Consequences of Glucose Enriched Diet on Oncologic Patients

Abstract

Malignant tumors demonstrate increased rates of glucose utilization and uptake. Therefore, clinical trials are being used to evaluate a variety of inhibitors of glycolytic metabolism. Antiglycolytic drugs have been proven to promote chemotherapy and radio-induced cell death. Glucose influences the levels and activation of pro-apoptotic BH3-only proteins, such as Puma, Bad, Noxa, and Bim, and the family of anti-apoptotic proteins Bcl-2; synergistic effects are probably the result of the regulation of the apoptotic machinery. Antiglycolytic medicines and glucose deprivation induce tumor cell death by caspase-8-mediated or mitochondrial apoptosis or even necrosis. The last is known to activate the effector caspases, principally through the cleavage of the Bcl-2 family member Bid and the consequent activation of the mitochondrial pathway. Modifications to the host’s diet can modify the availability of nutrients in the tumor microenvironment, which could offer a feasible technique to restrict growth. Dietary alterations can reduce particular nutritional requirements of the tumor that target the metabolic vulnerabilities or boost the cytotoxicity of anticancer medications. According to recent studies, increasing the amount of key minerals in the diet can affect how well cancer therapies can function. The research reveals that the eating habits and nutritional state of a patient should be regarded during cancer research and therapy.

1. Introduction

Apoptosis, also known as programmed cell death, is the outcome of a series of biochemical events, including the activation of a set of cytosolic cysteine proteases known as caspases, which cause certain cell morphological changes and, finally, cell death [1,2]. Traditionally, two apoptotic processes have been described: the extrinsic system, which is dependent on cell-surface death receptors, and the intrinsic pathway, which is dependent on mitochondria [3,4,5]. Extracellular ligands activate the death receptors in the plasma membrane, starting the apoptosis via the extrinsic route. A cytosolic death domain is present in these receptors [4,6,7]. Intracellular events such as DNA damage, the absence of growth hormones, oxidative stress, and endoplasmic reticulum stress trigger the intrinsic apoptotic pathway [5]. Endoplasmic reticulum stress, which is predominantly induced by a drop in the intraluminal free calcium concentration, has also been reported to promote apoptosis [8]. Typically, human cells divide and expand in order to make new cells when the body requires them. When cells are injured or old, telomeres shorten, producing apoptosis, or programmed cell death, and new cells take their place. Thus, apoptosis is considered a sort of cell death that is controlled by genes and is important for normal growth and tissue homeostasis [9]. However, when this regulation is compromised and cells bypass the checkpoints, which are the cellular regulation points, cancer arises. This dysregulation is caused by imbalances in distinct CDK genes. These cancer cells divide constitutively and develop tumors [10,11]. In Figure 1, the phenomena that occur in the cell in each phase of the cycle are described, indicating some of the checkpoints of the cell cycle: G1 that blocks the beginning, S that reduces the replication rate, the checkpoint of the G2–M transition that arrests the cycle in this transition, and the internal mitotic control. The myriad ways that cancer cells diverge from normal cells allow them to expand and flourish unchecked. Unlike normal cells, which evolve into a range of diverse cell types with unique activities, cancer cells are less specialized [11]. When the mechanisms that govern apoptosis fail, both by excess and by default, the balance is upset and numerous diseases can emerge. Resistance to apoptosis is one of the traits that contribute to the creation of a tumor [12] and can also be the cause of various autoimmune disorders. In the opposite case, an excess of apoptosis could be related to neurodegenerative disorders [13]. Cancer is a hereditary disease that can be caused by alterations in proto-oncogenes and tumor suppressor genes, which are genes that regulate the way our cells divide, grow, and work. The genetic alterations that generate cancer can be inherited from parents. They can also develop during a person’s life due to mistakes that may happen due to DNA damage caused by environmental exposures, such as chemicals in cigarette smoke and radiation, such as ultraviolet rays from the sun, or as cells divide [11]. The genetic alterations caused by cancer involve three primary categories of genes: DNA repair genes, tumor suppressor genes, and proto-oncogenes [11]. Proto-oncogenes are involved in proper cell division and proliferation. However, when these genes are more active than normal or are modified in a certain way, they can become cancer-causing genes (or oncogenes), allowing cells to survive and thrive when they should not. Tumor suppressor genes are connected to the control of cell division and proliferation. Cells with defective tumor suppressor genes can divide abundantly. DNA repair genes are involved in the repair of damaged DNA. Mutated cells in these genes are likely to produce additional mutations in other genes. Together, these alterations can cause cells to become malignant. Cancer cells also tend to avoid the immune system. Although damaged or abnormal cells are generally cleared from the body by the immune system, certain cancer cells can remain “hidden”. Cancer cells have the ability to fool the immune system into helping them stay alive and develop [11]. The immune system consists of adaptive and innate immune components that, when triggered, eliminate cancer cells and infectious pathogens. During the antimicrobial or anticancer immune response, there are inhibitory systems that frequently sustain self-tolerance and counteract the activation process to avoid excessive injury and limit collateral tissue damage. These inhibitory pathways, which consist of ligands and receptors, are called “immune checkpoints” and cancer cells may employ them in order to elude immune destruction. These checkpoints include the revolutionary PD-1 and CTLA-4, as well as the lately identified B7-H3, CD96, TIGIT, TIM-3, and LAG-3 as well as the more recently recorded checkpoint members of the Siglecs family, CD47 and CD200 [13]. There are alterations in the tissues of the body that are not malignant. However, they can turn into cancer if they are not treated [11]. Hyperplastic cells arise first. This occurs when cells within a tissue divide faster than normal and excess cells collect. However, the cells and the way the tissue is structured look normal under the microscope as they are healthy but accumulated. Hyperplasia can be produced by various illnesses or circumstances, including prolonged inflammation [11]. After this phase, dysplastic cells develop, which accumulate. However, the cells are abnormal and they have distinct structure and properties, which leads to the organization of the tissue. Generally, the more aberrant the tissue and cells look, the more likely it is that cancer will form. Some types of dysplasia may need to be treated or monitored. Among the numerous examples of dysplasia, we may discover an aberrant mole (called a dysplastic nevus) that arises on the skin [11]. Carcinoma in situ is a condition that is substantially more dangerous. Since the abnormal cells do not spread outside of the original tissue, carcinoma in situ is not cancer despite being frequently referred to as such. In other words, unlike cancer cells, they do not infect surrounding tissue. Nonetheless, because certain carcinomas in situ can evolve into cancer, they are routinely treated [11]. Metastatic cancer arises when these malignant cells proliferate. It is cancer that has been transmitted from the place of its inception to another area in the body [11]. Tumor development takes place in different steps: (1) Hyperplasia in which aberrant cells show rapid and uncontrolled proliferation. (2) Dysplasia, wherein developing cells alter their initial shape. More immature cells are present than mature ones. (3) Cancer in situ represents a neoplastic lesion where cells do not enter the maturation process, have lost their tissue identity, and develop unregulated. (4) With a malignant tumor, the growing cells invade other locations by breaking the basement membrane. (5) Metastases take place when cancer cells reach distant parts through the blood circulation and lymphatic system [13]. There are more than 100 forms of cancer. Cancer kinds are often called based on the organs or tissues where they develop. Cancers can also be characterized by the type of cell that developed them, such as an epithelial cell or a squamous cell [11].

