed in mice on the low CHO diet. Moreover, whereas only 1 mouse on the Western diet achieved a normal life span, due to cancer-associated deaths, more than 50% of the mice on the low CHO diet reached or exceeded the normal life span. Taken together, our findings offer a compelling preclinical illustration of the ability of a low CHO diet in not only restricting weight gain but also cancer development and progression.
Highlights
More than 80 years ago, Otto Warburg found that most cancer cells, unlike normal cells, rely more on glycolysis than oxidative phosphorylation (OXPHOS) to meet their energy needs, even under normoxic conditions [1]
As it is well established that most human and murine tumors take up more glucose than normal tissues [6], we asked if we could decrease blood glucose (BG) levels sufficiently, by decreasing dietary CHO, to significantly reduce tumor growth rates
Comparing the effect of this diet, given ad libitum, with an isocaloric Western diet (TestDiet 5058; Table 1) on BG levels in nontumor bearing Rag2M mice revealed that BG, dropped significantly after 4 to 7 days on the 8% CHO diet to a new, stable plateau (Fig. 1A), in keeping with previous reports showing that BG drops within 7 days on a ketogenic diet [20]
Summary
More than 80 years ago, Otto Warburg found that most cancer cells, unlike normal cells, rely more on glycolysis than oxidative phosphorylation (OXPHOS) to meet their energy needs, even under normoxic conditions [1]. He postulated that this "aerobic glycolysis" was due to irreversible defects in mitochondrial respiration [2]. Whereas some studies have linked mitochondrial mutations to cancer [3], a causal. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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