Cancer Metabolism as a Therapeutic Target and Review of Interventions

1. Introduction

Warburg’s hypothesis for cancer progression is that cancer cells undergo a two-step transformation. First, there is irreversible failure of respiration, and secondly, the cell survives by fermentation energy. Fermentation energy is far less efficient than aerobic glycolysis, producing only 2 ATP for a glucose molecule as opposed to 38 via aerobic glycolysis [1].

Cancerous cells shunt a majority of glucose through the anaerobic pathway [2], and cancerous cells do have enhanced glycolysis [3]. This effect serves as the basis of radiolabeled glucose positron emission tomography (PET) imaging of tumors [4]. Cancerous tumors using anaerobic glycolysis produce waste products and acidify the intracellular space [5,6], which necessitates the evolution of surrounding cells towards acid-resistant phenotypes [7]. Additionally, the hypoxia-resistant phenotype of cancer cells is especially useful for pre-malignant lesions growing further away from blood vessels [7].

To test the validity of the metabolic theory of cancer, nuclear transplantation experiments were performed [8]. These experiments demonstrated that while inserting the nucleus of a cancerous cell into a healthy cell was insufficient to induce the cancer phenotype, inserting the cytoplasm of a cancerous cell, which contains the mitochondria, was sufficient to transform a previously healthy cell into a cancerous cell [8].

Until recently, the Warburg hypothesis had not received much attention for its treatment implications for cancer. Case reports on the ketogenic diet for treatment in cancer were published in the 1990s [9], and a pilot trial of 16 participants was published in 2011 [10]. Adherence to the diet is a common difficulty [10,11]. Given the profusion of interest in ketogenic diets, there are now more keto-friendly foods and cookbooks available, which can help with diet adherence.

Metabolic approaches work systemically [12], as opposed to targeted therapies, which require specific targeting towards an individual’s cancer genetics [13]. Given that the Warburg effect is a hallmark of cancer [14], a reduction in the fuel available to cancer cells can systemically shift the body environment to be more hostile to cancer [15].

There are multiple interventions that one can apply, each of which affects a less conducive environment for cancer growth. Therapeutic combinations that stress the cancer through multiple pathways can prevent cancer progression, encouraging reversal and remission. Typically, therapeutic combinations are studied either in isolation or in combination with a few other (often complementary) therapeutic interventions.

Cancer fitness is a multidimensional landscape, and combinations of interventions can be selected to reduce tumor fitness while maintaining the fitness of normal cells. Metabolic reprogramming in cancer cells opens a significant number of therapeutic modalities. Not only does dietary ketosis proportionately disfavor cancer cells from an energy availability standpoint, but it also deprives the cancer cell of the vital building blocks for cell replication [16], and ketones may act independently as anti-oncogenic factors [17,18,19,20].

The metabolic shift to glycolysis is also useful for the tumor microenvironment prior to angiogenesis, which is a hypoxic condition [7]. The rapidly dividing nature of cancer cells prioritizes glycolytic metabolism, and the Warburg effect enables faster glucose breakdown [21,22]. Glycolysis provides substrates for nucleic acid biogenesis in rapidly dividing cancer cells [23], and can produce more energy per unit time compared to non-cancerous cells, despite the inefficiencies [24].

Beyond anaerobic glycolysis (i.e., the Warburg effect), other metabolic shifts occur in cancer cells. In a 2016 review, authors Pavlova and Thompson identified six metabolic hallmarks: (1) deregulated uptake of glucose and amino acids, (2) use of opportunistic modes of nutrient acquisition, (3) use of glycolysis/TCA cycle intermediates for biosynthesis and NADPH production, (4) increased demand for nitrogen, (5) alterations in metabolite driven gene regulation, and (6) metabolic interactions with the microenvironment [25]. That is to say that the differences between cancer and healthy cell metabolism are not limited to the Warburg effect. A more recent review adds the following emerging metabolic hallmarks of cancer: an increased need for electron receptors and a greater reliance on oxidative stress protection mechanisms. Additionally, the heterogeneity of metabolic reprogramming, even within a single tumor, is worth considering, as well as the interaction of the tumor with whole body metabolism [26].

The metabolic paradigm of cancer research is still novel and requires much more fervent investigation. However, it demonstrates great therapeutic promise, both in terms of mechanistic understanding and clinical data [27].

Several existing and investigational anticancer agents act on metabolic pathways. Dichloroacetate, for example, inhibits pyruvate dehydrogenase kinase, in turn increasing pyruvate flux into the mitochondria. This promotes glucose oxidation, as opposed to glycolysis [28], which is the primary source of energy for cancer cells [24], thereby decreasing the energy available to cancer cells [29].