1.1. Glucose and Its Influence on Cancer

Glucose is the principal source of metabolic energy in most organisms. Its transport through cellular membranes, which are impermeable to polar molecules, is done through glucose transporters, which mediate glucose transport by assisted diffusion or by secondary active transport.

Aerobic glycolysis is a crucial mechanism in cancer cells’ glucose metabolism, in which glucose is first supplied into the cells by glucose transporters and subsequently transformed to pyruvate by multiple enzymes. The implication of enzymes in this pathway is highly important, with phosphofructokinase (PFK), pyruvate kinase (PK), and hexokinase II (HKII) being the most important [14].

Facilitative sugar transporter (GLUT) and Na+/glucose co-transporter (SGLT) families are the principal glucose transporters in mammalian cells [15,16]. The plasma membrane’s existing gradients in sugar concentration between the inner and outer sides are utilized by GLUT transporters to aid in their translocation. On the contrary, SGLT proteins transfer sugars within cells against the concentration gradient with the consequent energy expenditure [17,18].

Glucose absorption is the step that controls the pace of its usage, underlining the relevance of the GLUT transporters in metabolism [6]. The cell has to acquire glucose in order to commence glycolysis, which is the first conversion to obtain energy. In healthy cells, glucose is fully oxidized to ATP [13,17]. This is why glucose absorption and metabolism are so critical for cell development and division [13,17]. For this reason, sugar consumption is associated to cell proliferation and hence to the development of cancer [18].

1.2. Role of Sugar in Cancer Metabolism

Due to enhanced activation of various metabolic pathways, cancer cells create a high quantity of reactive oxygen species (ROS) with respect to normal cells [19]. The metabolism of cancer cells is directly tied to ROS homeostasis; they generate ROS detoxifications by utilizing a number of metabolic intermediates and substrates in metabolic pathways, the most famous of which being glycolysis via the Warburg effect and pentose phosphate pathway (PPP) [20]. The Warburg effect preserves the redox equilibrium by being independent of mitochondrial OXPHOS, which produces a massive amount of ROS [21], and PPP, which produces the ROS-detoxifying molecule NADPH via G6PD and 6-Phosphogluconate dehydrogenase (6PGDH) [22].

Oncogenes, such as MYC, Src, and Ras, and transcription factors, for instance, signaling pathways such as phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR), hypoxia-inducible factor-1 (HIF-1), and tumor suppressors such as p53 are all implicated in the modulation of glucose metabolism in cancer. Ras, Src, and MYC oncogenes improve HIF-1 expression, which raises the production of several glycolytic enzymes, and MYC, KRAS and HIF-1 oncogenes worsen glucose absorption by enhancing GLUT expression. Furthermore, the PI3K/Akt/mTOR pathway increases the synthesis of GLUT and glycolytic enzymes, whereas p53 regulates GLUT and glycolysis via AMP-activated protein kinase (AMPK) and mTOR [23,24].

The metabolism of tumors are very specific. Among the many contrasts with healthy cells, possibly the most crucial is that cancer tissues depend exclusively on glucose as a source of carbon and energy. Because of how rapidly cancer cells seek glucose, they can be spotted by positron emission [25].

Cancer cells have been recognized for decades to demonstrate higher metabolic rate and glucose use rather than cellular respiration. The glycolytic change was considered to be produced by abnormalities in mitochondrial respiration because of mutations in mitochondrial DNA. Yet, it is currently argued that tumor cells require glucose because they make use of it to build metabolites required for proliferation, notably, fatty acids and nucleic acids. Instead of employing the bulk of the glucose to create ATP through respiration, alterations in metabolism enable cells to grow more quickly [26,27].

