We recently showed that a low carbohydrate (CHO) diet containing soy protein and fish oil dramatically reduces lung nodules in a mouse model of lung cancer when compared to a Western diet. To explore the universality of this finding, we herein compared this low CHO diet to a Western diet on in preventing breast and prostate cancer using a mouse model that expresses the SV40 large T antigen specifically in breast epithelia in females and prostate epithelia in males. We found that breast cancer was significantly reduced with this low CHO diet and this correlated with a reduction in plasma levels of glucose, insulin, IL-6, TNFα and PGE2. This also corresponded with a reduction in the Ki67 proliferation index within breast tumors. On the other hand, this low CHO diet did not reduce the incidence of prostate cancer in the male mice. Although it reduced both blood glucose and insulin to the same extent as in the female mice, there was no reduction in plasma IL-6, TNFα or PGE2 levels, nor in the Ki67 proliferation index in prostate lesions. Based on immunohistochemistry studies with antibodies to PFKFB3, CPT1a and FAS, it is likely that this difference in response of the two cancer types to this low CHO diet reflects differences in the glucose dependence of breast and prostate cancer, with the former being highly dependent on glucose for energy and the latter being more dependent on fatty acids.

We recently found that a diet composed of 15% of total calories as carbohydrate (CHO), primarily as amylose, 35% soy protein and 50% fat, primarily as fish oil (FO) (15%Amylose/Soy/FO) was highly effective at preventing lung nodule formation in a nicotine-derived nitrosamine ketone (NNK)-induced lung cancer model. We asked herein whether adopting such a diet once cancers are established might also be beneficial. To test this, NNK-induced lung nodules were established in mice on a Western diet and the mice were then either kept on a Western diet or switched to various low CHO diets. Since we previously found that sedentary mice develop more lung nodules than active mice, we also compared the effect of exercise in this cancer progression model. We found that switching to a 15%Amylose/Soy/FO diet reduced lung nodules and slowed tumor growth with both ‘active’ and ‘sedentary’ mice. Ki67, cleaved caspase 3 and Terminal Deoxynucleotidyl Transferase-Mediated dUTP Nick End Labeling assays suggested that the efficacy of the 15%Amylose/Soy/FO in lowering tumor nodule count and size was not due to a reduction in tumor cell proliferation, but to an increase in apoptosis. The 15%Amylose/Soy/FO diet also significantly lowered liver fatty acid synthase and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 expression, pointing to a global metabolic switch from glycolysis to fatty acid oxidation. Mice fed the 15%Amylose/Soy/FO diet also had significantly reduced plasma levels of interleukin (IL)-1β, IL-6 and tumor necrosis factor α. These results suggest that the 15%Amylose/Soy/FO diet may slow tumor growth by suppressing proinflammatory cytokines, inducing a metabolic switch away from glycolysis and inducing apoptosis in tumors.

ObjectivesGiven the current controversy concerning the efficacy of omega 3 supplements at reducing inflammation, we evaluated the safety and efficacy of omega 3 on reducing inflammation in people with a 6-year lung cancer risk >1.5% and a C reactive protein (CRP) level >2 mg/L in a phase IIa cross-over study.Materials and methodsForty-nine healthy participants ages 55 to 80, who were still smoking or had smoked in the past with ≥30 pack-years smoking history, living in British Columbia, Canada, were randomized in an open-label trial to receive 2.4 g eicosapentaenoic acid (EPA) + 1.2 g docosahexaenoic acid (DHA)/day for 6 months followed by observation for 6 months or observation for 6 months first and then active treatment for the next 6 months. Blood samples were collected over 1 year for measurement of plasma CRP, plasma and red blood cell (RBC) membrane levels of EPA, DHA and other fatty acids, Prostaglandin E2 (PGE2), Leukotriene B4 (LTB4) and an inflammatory marker panel.ResultsTwenty one participants who began the trial within the active arm completed the trial while 20 participants who started in the control arm completed the study. Taking omega 3 resulted in a significant decrease in plasma CRP and PGE2 but not LTB4 levels. Importantly, the effect size for the primary outcome, CRP values, at the end of the intervention relative to baseline was medium (Cohen's d = 0.56). DHA, but not EPA levels in RBC membranes inversely correlated with PGE2 levels. Omega 3 also led to a significant reduction in granulocytes and an increase in lymphocytes. These high-dose omega 3 supplements were well tolerated, with only minor gastrointestinal symptoms in a subset of participants.ConclusionOmega 3 fatty acids taken at 3.6 g/day significantly reduce systemic inflammation with negligible adverse health effects in people who smoke or have smoked and are at high risk of lung cancer.ClinicalTrials.gov, NCT number: NCT03936621.

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Since our previous studies found a low carbohydrate (CHO) diet containing soy protein and fish oil (15%Amylose/Soy/FO) significantly reduced lung and breast cancer in mice we asked herein if this low CHO diet could also delay the onset of myeloid malignancies. To test this we employed a miR-146a knock-out (KO) mouse model and found the 15%Amylose/Soy/FO diet increased their median lifespan by 8.5 month, compared to these mice on a Western diet. This was associated with increased lymphocytes and reduced monocytes, granulocytes, blood glucose and insulin levels. Inflammatory cytokine/chemokine studies carried out with 6-month-old mice, before any signs of illness, revealed the 15%Amylose/Soy/FO diet significantly reduced pro-inflammatory cytokines. This low CHO diet also led to an increase in plasma β-hydroxybutyrate and in liver fatty acid synthase levels. This, together with higher liver carnitine palmitoyltransferase I levels suggested that the 15%Amylose/Soy/FO diet was causing a systemic metabolic shift from glucose to fatty acids as an energy source. Lastly, we found the 15%Amylose/Soy/FO diet resulted in significantly higher numbers of primitive hematopoietic stem cells (HSCs) in the bone marrow of 6-month-old mice than those fed a Western diet. Taken together, these results suggest a 15%Amylose/Soy/FO diet reduces chronic inflammation and increases fatty acid oxidation and that this, in turn, may prevent HSC proliferation and exhaustion, thereby delaying myeloid malignancy-induced death of miR-146a KO mice. We suggest a low CHO diet containing soy protein and fish oil could be beneficial in reducing the risk of myeloid malignancies in patients with low miR-146a levels.