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

Abstract

The Warburg effect and tumor hypoxia underlie a unique cancer metabolic phenotype characterized by glucose dependency and aerobic fermentation. We previously showed that two non-toxic metabolic therapies – the ketogenic diet with concurrent hyperbaric oxygen (KD+HBOT) and dietary ketone supplementation – could increase survival time in the VM-M3 mouse model of metastatic cancer. We hypothesized that combining these therapies could provide an even greater therapeutic benefit in this model. Mice receiving the combination therapy demonstrated a marked reduction in tumor growth rate and metastatic spread, and lived twice as long as control animals. To further understand the effects of these metabolic therapies, we characterized the effects of high glucose (control), low glucose (LG), ketone supplementation (βHB), hyperbaric oxygen (HBOT), or combination therapy (LG+βHB+HBOT) on VM-M3 cells. Individually and combined, these metabolic therapies significantly decreased VM-M3 cell proliferation and viability. HBOT, alone or in combination with LG and βHB, increased ROS production in VM-M3 cells. This study strongly supports further investigation into this metabolic therapy as a potential non-toxic treatment for late-stage metastatic cancers.

Tumor Metabolism, the Ketogenic Diet and β-Hydroxybutyrate: Novel Approaches to Adjuvant Brain Tumor Therapy

“…They used the VM (Shelton et al, 2010) and CT-2A (Marsh et al, 2008) mouse tumor models to show that a KD, especially when given in restricted amounts, extends survival. D’Agostino and co-workers have added hyperbaric oxygen and ketone supplementation to demonstrate reduced tumor cell growth and metastatic spread in the VM metastatic tumor model (Poff et al, 2014, 2015). We used the syngeneic intracranial GL261-luc/albino C57/Bl6 model to demonstrate that CR was not necessary for the anti-tumor effects of the KD (Stafford et al, 2010), particularly when a 4:1 fat:carbohydrate plus protein formulation is used (Scheck et al, 2012; Woolf et al, 2015; Lussier et al, 2016).…”

“…The KD and similar diets used as a monotherapy have a pluripotent effect on the growth on tumors both in vitro and in vivo which may depend, at least in part, on the model system, the specific metabolic intervention and the molecular underpinnings of the tumor itself (Freedland et al, 2008; Otto et al, 2008; Mavropoulos et al, 2009; Stafford et al, 2010; Kim H. S. et al, 2012; Caso et al, 2013; Poff et al, 2013, 2015; Simone et al, 2013; Lv et al, 2014; Shukla et al, 2014; Hao et al, 2015; Woolf et al, 2015). In addition, the exact composition of the diet may also alter its effects, and there are studies in some cancers looking specifically at polyunsaturated fatty acids (PUFAs), particularly the omega-3 class, for their anti-cancer properties (Sauer et al, 2007; Pifferi et al, 2008; Wang et al, 2012, 2016; Hofmanova et al, 2013; Abel et al, 2014).…”

Fasting, Fats, and Physics: Combining Ketogenic and Radiation Therapy against Cancer

“…While HBO alone is of limited clinical efficacy, the D'Agostino lab has shown that HBO therapy increased ROS production and inhibited the growth of highly aggressive VM-M3 mouse tumor cells. Feeding mice a KD and/or exogenous ketones thereby enhanced its efficacy in vivo [41,110]. This would support the use of both ketogenic therapy and HBO prior to an RT session as a complementary treatment approach.…”

Ketosis as a treatment for multiple metabolic and neurodegenerative pathologies

“…To date, it has been broadly demonstrated how the metabolic state of mild ketosis, which can be induced through KD administration, calorie restriction or fasting, represents an emerging tool for the metabolic management of epilepsy and a number neurodegenerative disease [25], amyotrophic lateral sclerosis [26], and some types of cancer [27,28]. In addition, nutritional treatments represent a valid alternative whereas pharmaceutical approaches have shown a number of failures and ineffectiveness, not to mention the elevated number of side effects and costs for public health to be faced every year worldwide.…”

“…The KD induces a consistent increase in blood ketone concentration, notably AcAc and acetone [13,16] and its full success has been shown in about 50% of epileptic cases (complete seizure elimination), whereas it still significantly improves the quality of life for the remaining 50% of patients [16]. Furthermore, it has been reported that ketosis may be beneficial against cancer by decreasing blood glucose levels, the primary metabolic fuel for cancer cells [27,[47][48][49]. In fact, previous work highlighted that blood ketone concentration was negatively correlated with tumor growth.…”