1.2.1. Sugars in the Diet and Cancer Risk

It has been claimed that high-sugar diets may promote carcinogenesis by promoting the synthesis of insulin and insulin-like growth factor-I (IGF-I), which produces oxidative stress. Various naturally occurring sugars in foods, such as dairy products, fruits, and vegetables, partly explain the consumption of sugars; though, highly processed foods and beverages, to which syrups and sugars are added during preparation or processing, or added syrups and sugars at the table, become more important sources of sugars. Intake of added sugars in the population substantially exceeds the recommended level for discretionary calorie intake, according to data from the United States (US) National Health and Nutritional Examination Survey 2003–2004. In females and males under the age of 18, the mean added sugar intake was 2.8- and 1.5-times higher, respectively [25]. These data are from a large prospective study from the USA [25] comprising almost half a million people to explore the link between the incidence of 24 malignancies and dietary sugars. Sugar intake has been speculated to be implicated with an elevated risk of cancer. The influence of several forms of sugars, including sucrose, fructose, and total sugars, and the effect of added sugars, added fructose, and sucrose on cancer risk have been researched. Despite being chemically identical, the physiological effects of sugars can vary depending on whether they are a vital component of the food’s cellular structure along with bioactive substances and micronutrients or whether they are free in solution, found in highly processed foods, with little fiber and rapid digestion, making them easily metabolizable. A higher rate of metabolism, absorption, and ingestion of additional sugars can favor their unfavorable consequences, according to an experimental study [25].

In women, intake of total sugars and high fructose intake were linked to an enhanced risk of bladder cancer, and fructose and added sugars were positively related to the risk of leukemia. The observed link with bladder cancer was marginal according to the results of two case-control studies that revealed a greater risk with the intake of foods high in added sugar [25]. Yet, for both bladder cancer and leukemia, the enhanced risk estimated in the replacement model was no longer significant in the partition model. It may be that, in the first situation, the increased risk is attributable to the decline in foods that give energy with a high concentration of bioactive chemicals and protective micronutrients, rather than due to an increase in the intake of sugars [25].

All examined sugars were inversely linked with ovarian cancer risk. The influence of carbs other than lactose on ovarian cancer has only been addressed in one cohort study, and it offered evidence that postmenopausal women may be more at risk for total sugar consumption. A total of 97% of ovarian cancer cases in this group were postmenopausal. Ovarian cancer risk factors are not well understood; consequently, the findings may have been indicative of a dietary trend or confounded by unknown factors [25].

Intake of sugars, sugary beverages, and foods in relation to the risk of cancer connected to obesity

A prospective cohort study [28] specifically explored the connections of sucrose and fructose in the diet along with type and number of sugary beverages and foods with general and site-specific adiposity-related cancer risk by taking into account data from US adults. Sugary foods were not associated with cancer risk. Nevertheless, in stratified exploratory analysis, total consumption of sugary beverages was associated with a 59% increased risk of adiposity-related malignancies in persons with excessive central adiposity. A higher intake of fruit juice was associated in a separate investigation within this cohort to a 58% increase in the risk of prostate cancer, despite the total consumption of sugary beverages not being linked to the risk of the individual tumors of the examined region [28]. In this study of American adults [28], the conclusions revealed that a larger intake of sugary beverages is implicated in an enhanced risk of adiposity-related malignancies, among those who shown an excessive central adiposity. Prostate cancer risk was observed to be increased among individuals who consumed more than seven servings of fruit juices per week (more than one serving per day) [28].

In a context where the WHO questioned the level of evidence of scientific data supporting the implementation of a tax on sugary drinks, the outcomes of another observational work with a total of 101,257 participants based on a huge prospective cohort suggested that high consumption of sugary beverages is linked to an increased risk of breast cancer and general cancer [29]. Notably, in this analysis, 100% fruit juices were connected to an increased risk of cancer in general. If these results were replicated in more large-scale prospective studies and supported by mechanistic experimental data, along with the relevant place that sugary drinks have in Western countries’ diet, in addition to their well-established impact on cardio metabolic consequences, these drinks may represent a modifiable risk factor for cancer prevention. In contrast, this study revealed no association between drinking artificially sweetened beverages and an increased risk of cancer. These findings held up following a number of sensitivity studies [29].

Adaptation of Cells to a Lack of Glucose

When challenged by energy stress or glucose deprivation, cells limit protein production and proliferation by activating p53 and AMPK and by inactivating mTOR. These pathways also promote alternate methods to obtain energy. One of those energy reservoirs is fatty acids. In reaction to glucose scarcity, AMPK modifies fatty acid synthesis and stimulates their oxidation. According to various investigations, glioblastoma cells are protected from glucose deprivation when fatty acid oxidation takes place [26,30]. Glioblastoma cells have been found to utilize glutamine when glucose is low, and if glutamine metabolism is disrupted, the cells are unable to survive without glucose. Therefore, cells employ fatty acids and amino acids to try to maintain homeostatic functions and energy levels when glucose is not available [26].

A conserved reaction to a dearth of nutrition and oxygen is autophagy. It is believed that low glucose levels activates autophagy, and in apoptosis-deficient cells subjected to hypoxia and glucose deprivation, autophagy is important for maintaining cell life [26,31].

Sensitivity of oncogenes to glucose restriction

Proliferating cells react to the absence of glucose by actively pushing cell cycle arrest as well as blocking biosynthetic pathways. Still, tumor cells typically demonstrate hyperactivation of pathways associated with alterations in cell cycle inhibitors and proliferation. This makes the cells hypersensitive to glucose deprivation, as the proliferation of the cells are enhanced, but they lack the necessary building blocks for this purpose. Since they are unable to inhibit anabolism in this scenario, cells undergo energy stress and eventually die [26].

A substantial majority of tumor cells lack LKB1, which is the most critical kinase linked with AMPK activation. Because cells missing LKB1 do not respond properly to energy stress, they are hypersensitive to energy-depleting agents. Downstream of AMPK, glucose shortage supports the activation of p27 and p53, which induce autophagy and support cell cycle arrest, which contribute to their survival effects in the absence of glucose [26,32].

Bcl-2 antiapoptotic proteins and glucose deprivation

Bcl-2 is the prototype member of a family of proteins that contain at least one Bcl-2 (BH) region of homology. This family of proteins is divided into antiapoptotic multidomain proteins (prototypes: Bcl-XL and Bcl-2), which contain four BH domains (BH1234), which correspond to the α-helix segment (Figure 2) [33,34]; multidomain proteins (prototypes: Bak and Bax), containing three BH domains (BH 123); and pro-apoptotic proteins BH3 (prototypes: Bad and Bid) [35]. The principal location of action of Bcl-2-like proteins is presumably the mitochondrial membrane [36].

