Review: Ketogenic diet in the treatment of cancer – Where do we stand? 評論:生酮飲食治療癌症-我們的立場是什麼?

中文版谷歌中文翻譯(90% 準確率) | English translation
Buy/Sell Your Domains Here。在這裡購買/出售您的域名
Contact Dr. Lu for information about cancer treatments。聯繫盧博士,獲取有關癌症治療資訊。

2. Fundamentals of the ketogenic diet

The KD is a high-fat, low-carbohydrate diet with adequate protein and calories originally developed in the 1920s as a treatment for intractable epilepsy [10]. At that time, ketone bodies were found in the blood of subjects on a starvation diet or a diet extremely low in carbohydrates [11]. Furthermore, it was proposed that the benefits of fasting could be obtained if the levels of ketone bodies could be elevated by other means [10]. Therefore, a new diet regime intended to mimic the effects of fasting was developed and termed the “ketogenic diet” [10], [12].

2.1. Types of ketogenic diets

The traditional KD is a 4:1 formulation of fat content to carbohydrate plus protein [10]. A classic 4:1 KD delivers 90% of its calories from fat, 8% from protein and only 2% from carbohydrate. KDs of the 1920s and 1930s were extremely bland and restrictive diets and, therefore, prone to noncompliance. In recent years, alternative KD protocols have emerged, making adherence to the diet much easier. Other characteristics besides macronutrient composition are increasingly recognized as important factors for long-term adherence to and efficacy of the KD [13]. These characteristics include fatty acid composition and nutrient density. Alternatives to the traditional KD are, for example, a medium-chain triglyceride (MCT)-based KD and the Atkins diet.

Compared to long-chain triglycerides, MCTs are more rapidly absorbed into the bloodstream and oxidized for energy because of their ability to passively diffuse through membranes [14]. Another characteristic of MCTs is their unique ability to promote ketone body synthesis in the liver [15]. Thus, adding MCTs to a KD would allow significantly more carbohydrate to be included [16], [17].

The Atkins diet, designed in the 1970s by Dr. Robert Atkins for weight loss, is characterized by carbohydrate restriction and its emphasis on fat. It is very similar to the classic KD but does not restrict protein or calories. The main difference between the Atkins diet and the modified Atkins diet (MAD) is that the MAD strongly encourages high-fat foods, carbohydrate intake is more restrictive and weight loss is not the primary goal [18]. In 2012, a review of the MAD for epilepsy was published, concluding that the MAD is effective for seizure control and should be the diet of first choice in that patient population [19].

As already mentioned, other characteristics besides macronutrient composition are increasingly recognized as important factors for long-term adherence to and efficacy of the KD. For far too long the sole focus of dietary advice was on macronutrient composition. The categorization of food into protein, carbohydrate, and fat is not sufficient to describe a well-formulated diet regarding its micronutrient density and hormonal or inflammatory effects on the human body. Unfortunately, in the literature, no clear definition of a KD is provided, and many studies define a KD as any diet which leads to an increase in blood ketones, for example diets in which no more than 50% of total calories are from fat [20]. In contrast, clinically used KDs mainly have a fat to carbohydrate and protein ratio of at least 2:1 to 3:1, meaning that the percentage of calories from fat is a minimum of 80%. The MAD can be considered as a mild KD. Thus, clear differentiation of low-carbohydrate diets and KDs cannot be made. In this paper, we review studies which use the terms KD and cancer. In the summary tables, we include the composition of the diets as far as provided by the studies (Table 1, Table 2).

2.2. Ketone body synthesis

Ketones are organic compounds that are mainly produced by mitochondria of hepatocytes, but also, to some extent, in the heart, gut, kidneys and brain [21], [22]. The three main ketone bodies are acetoacetate (AcAc), β-hydroxybutyrate (BHB) and acetone. As an energy substrate, only AcAc and BHB are important, of which the latter is the most abundant ketone body in the blood. Acetone is formed spontaneously and breathed off via the lungs or further metabolized to pyruvate, lactate, and acetate [23]. The predominant substrates for ketone synthesis are fatty acids, although a small proportion of ketones is synthesized from leucine and in phenylalanine-tyrosine metabolism [24]. Free fatty acids are transported from adipose tissue to the liver and undergo β-oxidation to form acetyl-CoA. Under high-glucose conditions, acetyl-CoA is further shuttled into the TCA cycle and then into the electron transport chain to release energy. Under low-glucose conditions, acetyl-CoA generated from increased β-oxidation accumulates and challenges the processing capacity of the TCA cycle. Under these circumstances, the activity of the TCA cycle is low because of the low number of intermediates. Consequently, two molecules of acetyl-CoA are used for ketone synthesis via acetoacyl-CoA and β-hydroxy-β-methylglutaryl-CoA (HMG-CoA) driven by the ketogenic enzymes thiolase and HMG-CoA synthase, respectively [22]. HMG-CoA lyase splits HMG-CoA to re-generate acetyl-CoA and form one molecule of AcAc, which is further reduced by BHB-dehydrogenase to BHB [22].

