Anti-Cancer Peptide PNC-27 Kills Cancer Cells by Unique Interactions with Plasma Membrane-Bound hdm-2 and with Mitochondrial Membranes Causing Mitochondrial Disruption.

Objective: We have previously shown that the anti-cancer peptide PNC-27 kills cancer cells by co-localizing with membrane-expressed HDM-2, resulting in transmembrane pore formation causing extrusion of intracellular contents. We have also observed cancer cell mitochondrial disruption in PNC-27-treated cancer cells. Our objectives are to determine: 1.

Ketone Bodies Induce Unique Inhibition of Tumor Cell Proliferation and Enhance the Efficacy of Anti-Cancer Agents.

The ketone bodies, sodium and lithium salts of acetoacetate (AcAc) and sodium 3-hydroxybutyrate (3-HB; commonly called beta-hydroxybutyrate) have been found to inhibit the proliferation of cancer cells. Previous studies have suggested that lithium itself may be an inhibiting agent but may be additive or synergistic with the effect of AcAc. We previously found that sodium acetoacetate (NaAcAc) inhibits the growth of human colon cancer cell line SW480.

The biochemistry of low-carbohydrate and ketogenic diets.

Purpose Of Review: To summarize the underlying biochemical basis for low-carbohydrate and ketogenic diets (LC/KD) and provide mechanisms to account for demonstrated effectiveness.

Recent Findings: LC/KD continue to have success, to outperform other diets as well as most drugs for weight loss and diabetes treatment. In many cases, LC/KD can effect remission (absence of drugs) or reversal (only metformin or nondiabetes drugs) of type 2 diabetes and can provide a significant adjunct to pharmacology in type 1.

Insulin, carbohydrate restriction, metabolic syndrome and cancer.

We propose that dietary carbohydrate restriction, particularly ketogenic diets, may provide benefit as a therapeutic or preventive strategy in cancer, alone or as an adjunct to pharmacology. The argument derives from several points of evidence: There is a close association between cancer and both diabetes and obesity. Extensive evidence shows that low carbohydrate diets are the most effective dietary treatment of Type 2 diabetes and dietary adjunct in Type 1.

Dietary carbohydrate restriction as the first approach in diabetes management: critical review and evidence base.

The inability of current recommendations to control the epidemic of diabetes, the specific failure of the prevailing low-fat diets to improve obesity, cardiovascular risk, or general health and the persistent reports of some serious side effects of commonly prescribed diabetic medications, in combination with the continued success of low-carbohydrate diets in the treatment of diabetes and metabolic syndrome without significant side effects, point to the need for a reappraisal of dietary guidelines. The benefits of carbohydrate restriction in diabetes are immediate and well documented. Concerns about the efficacy and safety are long term and conjectural rather than data driven.

Fructose in perspective.

Whether dietary fructose (as sucrose or high fructose corn syrup) has unique effects separate from its role as carbohydrate, or, in fact, whether it can be considered inherently harmful, even a toxin, has assumed prominence in nutrition. Much of the popular and scientific media have already decided against fructose and calls for regulation and taxation come from many quarters. There are conflicting data, however.

Targeting insulin inhibition as a metabolic therapy in advanced cancer: a pilot safety and feasibility dietary trial in 10 patients.

Objective: Most aggressive cancers demonstrate a positive positron emission tomographic (PET) result using ¹⁸F-2-fluoro-2-deoxyglucose (FDG), reflecting a glycolytic phenotype. Inhibiting insulin secretion provides a method, consistent with published mechanisms, for limiting cancer growth.

Methods: Eligible patients with advanced incurable cancers had a positive PET result, an Eastern Cooperative Oncology Group performance status of 0 to 2, normal organ function without diabetes or recent weight loss, and a body mass index of at least 20 kg/m².

Response of C57Bl/6 mice to a carbohydrate-free diet.

High fat feeding in rodents generally leads to obesity and insulin resistance whereas in humans this is only seen if dietary carbohydrate is also high, the result of the anabolic effect of poor regulation of glucose and insulin. A previous study of C57Bl/6 mice (Kennedy AR, et al.: Am J Physiol Endocrinol Metab (2007) 262 E1724-1739) appeared to show the kind of beneficial effects of calorie restriction that is seen in humans but that diet was unusually low in protein (5%).

Fad diets in the treatment of diabetes.

Use of the term "fad diet" reflects the contentious nature of the debate in the treatment of diabetes and generally targets diets based on carbohydrate restriction, the major challenge to traditional dietary therapy. Although standard low-fat diets more accurately conform to the idea of a practice supported by social pressure rather than scientific data, it is suggested that we might want to give up altogether unscientific terms like "fad" and "healthy." Far from faddish, diets based on carbohydrate restriction have been the historical treatment for diabetes and are still supported by basic biochemistry, and it is argued that they should be considered the "default" diet, the one to try first, in diseases of carbohydrate intolerance or insulin resistance.

In the face of contradictory evidence: report of the Dietary Guidelines for Americans Committee.

Concerns that were raised with the first dietary recommendations 30 y ago have yet to be adequately addressed. The initial Dietary Goals for Americans (1977) proposed increases in carbohydrate intake and decreases in fat, saturated fat, cholesterol, and salt consumption that are carried further in the 2010 Dietary Guidelines Advisory Committee (DGAC) Report. Important aspects of these recommendations remain unproven, yet a dietary shift in this direction has already taken place even as overweight/obesity and diabetes have increased.