In most situations, a sequence conservation is present in all four domains of the anti-apoptotic components. Pro-apoptotic molecules usually show poorer sequence conservation of the first α-helical region, BH4 [37].

Originally integral membrane proteins, anti-apoptotic components can be situated in the endoplasmic reticulum, mitochondria, or nuclear membrane [38,39,40]. On the contrary, a large part of certain pro-apoptotic components are located in the cytosol or the cytoskeleton prior to the death signal [41].

Under certain circumstances, pro-apoptotic stimuli stimulate a signaling of the (AP) -1/p53 transduction pathway; these families of transcription factors control the Bax promoter, leading to apoptosis dependent on protein synthesis by increasing the Bax/Bcl-2 ratio and Bax levels [42]. Nevertheless, apoptotic stimuli often activate more than Bax regulation. Chaperones in the cytoplasm of live cells contain the protein Bax such as Ku/70 [43] and 14-3-3 [44]. Apoptotic stimuli release Bax through Ku70 acetylation [45] or JNK-dependent 14-3-3 phosphorylation [46]. Bax release is essential but not enough for triggering, and there must be further particular events. Bax can be triggered by a number of stimuli, through unique processes that are focused on different domains of the protein, and can lead to diverse end consequences [47].

The mPTP is a megachannel that forms in the mitochondrial membrane at the location where the outer and inner mitochondrial membranes meet, and it is considered a vital step for the intrinsic pathway of apoptosis [36,48]. Several members of the Bcl-2 protein family are recruited to assist pore formation in its high conductance state under circumstances such as calcium excess, low ATP levels, and oxidative stress [7,36,48,49,50].

Several members of the Bcl-2 family are activated during apoptosis. Caspase 8 activation, for example, triggers rapid stimulation of Bid as well as its translocation to mitochondria as tBid via stimulation of Fas in the plasma membrane. With a molecular weight of 15 kDa, tBid can bind to Bax, allowing it to cling to the mitochondrial membrane, which is needed for the release of cytochrome c and the activation of MAP-1 [51,52,53]. Antiglycolytic medicines and glucose deprivation trigger tumor cell death, which can occur through caspase-8-mediated or mitochondrial apoptosis or necrosis. In the case of caspase-8, it is known that it activates the effector caspases [54,55], principally by the cleavage of the Bcl-2 family member Bid and the consequent activation of the mitochondrial pathway, which serves as an amplifier of the signal [55,56,57].

Antiapoptotic proteins of the Bcl-2 family prevent tumor cells from dying as a result of glucose restriction, which may indicate that glucose deprivation leads to mitochondrial apoptosis. For example, a research on the MCF-7 line of multidrug-resistant breast cancer demonstrated that, in the event of glucose deprivation, these cells suffer apoptosis, which may be avoided by the overexpression of Bcl-2. Furthermore, in Ba/F3 hematopoietic cells, it has been proven that under low glucose circumstances, constant synthesis of the antiapoptotic homolog Bcl-2 Bcl-xL inhibits cells from apoptosis as a result of IL-3 deficiency [26].

It has also been shown that Mcl-1, another member of the anti-apoptotic Bcl-2 family, plays a role in glucose deprivation-induced apoptosis, since reducing Mcl-1 levels sensitized the acute leukemia cell line Jurkat T-cell to glucose removal. It has been demonstrated that, by limiting its breakdown, the employment of glycolysis in hematopoietic cells maintains the equilibrium of Mcl-1 [58]. In contrast, as noted above, glucose deprivation resulted in AMPK-dependent deactivation of mTor; this was seen when the translation of Mcl-1 was suppressed. Therefore, Mcl-1 is regulated at translational and post-translational levels by glycolytic metabolism. Cells are made more vulnerable to pro-apoptotic stimuli by glucose restriction, and it is believed that Mcl-1 down-regulation has a primary role in this sensitivity [26].

Glucose Controls BH3-Only Proteins

The so-called BH3-only proteins control apoptosis by triggering Bax/Bak activation, either directly or indirectly, by blocking anti-apoptotic proteins Bcl-2 and sensing signals arising from diverse cellular processes [27]. BH3-only proteins have major roles in the sensitivity to chemotherapy and cancer. Some of these proteins have a key function to play in glucose deprivation-induced apoptosis in diverse settings [26].

Bim has been related to the production of cell death in numerous kinds of cells and tissues in response to several stimuli. It is the major BH3-only protein connected to stress-induced cell death. It was demonstrated that Bim as well as PUMA are activated in hematopoietic cells exposed to glucose deprivation, suggesting that the stimulation of Bim under glucose deprivation could be driven by the stimulation of ER stress. In contrast, in hematopoietic cells, the administration of glycolysis produced prevention of apoptosis triggered by Bim and overexpression of Mcl-1 [26].

Glucose restriction enhances AMPK-dependent mTor deactivation with consequent suppression of Mcl-1 translation. Induction of AMPK leads to the stimulation of p53 and the overexpression of PUMA BH3-only protein. Bim is created by both the ER stress response and AMPK stimulation thanks to the transcription factor CHOP. Furthermore, Noxa participates in glucose withdrawal apoptosis in leukemic cell lines and in activated T cells, probably by decreasing Mcl-1. Eventually, Bad is post-translationally controlled in glucose shortage by blocking its phosphorylation. Thus, unphosphorylated Bad can interact with members of the Bcl-2 family and trigger apoptosis. In contrast, Bad furthermore interacts with a glucose hexokinase (HK), and the phosphorylation of Bad is important for the hexokinase’s kinase activity [26].

