Ketogenic Diet for Cancer: Critical Assessment and Research Recommendations

Abstract

Despite remarkable improvements in screening, diagnosis, and targeted therapies, cancer remains the second leading cause of death in the United States. It is increasingly clear that diet and lifestyle practices play a substantial role in cancer development and progression. As such, various dietary compositions have been proposed for reducing cancer risk and as potential adjuvant therapies. In this article, we critically assess the preclinical and human trials on the effects of the ketogenic diet (KD, i.e., high-fat, moderate-to-low protein, and very-low carbohydrate content) for cancer-related outcomes. The mechanisms underlying the hypothesized effects of KD, most notably the Warburg Effect, suggest that restricting carbohydrate content may impede cancer development and progression via several pathways (e.g., tumor metabolism, gene expression). Overall, although preclinical studies suggest that KD has antitumor effects, prolongs survival, and prevents cancer development, human clinical trials are equivocal. Because of the lack of high-quality clinical trials, the effects of KD on cancer and as an adjunctive therapy are essentially unknown. We propose a set of research recommendations for clinical studies examining the effects of KD on cancer development and progression.

The Ketogenic Diet Improves Gut–Brain Axis in a Rat Model of Irritable Bowel Syndrome: Impact on 5-HT and BDNF Systems

“…The KD-associated reduction in carbohydrates forces the body to primarily use fat as fuel by miming the fasting state. It is used as a dietary intervention to treat several neurological and psychiatric disorders [30], although its role in treating other diseases such as nonalcoholic fatty liver disease [43], or even as an adjuvant treatment for cancer, is now emerging [44]. The beneficial effects of the intervention appear to rely on, among the other proposed mechanisms [31,32], the ability of KD to decrease biogenic amines such as 5-HT [45].…”

The Influence of the Ketogenic Diet on the Immune Tolerant Microenvironment in Glioblastoma

“…Relative to this long history, the majority of work evaluating the application of the KD as a form of cancer therapy only spans a decade. The initial rationale for extending this diet to treat cancer is its potential to target the glycolytic phenotype of cancer [ 7 , 8 ]. Accordingly, the primary focus of these studies involved how this diet could directly influence cancer cell growth.…”

“…A commonly ascribed mechanism underlying the anti-tumor activity of a KD relates to its ability to target the Warburg effect, which is characterized by a bioenergetic shift observed in cancer cells from oxidative phosphorylation and reliance upon glycolysis to fuel the energetic needs of these cells [ 7 , 8 ]. Therefore, it has been postulated that, based on the very low levels of carbohydrates present in this diet, the KD has the capacity to “starve” cancer cells of their requisite glucose [ 7 , 9 ]. Although a seemingly logical approach, recent investigations suggest additional layers of complexity and regulation between the KD and general glucose metabolism.…”

Ketone Bodies and SIRT1, Synergic Epigenetic Regulators for Metabolic Health: A Narrative Review

“…In humans, the KD was initially used as a therapeutic option for its anticonvulsant effects in children with refractory epilepsy [ 32 ]; then, a very low carbohydrate ketogenic diet (VLCKD) was introduced for the treatment of obesity and its complications, such as insulin-resistance, type 2 diabetes [ 33 ], nonalcoholic fatty liver diseases (NAFLD) [ 34 ], and obstructive sleep apnea syndrome [ 35 ]. Moreover, apart from weight loss, the KD is widely used for the improvement of cardiovascular [ 28 ], rheumatological [ 36 ], neuronal [ 37 ], and, currently, cancer diseases [ 38 , 39 ].…”