Limited effect of dietary saturated fat on plasma saturated fat in the context of a low carbohydrate diet.

We recently showed that a hypocaloric carbohydrate restricted diet (CRD) had two striking effects: (1) a reduction in plasma saturated fatty acids (SFA) despite higher intake than a low fat diet, and (2) a decrease in inflammation despite a significant increase in arachidonic acid (ARA). Here we extend these findings in 8 weight stable men who were fed two 6-week CRD (12%en carbohydrate) varying in quality of fat. One CRD emphasized SFA (CRD-SFA, 86 g/d SFA) and the other, unsaturated fat (CRD-UFA, 47 g SFA/d).

Acetoacetate reduces growth and ATP concentration in cancer cell lines which over-express uncoupling protein 2.

Background: Recent evidence suggests that several human cancers are capable of uncoupling of mitochondrial ATP generation in the presence of intact tricarboxylic acid (TCA) enzymes. The goal of the current study was to test the hypothesis that ketone bodies can inhibit cell growth in aggressive cancers and that expression of uncoupling protein 2 is a contributing factor. The proposed mechanism involves inhibition of glycolytic ATP production via a Randle-like cycle while increased uncoupling renders cancers unable to produce compensatory ATP from respiration.

Intention-to-treat. What is the question?

It has become commonplace for Randomized Controlled Trials (RCTs) to be analyzed according to Intention-to-Treat (ITT) principles in which data from all subjects are used regardless of the subjects' adherence to protocol. While ITT analyses can provide useful information in some cases, they do not answer the question that motivates many RCTs, namely, whether the treatments differ in efficacy. ITT tends to reduce information by combining two questions, whether the intervention is effective and whether, as implemented, it has good compliance.

Carbohydrate restriction has a more favorable impact on the metabolic syndrome than a low fat diet.

We recently proposed that the biological markers improved by carbohydrate restriction were precisely those that define the metabolic syndrome (MetS), and that the common thread was regulation of insulin as a control element. We specifically tested the idea with a 12-week study comparing two hypocaloric diets (approximately 1,500 kcal): a carbohydrate-restricted diet (CRD) (%carbohydrate:fat:protein = 12:59:28) and a low-fat diet (LFD) (56:24:20) in 40 subjects with atherogenic dyslipidemia. Both interventions led to improvements in several metabolic markers, but subjects following the CRD had consistently reduced glucose (-12%) and insulin (-50%) concentrations, insulin sensitivity (-55%), weight loss (-10%), decreased adiposity (-14%), and more favorable triacylglycerol (TAG) (-51%), HDL-C (13%) and total cholesterol/HDL-C ratio (-14%) responses.

Analysis of dietary interventions. A simple payoff matrix for display of comparative dietary trials.

Objective: To provide a simple method for presentation of data in comparative dietary trials.

Methods: Individual data from each diet are ranked and all possible paired comparisons are made and displayed in a pay-off matrix which can be color-coded according to the magnitude of the differences between the two diets. Probability of outcome can be calculated from the fraction of matrix elements corresponding to specified conditions.

Carbohydrate restriction as the default treatment for type 2 diabetes and metabolic syndrome.

Dietary carbohydrate restriction in the treatment of diabetes and metabolic syndrome is based on an underlying principle of control of insulin secretion and the theory that insulin resistance is a response to chronic hyperglycemia and hyperinsulinemia. As such, the theory is intuitive and has substantial experimental support. It has generally been opposed by health agencies because of concern that carbohydrate will be replaced by fat, particularly saturated fat, thereby increasing the risk of cardiovascular disease as dictated by the so-called diet-heart hypothesis.

Dietary carbohydrate restriction in type 2 diabetes mellitus and metabolic syndrome: time for a critical appraisal.

Current nutritional approaches to metabolic syndrome and type 2 diabetes generally rely on reductions in dietary fat. The success of such approaches has been limited and therapy more generally relies on pharmacology. The argument is made that a re-evaluation of the role of carbohydrate restriction, the historical and intuitive approach to the problem, may provide an alternative and possibly superior dietary strategy.

Dietary carbohydrate restriction induces a unique metabolic state positively affecting atherogenic dyslipidemia, fatty acid partitioning, and metabolic syndrome.

Abnormal fatty acid metabolism and dyslipidemia play an intimate role in the pathogenesis of metabolic syndrome and cardiovascular diseases. The availability of glucose and insulin predominate as upstream regulatory elements that operate through a collection of transcription factors to partition lipids toward anabolic pathways. The unraveling of the details of these cellular events has proceeded rapidly, but their physiologic relevance to lifestyle modification has been largely ignored.

Thermodynamics and metabolic advantage of weight loss diets.

Published reports show that low carbohydrate weight loss diets provide a metabolic advantage, a greater weight loss per calorie consumed compared to isocaloric high carbohydrate diets. These reports have not been refuted but rather largely ignored, presumably because of the apparent violation of the laws of thermodynamics ("a calorie is a calorie"). In this review, we show that there is no such violation of thermodynamic laws.