Another BH3-only protein regulated by p53 is Noxa. Noxa has been found to contribute to glucose deprivation-induced cell death in both primary and tumor cells. Noxa was found to participate in apoptosis after glucose removal, since Noxa’s down-regulation offers a competitive survival advantage to leukemic cell lines and primary T cells under low glucose conditions. It has been proposed that the involvement of Noxa in this milieu is connected with its ability to counteract the anti-apoptotic Bcl-2 homolog, Mcl-1. These data show that Noxa, similar to Bad, may have a role in both glucose deprivation-induced mortality and glucose metabolism [26].

The BH3 protein with the strongest link to glucose metabolism is named Bad. Glucose-deprived murine defective hepatocytes are protected against cell death relative to their normal counterparts. These data imply that, in response to glucose restriction, Bad operates as a proapoptotic protein distinct in the BH3 subgroup. Nevertheless, in this situation, Bad may indirectly cause cell death by regulating glucose metabolism [26].

1.2.2. Possible Significance of Sugar Transporters in Cancer and Its Connection with Anticancer Therapy

GLUT1 overexpression has been observed in various human malignancies. Furthermore, as dysregulation of GLUT1 expression may suggest the presence of alterations in a number of signaling pathways, GLUT1 expression levels have also been adversely linked with prognosis. Actually, high levels of glucose uptake, one of the hallmarks of malignant cells, are caused by activated Ras or SRC oncogenes, which are key components in the transmission of many signaling pathways. In this regard, it has been proven that mutations in KRAS or BRAF can cause an increase in glucose absorption and GLUT1 overexpression in colorectal cancer cell lines. Moreover, low glucose levels cause wild-type colorectal cancer cell lines to produce more KRAS mutations, upregulating GLUT1 and increasing glucose uptake as a result. Other important alterations in cancer implicated in GLUT1 overexpression affect the local hypoxic pathway and the expression of the MYC oncogene. Additionally, glucose transporters that are not significantly expressed under normal circumstances might be increased by tumor cells [17,25,26,27,28,29,30,31,32,58,59].

Similar to GLUT1, cancer cells also use SGLT1 stimulation to boost their glucose uptake and glycolysis, so that cancer cells obtain enough energy to support their expansive growth. Still, there is minimal study on SGLT transporter expression in malignancies. In a pioneering work, the activity or expression of an unknown SGLT cotransporter in the colon cancer cell line HT29 was revealed to be controlled by the supplement/deficit of glucose in the culture. In a more recent work, the expressions of the SGLT1 and SGLT2 genes were investigated by RT-PCR in autopsies of primary lung cancers with their metastatic lesions and normal lung. The expressions of SGLT1 and SGLT2 were observed to be unchanged between matched normal lung tissue and tumor samples. Analyzing the metastatic lesions (in lymph nodes and the liver) of the lung tumors, SGLT2 expression was observed to be much higher in the metastatic sites compared to that in the primary tumors, while SGLT1 expression did not alter. Ref. [17] shows a great way to analyze the expressions of SGLT1 and SGLT2 in lung cancer, even if the type of the sample (autopsies) may limit the value of the results obtained. Furthermore, using an immunohistochemical methodology, the expression of SGLT1 (as well as p53 and BCL2) in pancreatic cancer was examined in order to associate the results acquired with different survival determinants. This article indicates that, in pancreatic adenocarcinomas, SGLT1 overexpression was considerably related with disease-free survival. Furthermore, the enhanced expression of SGLT1 in primary pancreatic tumors was involved with a high expression of Bcl-2 [60,61,62]. This prospective investigation proposes that, although it should be tested by a more sensitive approach such as qRT-PCR7, Bcl-2 and SGLT1 are promising predictive biomarkers for pancreatic cancer [17].

Most cancers have elevated expressions of sugar transporters [17] and boosted glycolysis. This occurrence, which occurs even under aerobic conditions, that is, in the presence of enough oxygen to complete mitochondrial respiration, is called the Warburg effect, and it is regarded as a crucial metabolic change during malignant transformation. The biological basis for creating drugs that particularly target cancer cells by pharmacologically deactivating sugar transport and/or glycolysis is supported by the amplified dependence of tumor cells on sugars and the glycolytic pathway to create ATP. Glycolytic inhibitors are generally effective against cancers that demonstrate increased glycolytic activity owing to hypoxic circumstances or mitochondrial abnormalities. These events are generally involved in poor response to conventional treatment and resistance. Augmented glycolysis is found in a wide spectrum of human malignancies and, thus, the development of new inhibitors of glycolysis as anticancer medicines would have broad therapeutic uses [17].

1.2.3. Significance of Low-Carbohydrate Diets and Fasting

The research [63] assessed the association between applied fasting and the body’s immunity to cancer. The authors of the research discovered that, in mice, the introduction of a two-week period of fasting resulted in the prevention of tumor growth without generating a change in body weight. It was found that the introduction of fasting can promote autophagy in colon cancer cells, which ultimately decreases tumor growth by increasing immunity against cancer [63,64].

Metabolic alterations related with caloric limits significantly influenced health, including reduced angiogenesis, enhanced insulin sensitivity, and lower inflammation. Moreover, the introduction of processes influenced by caloric restriction are directly associated to the pathogenic mechanism of cancer, including the protection of toxic substances, accelerated autophagy, DNA repair processes, and the removal of cells damaged as a result of apoptosis [64].

In recent years, some publications have explored the association between ketogenic diet and tumors related to the nervous system. In 1995, the ketogenic diet model with 60% of calories coming from medium chain fatty acids was developed based on a study of two cases of adolescent patients with brain cancer (astrocytoma) in an advanced stage of the disease. The remaining macronutrients were distributed as follows: 20% of the energy share comes from proteins, 10% from the remaining fats, and 10% from carbohydrates. In the location where the tumor was positioned, glucose uptake was evaluated using positron emission tomography. Both patients followed the diet for 7 days, during which time there was a 28.7% decrease in glucose uptake in the tumor area. In one of the patients, a notable clinical improvement was noticed in terms of acquisition of new abilities and mood. During the continuance of the diet for 12 months, no advancement of the disease was identified [64].

