Ketone supplementation decreases tumor cell viability and prolongs survival of mice with metastatic cancer

Abstract

Cancer cells express an abnormal metabolism characterized by increased glucose consumption owing to genetic mutations and mitochondrial dysfunction. Previous studies indicate that unlike healthy tissues, cancer cells are unable to effectively use ketone bodies for energy. Furthermore, ketones inhibit the proliferation and viability of cultured tumor cells. As the Warburg effect is especially prominent in metastatic cells, we hypothesized that dietary ketone supplementation would inhibit metastatic cancer progression in vivo. Proliferation and viability were measured in the highly metastatic VM-M3 cells cultured in the presence and absence of β-hydroxybutyrate (βHB). Adult male inbred VM mice were implanted subcutaneously with firefly luciferase-tagged syngeneic VM-M3 cells. Mice were fed a standard diet supplemented with either 1,3-butanediol (BD) or a ketone ester (KE), which are metabolized to the ketone bodies βHB and acetoacetate. Tumor growth was monitored by in vivo bioluminescent imaging. Survival time, tumor growth rate, blood glucose, blood βHB and body weight were measured throughout the survival study. Ketone supplementation decreased proliferation and viability of the VM-M3 cells grown in vitro, even in the presence of high glucose. Dietary ketone supplementation with BD and KE prolonged survival in VM-M3 mice with systemic metastatic cancer by 51 and 69%, respectively (p < 0.05). Ketone administration elicited anticancer effects in vitro and in vivo independent of glucose levels or calorie restriction. The use of supplemental ketone precursors as a cancer treatment should be further investigated in animal models to determine potential for future clinical use.

Non-Toxic Metabolic Management of Metastatic Cancer in VM Mice: Novel Combination of Ketogenic Diet, Ketone Supplementation, and Hyperbaric Oxygen Therapy

“…We previously reported a similar response in VM-M3 cells with βHB supplementation to varied glucose concentration [22]. Combining LG, βHB, and HBOT elicited potent anti-proliferative effects in vitro (Fig 6B).…”

“…Viability was 19% less in the LG group than in the control group at 24 hour treatment (*p<0.05, one-way ANOVA; Fig 7). We previously reported a similar effect in VM-M3 cells treated with βHB supplementation [22]. Although HBOT did not decrease viability on its own, when administered with LG and βHB, this combination therapy significantly decreased viability by approximately 38%.…”

A Supplemented High-Fat Low-Carbohydrate Diet for the Treatment of Glioblastoma

“…Neuroblastoma has also shown decreased expression of succinyl-coenzyme A:3-oxoacid coenzyme A transferase (SCOT), a key enzyme in ketone body metabolism (46). In vitro treatment of glioma cells with acetoacetate or BHB is able to delay both cell growth and metabolic enzyme activity (8), and reduces proliferation and cell viability of VM-M3 cells (9). Other reports indicate BHB acts as an endogenous and specific inhibitor of class I histone deacetylases (HDAC; ref.…”

“…6). Ketone bodies are suitable energy replacements for normal cells with functional mitochondria (7), but have been shown to be unsuitable for tumor cells (8,9), as tumor cell mitochondrial functions are dysregulated (10). Existing preclinical data support the KD (11-13) and a calorie-restricted KD (RKD; refs.…”

Keton cisimlerinin insan meme kanseri hücrelerinde (MCF-7) canlılık üzerine etkileri

“…They also reported lower expression of the above mentioned enzyme in SK-N-AS cells compared to HFF cells. Poff and colleagues observed inhibition of ATP production by AA and proliferation in seven aggressive human colon and breast cancer cell lines, but did no effect on proliferation in healthy primary fibroblasts [7]. Similarly, BHB inhibited the proliferation of transformed lymphoblast, HeLa cells and melanoma cells in a dose-dependent manner up to 20 mM.…”