Metabolic approaches also demonstrate potential in the adjunctive setting, when combined with other approaches. Combining chemotherapy with a ketogenic diet can enhance the effect of chemotherapy [30,31,32]. Additionally, ketone body metabolism can suppress reactive oxygen species and enhance antioxidant capability [12], which may be a mechanism behind its positive impacts in cancer radiotherapy [33,34]. For the case of immunotherapy, the ketogenic diet may be beneficial in the adjunctive setting [35,36,37].

The interventions covered in this review are summarized in and the associated infographic Figure 1. This review is not intended as a guide for treatment, but it may inform cancer treatment using repurposed drugs in the future.

Figure 1. An infographic of Tier 1 (strong recommendation) and Tier 2 (weak recommendation) repurposed drugs.

Additionally, non-recommended interventions with a lower evidentiary basis for their efficacy are included in and the associated infographic Figure 2.

Figure 2. An infographic of Tier 3 (equivocal evidence) and Tier 4 (recommend against) repurposed drugs.

2. Lifestyle Interventions for Preventing and Treating Cancer

2.1. Glucose Management and Ketogenic Diet

A carbohydrate-restricted diet, specifically a ketogenic diet, high in saturated fat and Omega-3 fatty acids, is suggested for various health benefits, including its potential role in cancer management [257]. The diet emphasizes avoiding processed foods, particularly those with high glycemic index values, and promotes the consumption of real foods such as vegetables, nuts, fish, chicken, eggs, and certain fruits [257,258,259]. Continuous glucose monitoring is recommended to track blood glucose levels, and a blood ketone meter is advised to confirm the patient’s state of ketosis [260].

To flatten the blood glucose curve, various interventions are recommended, including eating foods in the right order (starting with vegetables, followed by protein and fat, and ending with starches), skipping breakfast, avoiding snacking, and incorporating vinegar or fiber tablets before consuming starchy or sweet foods [261]. Establishing and restoring a normal microbiome is highlighted as an essential aspect of regulating blood glucose levels and improving insulin sensitivity, with suggestions including consuming a diverse range of foods, fermented foods, and prebiotic fiber, and reducing stress and unnecessary antibiotic use [262,263,264,265,266,267,268]. Avoiding seed oils high in linoleic acid is advised, while using healthy oils such as olive oil, avocado oil, coconut oil, flaxseed oil, walnut, and pecan oils, and butter is recommended [269,270,271,272].

Overall, these dietary and lifestyle recommendations aim to support health and potentially impact cancer management positively by optimizing blood glucose levels, promoting a favorable microbiome, and ensuring a balanced intake of fats and oils.

2.2. Exercise

Lifestyle modification is crucial for reducing the risk of death from cancer and improving quality of life. This includes exercise, a healthy diet, and stress reduction [49,294]. Patients with cancer and metabolic syndrome face an increased risk of distant metastasis compared to those without the syndrome [295]. Regular exercise, combining aerobic activity and resistance training, is recommended during cancer treatment to improve cardiovascular fitness, cognition, and mood, and reduce fatigue, anxiety, and depression [50,296,297,298,299,300]. Resistance training also helps preserve muscle mass, reducing insulin resistance, improving glucose control, and potentially increasing overall survival, as sarcopenia is a negative prognostic factor in cancer patients [301].

The Combined Aerobic and Resistance Exercise (CARE) Trial demonstrated that a combined dose of 50–60 min of aerobic and resistance exercise performed three times weekly led to better patient-reported outcomes and health-related quality of life compared to performing aerobic exercise alone during breast cancer chemotherapy [302]. Meta-analyses have shown the benefits of exercise in various types of cancer, including breast cancer treated with adjuvant chemotherapy and/or radiotherapy, colorectal cancer treated with chemotherapy, lung cancer treated with chemotherapy, prostate cancer treated with radiation therapy, and hematologic malignancies [296]. Engaging in at least 30 min of moderate-intensity physical activity at least five days a week, or 75 min of more vigorous exercise, along with two to three weekly strength training sessions, is encouraged for patients [49,50]. There is evidence of an inverse dose–response effect between hours per week engaged in physical activity and breast cancer mortality, indicating that more hours of exercise have increased benefits [303,304]. Walking, particularly in the sunshine, is beneficial for physical, emotional, and psychological well-being [305,306].

2.3. Stress Reduction and Sleep

Psychosocial stress is associated with a higher incidence of cancer and poorer survival in cancer patients [52]. To reduce stress, patients are advised to engage in stress-reducing activities like meditation, yoga, and mindfulness exercises, along with getting at least 8 h of high-quality sleep [52,307,308,309,310,311,312]. Ashwagandha, an adaptogenic herb, has been proven to be safe and effective in combating stress and improving sleep quality [313,314,315]. In randomized controlled trials, Ashwagandha extract significantly reduced stress levels and cortisol levels, and improved cognition and mood [316]. Meta-analyses also demonstrated that Ashwagandha supplementation significantly reduced anxiety and stress levels compared to placebo, with an optimal dosage of up to 12,000 mg daily for anxiety and 300–600 mg daily for stress [146,317]. However, caution should be exercised as Ashwagandha can activate the immune system and should not be used with immunosuppressive drugs or during pregnancy and breastfeeding [316].