The other version of the case referred to a 65-year-old patient who was diagnosed with glioblastoma multiforme (GBM). The ketogenic diet was also included into normal care in this example following surgical resection of GBM, employing a 4:1 ratio (4 g of fat to 1 g of proteins and carbohydrates in total). The daily calorie intake was fixed at the 600 Kcal level. The patient’s body mass reduced by roughly 20% after two months of administration of the diet and the presence of brain cancer cells was not observed. For six months, the stringent diet was continued. Relapse of the disease was identified by magnetic resonance imaging two months following the course of the same [64,65].

In the ERGO research, 20 patients with recurrent gliomas were reviewed 3 months after the finish of radiation therapy to see whether a ketogenic diet (60 g of carbohydrates daily) might be employed [64]. The diet comprised, among other things, vegetable oils and fermented milk drinks (500 mL). Patients were given rules regarding which items they could eat as part of the dietary model, which did not require caloric restriction. The treatment was boosted by the diet that was put into place. The median progression-free survival time was 5 weeks and the median survival was 32 weeks. The study points out that due to the absence of randomization, the restricted number of patients, and the fact that there was no control group in the experiment, the effectiveness of the ketogenic diet could not be confirmed with certainty [64,66] (

Table 1. Clinical studies of oncologic patients.

Patient	Diagnosis	Diet	After Treatment
1 patient, 65 years old	Glioblastoma multiforme	600 Kcal	The patient’s body mass reduced by roughly 20% after two months of administration of the diet and the presence of brain cancer cells was not observed. For six months, the stringent diet was continued. Relapse of the disease was identified by magnetic resonance imaging two months following the course of the same [65].
20 patients	Gliomas	Ketogenic diet (60 g of carbohydrates daily) that comprised, among other things, vegetable oils and fermented milk drinks (500 mL).	The median progression-free survival time was 5 weeks and the median survival was 32 weeks [64,66].
10 patients	End-stage cancer patients	Ketogenic diet for 28 days	The ketogenic diet may function in part by blocking insulin signaling in tumors [64].

).

1.2.4. Targeting the Warburg Effect for Cancer Treatment: Ketogenic Diets for Management of Glioma

The Warburg effect, named after the German scientist Otto Warburg who originally identified it in the 1950s, is the metabolic reprogramming of cancer cells, which happens when they make energy through glycolysis rather than mitochondrial oxidative phosphorylation [67]. He stated that an increase in glycolysis causes cancer cells to secrete a lot of lactate. Glucose transporters can enter cancer cells during the glycolysis process. As a result, a number of glucose metabolites are generated, some of which are connected to specific metabolic pathways such as the serine/glycine metabolic pathway and PPP [15].

Thanks to the Warburg effect, dietary glucose plays the role of the principal metabolic fuel for various cancers. This finding led to the original exploration of the ketogenic diet as a cancer treatment, and it is considered that the principal mechanism by which the ketogenic diet may delay tumor progression is by carbohydrate restriction-induced glucose deprivation. It is well-known that hyperglycemia accelerates the rate of tumor growth in people and animals. Therefore, ketogenic diet is believed to function mostly by lowering the availability of glucose to the tumor. As indicated, ketogenic diet has been demonstrated to limit glucose uptake by the malignancies in people [68,69].

The ketogenic diet reduces pancreatic insulin production by reducing carbohydrate consumption. Additionally, it has been found to improve the sensitivity of healthy tissues to insulin, which reduces the quantity of circulating insulin in the blood. Indeed, a conversion from a regular diet to a low-carb diet resulted in reduced total insulin levels in clinical testing by 41% in type 1 diabetes and 50% in healthy participants, while boosting sensitivity to insulin up to 75% in type 2 diabetics [69].

In a small human experiment with 10 patients, end-stage cancer patients who received a ketogenic diet for 28 days demonstrated a considerable decline in blood insulin. The degree of relative ketosis, which was favorably correlated with the therapeutic response, and this drop in insulin were both inversely related. Thus, the ketogenic diet may function in part by blocking insulin signaling in tumors [69].

1.2.5. Dietary Changes for Effective Cancer Therapy

According to [70], several fasting practices have been indicated to suppress cancer in mice. Even when initiated later in life, intermittent fasting reduces the growth of lymphoma and sarcoma in mice and prevents lymphoma in old mice (from 7 to 10 months of age). The combination of chemotherapy and prolonged fasting cycles (48–60 h) dramatically boosted responsiveness to therapy in mice xenograft models of neuroblastoma, glioma, melanoma, and breast cancer. A drop in systemic levels of insulin-like growth factor 1 (IGF1) is most likely the principal mechanism by which fasting reduces the development of cancer, however, pharmacological or genetic alterations are still needed to validate the molecular components of fasting’s anticancer effect. An alternate fasting mimetic diet consisting of a periodic regimen low in protein and calories resulted in an anticancer effect similar to that of continuous fasting [71]. This diet may be more beneficial than the severe extended fasting routine since it is simpler to comply with and would likely not affect the patient’s fitness as much as prolonged fasting would, which is significant because cancer patients are typically more fragile than healthy people [70,71,72].