Key regulators of ketogenesis are the hormones insulin and glucagon. Insulin inhibits ketogenesis, whereas glucagon stimulates ketogenesis [22]. The regulatory metabolic pathway works via hormone-sensitive lipase and acetyl-CoA-carboxylase, as well as HMG-CoA synthase. Insulin reduces lipolysis via inhibition of hormone-sensitive lipase and lowers the amount of free fatty acids, the substrate of ketogenesis. Insulin stimulates acetyl-CoA-carboxylase which controls lipogenesis. Additionally, insulin inhibits mitochondrial HMG-CoA synthase, which is the rate-limiting step in ketogenesis [24].

2.3. Ketone body utilization

In extrahepatic tissues, ketone bodies are taken up by the monocarboxylate transporters. These are found throughout the whole body and transport not only ketones but also lactate and pyruvate across the plasma membrane [25]. Ketolysis is the process by which ketone bodies are converted back to acetyl-CoA. Acetyl-CoA is further oxidized via the TCA cycle and the electron transport chain. Ketolysis occurs in almost all extrahepatic tissues [22]. Ketolysis is facilitated by three mitochondrial enzymes, d-β-hydroxybutyrate dehydrogenase (BDH1), 3-oxoacid CoA-transferase 1 (OXCT1), and acetyl-CoA acetyltransferase (ACAT1) [26]. BDH1 catalyzes the interconversion of AcAc and BHB. OXCT1, also known as succinyl CoA: 3-oxoacid CoA transferase 1 (SCOT), catalyzes the transfer of coenzyme A from succinyl-CoA to AcAc, leading to the formation of acetoacetyl-CoA, and is the key enzyme of ketone body utilization. Acetoacetyl-CoA is further catalyzed by ACAT1 to form two molecules of acetyl-CoA, which can be shuttled into the TCA cycle and oxidized to produce ATP.
2.4. Energy production from ketones

Per each 2-carbon unit, BHB yields more energy than glucose. Ketone bodies are, therefore, considered metabolically more efficient than glucose [27]. Ketones play a vital role as energy substrates for peripheral organs and the brain, especially during times of starvation and in early childhood brain development [28], [29], [30]. After 3 days of fasting, 30–40% of total energy requirements are covered by ketones. Ketone bodies rapidly increase during the first 10 days of a fast and reach a plateau after about 30 days [31]. In particular, the heart, skeletal muscle, kidney, and brain start to use ketones early. During fasting or under a KD, when glucose levels are low, the brain receives 60–70% of its required energy from ketones. The liver lacks the rate-limiting enzyme SCOT to use ketones as energy [22]. Therefore, although the liver can produce ketones, it cannot use a significant amount of them. The shift from glucose to ketones and fatty acids as the main source of energy can take up to one week [32].

2.5. Effects of the ketogenic diet on metabolic parameters

Besides the traditional use of the KD in therapy-resistant epilepsy, patients with malfunctions in glucose metabolism such as glucose transporter 1, pyruvate carboxylase, or pyruvate dehydrogenase deficiency benefit from a KD [33], [34]. Evidence also supports the KD as a therapeutic option for obesity, type 2 diabetes, polycystic ovary syndrome, acne, neurological diseases such as Alzheimer’s disease and Parkinson’s, and cancer [33], [34]. Owing to its high fat content, there is a general concern among clinicians that a KD may cause deterioration of certain metabolic markers, especially cholesterol and triglycerides. However, studies point toward an overall improvement of body composition and blood parameters [35], [36], [37]. Biological markers associated with the metabolic syndrome such as high blood lipid and cholesterol levels, elevated blood glucose and insulin levels, and reduced insulin sensitivity have been shown to improve significantly in patients with atherogenic dyslipidemia who consumed a carbohydrate-restricted diet for 12 weeks [38]. A further study in type 2 diabetic patients who consumed a KD for 56 weeks reported a significant reduction in body weight, body mass index, total cholesterol, low density lipoprotein (LDL) cholesterol, triglycerides, and blood glucose levels, and a significant improvement of high density lipoprotein (HDL) cholesterol [39]. However, in epileptic children with refractory seizures who consumed a KD for six months, one study detected increased serum lipid and cholesterol levels [40], whereas other studies reported normal lipid profiles [41], [42], [43]. Importantly, none of the listed studies reported severe adverse effects of the KD. Based on the available evidence, there is no obvious reason why a low-carbohydrate diet or a balanced KD might be contraindicated in adults. However, especially in patients, use of the KD should be meticulously planned and monitored by physicians and qualified dieticians. Because the classic KD (ratio 4:1) and KDs based on artificial foods potentially lack vitamins and minerals such as vitamin B, vitamin D, calcium, and iron, adequate supplementation of these micronutrients is essential [44], [45].
3. Ketogenic diet in the treatment of cancer – where do we stand?

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