As demonstrated in Figure 3, at point a, the tumors feed on the patient’s nutrition. The nutrients that cancer patients ingest become accessible to the tumors. Dietary alterations of certain nutrients can have an anticancer effect through numerous pathways, which are schematically indicated here. Hypothetically, it is conceivable to boost the efficiency of antineoplastic medications through dietary modifications by multiple methods. For instance, dietary histidine supplementation increases the response to methotrexate in a mouse model with leukemia. Cancer immunotherapy is used to treat numerous types of cancer and is currently being studied to detect additional kinds of cancer. There is a clear association between the immune response relevant to the tumor and the diet. For example, ketogenic or low-calorie diets are connected to a decrease in the production of immune suppressive ligands such as PDL-1 (orange) and an increase in tumor-infiltrating CD8 + T cells (purple). A vitamin that is innocuous to healthy tissues but could be harmful to cancer cells due to its extraordinary metabolism may inhibit tumor progression if supplied through diet. For example, when paired with chemotherapy, mannose stops pancreatic cancer xenografts from progressing. Since nutrients provided by the host are crucial for the survival and growth of tumors, reducing the intake of nutrients that are important for the tumor but not for other organs can slow tumor growth [70].

Most of the glucose that enters cancer cells is directed into glycolysis and consequently pyruvate production. Even though the quantity of pyruvate required in the tricarboxylic acid (TCA) cycle for the creation of ATP in tumors is surprisingly minimal, this part of glucose metabolism is crucial for in vivo cancers. Although the degree of the Warburg effect varies among tumor types in vivo, it gives a fair illustration of how tumor cells can reorganize their metabolic programs to satisfy their own metabolic needs [70].

Glucose increases pro-oncogenic signaling. In vivo, the effects of insulin efficiently reduce blood glucose levels. Dietary sugar intake boosts blood glucose levels; the pancreatic beta cells detect this and quickly release insulin in response. Insulin decreases blood glucose levels principally thanks to the increase of glucose absorption by the liver and skeletal muscle. Yet, insulin is also recognized by tumor cells, which have insulin receptors that initiate the downstream phosphoinositide 3-kinase (PI3K) signaling pathway. Most cancer cells demonstrate abnormal PI3K activation, which promotes cancer growth through anabolic metabolism, survival, positive cell cycle control, and other mechanisms. The tumor suppressor PTEN is inhibited, and mutations in the PIK3CA and AKT kinase gene clusters activate the PI3K pathway. Stimulation of PI3K signaling by mutations or by insulin activates mTORC1, which lowers autophagy and enhances anabolic activity, biomass accumulation, and proliferation. As a result, the molecular connections between oncogenic signaling, glucose consumption, and blood insulin have been fully described. Additionally, chronically high insulin levels are connected to an increased risk of cancer, such as those reported in people with obesity and/or diabetes. Though additional factors beyond glucose and insulin are expected to play a pro-tumorigenic role in people with diabetes and obesity, insulin and, by proxy, glucose in the diet contribute to the start of cancer and thus, could also be the objective of cancer prevention [70].

The most tested glucose-lowering dietary restriction strategy is caloric restriction, sometimes termed dietary restriction. These diets decrease overall calorie intake by many degrees and result in a drop in blood glucose. For instance, in a human research with 18 participants, a 15% decrease in blood glucose was observed following a 50% decrease in total calorie intake. However, they also have considerably broader metabolic effects. Dietary or calorie restriction, while probably advantageous for cancer patients in terms of glucose deprivation to tumors, is not optimal as a suggested diet for patients, as they may affect the general physical state of patients and they are difficult to adhere to. Perchance, a diet that is poor in glucose but has a normal caloric value (an isocaloric diet), such as the ketogenic diet, is a better technique [73]. The ketogenic diet, which is high in fat but low in carbohydrates, may inhibit the progression of cancer. A 30% drop in blood glucose was reached in persons after an isocaloric diet where carbs made up just 8% of the total caloric intake. The ketogenic diet boosts ketone bodies, which are not absorbed by many cancer cells but offer energy to the brain and other tissues. The ketogenic diet is likely most useful when food consumption is controlled and portioned out, allowing the patient to consume just a regular amount of calories. Mechanically, the ketogenic diet reduces circulation of insulin [70], which diminishes activity in pro-proliferative signaling pathways mTORC1 and PI3K and can also exacerbate oxidative stress in cancer cells [70,73].

Restricting carbs has less of an influence on the proliferation of cancer cells that have PI3K pathway mutations. Although these cells still need glucose for sustenance, the downstream signaling of PI3K is constitutively active, rendering them resistant to the signaling implications of glucose restriction. These results underscore the crucial role of systemic glucose as an insulin-dependent initiator of the PI3K pathway and suggest that blocking this mechanism will limit glucose tumor-promoting actions and effectively impede tumor growth. This method shows potential for patients with cancers that possess mutations in the PIK3C genes, due to the tumors’ addiction to insulin signaling. Nevertheless, since most cancers survive on the proliferative downstream signals of PI3K and insulin and require huge amounts of glucose, this technique could be equally as effective in preventing tumors as non-mutated PI3K. Regrettably, drug-induced PI3K inhibition is surprisingly inefficient since compensatory insulin production confers tolerance to this strategy. In mice, blood insulin levels enhance in a few hours after the suppression of the insulin-PI3K-AKT-mTOR signaling pathways, which allows greater glucose uptake and stimulation of oncogenic PI3K signaling by tumors, avoiding the antitumor effects of the treatment [70].

A combination of pharmacological and dietary insulin suppression is likely a more effective way to stop tumor growth. After pharmacologically inhibiting PI3K, this strategy was tested in animals, and it was discovered that dietary glucose restriction using a ketogenic diet prevented compensatory insulin secretion and hyperglycemia. The combination approach resulted in decreased pro-oncogenic signaling through mTOR, improved tumor suppression, and enhanced survival of tumor-bearing mice in multiple cancer types. These findings are highly promising for individuals treated with PI3K inhibitors [70].

Although most cancers develop efficiently in the presence of excess glucose and all tumors feed on glucose, some tumors progress more rapidly when fat is supplied for energy. In these rare instances, patients will gain from diets in which carbohydrates serve as the primary energy source. For that reason, before making any suggestions to the patients, it is vital to finish the preclinical study of the results of the changes in the diet’s energy source and investigate the metabolic preferences of each tumor type. The potential advantages of a ketogenic diet for cancer patients have been investigated in numerous clinical studies. These trials were performed utilizing a small number of participating patients, making it impossible to infer whether the ketogenic diet has important benefits. In addition, the lack of a standardized procedure for this diet, as well as the considerable diversity in patients’ adherence to the diet, makes it impossible to compare their results. Nevertheless, a handful of these studies have shown positive data that dietary sugar restriction with a ketogenic diet is viable for persons with various forms of advanced cancer is safe and produces superior results in cancer patients. Although several of these trials did not demonstrate that glucose withdrawal significantly suppressed tumor growth, they laid the framework for future research that should focus on meticulous compliance monitoring and a standardized regimen for a ketogenic diet. Evaluation of the ketogenic diet’s efficacy in the earliest stages of cancer progression is also anticipated to generate superior results. Moreover, limiting glucose intake, managing insulin secretion and blood glucose levels, and assisting patients in maintaining low-carbohydrate diets are likely to improve cancer patients’ survival [70].

In the Western diet, fructose is extremely common. In light of the emerging understanding regarding the fate of fructose absorbed through diet and its role in cancer progression, cancer patients’ fructose intake must be carefully evaluated. Only epidemiological studies had previously demonstrated a negative pro-tumorigenic effect of fructose consumption, but this is now evident. Tumor cells can use fructose as an energy source, and many cancers import massive amounts of fructose by upregulating the fructose transporter GLUT5. The inhibitory effect of GLUT5 silencing on the growth of cancer in animal and in vitro models highlights the dependence of malignancies on fructose as an energy source. Although fructose is processed and absorbed mostly via the intestine, it gets spilled to the liver if it is ingested in large quantities, thus overwhelming the intestinal capacity for fructose absorption. When fructose reaches the liver, it leads to obesity, type 2 diabetes, de novo lipid synthesis, fatty liver, and increased blood triglyceride production. In an Apc mice model, even modest chronic fructose consumption (equivalent to one can of soda per day) has been found to increase the risk of colon cancer [74]. The discovery that this low amount is sufficient to induce fatty acid production, tumor growth, and glycolysis in intestinal tumors contradicts the commonly held belief that, at least in the intestine, only a considerable excess of fructose can cause cancer [70,74].

2. Conclusions

Life requires nutrients, and the availability of nutrients regulates cell death. The metabolic regulation of cell death probably happens on multiple levels, ranging from the control of BH3-only protein stability and stimulation to the control of caspase stimulation in the Death Inducing Signaling Complex.

Utilizing the glucose requirement of tumor cells for diagnostic purposes, because tumor cells demand more glucose than normal cells, clinical studies were designed that have demonstrated that antiglycolytics often induce cell death in tumor cells.

Surprisingly little is known about the apoptotic pathways implicated in tumor cell death in response to fasting. The apoptotic role of BH3-specific proteins or caspase-8 has only been examined in non-transformed cells or in a few tumor cell lines in a number of previously cited studies. In addition to these few studies, the precise mechanisms by which glucose deprivation or antiglycolytics destroy tumor cells remain unknown. Numerous tumor cells experience necrosis and perish in the absence of glucose, as proven by research.

Molecules like RIPK1 are particularly effective in controlling some types of necrosis; understanding the probable molecules associated with tumor cell necrosis would help in its pharmaceutical regulation. In addition, it would be beneficial to discover the key chemicals involved in the sensitivity of tumor cells to chemotherapy and radiotherapy in order to build more effective combinations with antiglycolytics. All of these studies raise the potential that brief hunger can enhance the efficacy of chemotherapy. Calorie restriction is known to increase the life span. To determine whether this would be true for cancer patients, numerous additional clinical trials and tests would be required.

Alternative dietary interventions appear to be viable methods for assisting cancer patients, however, patients could not accept them due to their strictness. Patients who were able to maintain low-carbohydrate diets demonstrated slower growth, improved health, or decreased tumor mass. Fasting can sensitize cancer cells to chemotherapy and redirect energy to the maintenance and repair of healthy cells. Alternately, fasting can also increase autophagy regulation, and its process can have a bidirectional effect.

Despite the fact that dietary alterations of several of the investigated metabolites have exhibited demonstrable benefit and some of them have shown promise in clinical studies, there are currently no definite guidelines or proposed dietary modification regimens for cancer patients. It is improbable that there is a single dietary composition or prescription for the treatment or prevention of cancer that applies to the complete diet. The dietary requirements, metabolic activity, and preferred energy source of various cancer forms differ. In addition, dietary modifications can affect the effectiveness of the drugs. Moreover, dietary modifications will not modify nutrient levels uniformly in all tumor microenvironments and tissues, therefore, the efficacy of dietary adjustments is highly dependent on the location of the tumor. This implies that, similar to new drug combinations, the combination of dietary modification and medicinal therapy must be clinically customized and studied for each kind, grade, and location of cancer.

On the basis of recent promising preclinical and clinical discoveries, it has been determined that certain dietary interventions must be clinically evaluated to establish their therapeutic potential. These include lowering carbohydrate intake, which is expected to be beneficial for a substantial proportion of cancer patients since they are safe and simple dietary adjustments that can be easily examined clinically for their benefit in specific situations.

It has not been established that sugar consumption directly increases cancer risk or progression. However, sugars and beverages that are significant sources of these sugars contribute a large number of calories to the diet, which can lead to weight gain. In addition, the majority of high-sugar foods do not contribute many nutrients to the diet and frequently substitute healthier ones.

Final Conclusion

It is suggested that sugar consumption is reduced in cancer patients.