Adequate and high-quality sleep is crucial for neural development, learning, memory, and cardiovascular and metabolic regulation [56]. Disruptions in sleep are associated with a greater cancer risk [318]. Additionally, in those receiving treatment for cancer, sleep disruptions are common [55,319]. For healthy individuals, the National Sleep Foundation recommends seven to nine hours of sleep for younger adults and seven to eight hours for older adults [57]. Healthy sleep is characterized by good quality, indicated by factors such as short sleep latency, minimal awakenings during the night, and high sleep efficiency [320]. Insomnia, defined as difficulty initiating or maintaining sleep, is associated with daytime symptoms like fatigue, cognitive impairment, or depression [321]. Short sleep duration, less than six hours per day, is associated with increased mortality [322]. Ashwagandha supplementation has been found to improve sleep, particularly in adults with insomnia, with positive effects on sleep quality, sleep onset latency, total sleep time, wake time after sleep onset, and sleep efficiency [321]. The optimal treatment dosage is >600 mg daily for more than 8 weeks [321].

3. Recommended Supplements and Medications for the Treatment of Cancer

This review summarizes the most promising repurposed drugs for treating cancer, including their mechanism of action, clinical efficacy (if available), and dosing considerations, including safety. These are summarized in .

For evidence, we include first meta-analyses of clinical trials. If these are not available, we then include individual clinical trials. If these are not available, we include case series, and then case studies. If human studies are not available, we rely on preclinical evidence.

The prices of the different compounds have been compiled in , which includes their prices through common bulk suppliers for natural products, supplements, and nutraceuticals. For the case of drug prices, US prices are found using the website https://www.pharmacychecker.com/ (accessed on 11 September 2023).

3.1. Vitamin D

Vitamin D is synthesized in the human skin through the influence of UV B radiation and is then converted into the active form, 1,25-dihydroxyvitamin D3 (calcitriol), in the kidney [323,324,325]. 25-hydroxyvitamin D3 (25(OH)D3) is considered the best indicator of vitamin D status, with a level > 30 ng/mL considered normal, 20–30 ng/mL considered insufficient, and <20 ng/mL considered deficient [324,325,326]. Recent data suggest that a level > 50 ng/mL is desirable, and, ideally, targeting a level between 55 and 90 ng/mL is preferable [323,327,328,329]. Adequate vitamin D supplementation is important to achieve optimal levels in patients with low vitamin D levels, and using 50,000 IU D3 capsules in divided doses over a few days is recommended [323,328,329] .

Vitamin D plays a critical role in various physiological pathways, including energy metabolism, immunity, and cellular growth [330]. It has pleiotropic functions and regulates over 1200 genes within the human genome, with a significant role in the modulation of the immune system [323,331,332]. Observational and randomized controlled studies indicate that a low vitamin D status is associated with higher mortality from conditions like cancer and cardiovascular disease [333,334]. Vitamin D deficiency increases the risk of breast, colon, prostate, and other cancers, while supplemental vitamin D intake has an inverse relationship with cancer risk [324,335]. Higher latitudes are associated with increased risk of vitamin D deficiency and various cancers, with vitamin D supplementation likely playing a crucial role in cancer prevention [324,336]. Achieving a vitamin D level of 80 ng/mL may reduce cancer incidence rates by 70% [337].

3.2. Melatonin

Melatonin, a lipophilic molecule synthesized by the pineal gland with a circadian pattern, exhibits elevated levels at night and contributes to homeostatic metabolic rhythms and disease protection [72]. It acts through MT1 and MT2 receptors found throughout the body, functioning as a potent antioxidant and playing a crucial role in normal mitochondrial function and oxidative phosphorylation [361]. Exposure to light at night can disrupt melatonin production and the circadian rhythm, and melatonin levels decrease with age after 40 [362]. Melatonin’s widespread biological effects are facilitated by its receptors, and it is also produced in mitochondria under near-infrared irradiation, further adding to its diverse properties [363,364].

3.3. Green Tea

3.4. Metformin

3.5. Curcumin

Curcumin, popularly called “curry powder” or turmeric, is a polyphenol extracted from Curcuma longa. Curcumin has antioxidant, anti-inflammatory, antimicrobial, antiviral, and anticancer properties [88].

3.6. Mebendazole

3.7. Omega-3

Polyunsaturated fatty acids (PUFA), including alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), have been extensively studied for their therapeutic effects against various human diseases, including cardiovascular and neurodegenerative diseases, and cancer [97]. These studies have shown the clinical usefulness and safety of these natural substances. Recent research has also demonstrated the potential of omega-3 FAs in improving outcomes in certain types of cancer, enhancing the efficacy and tolerability of chemotherapy, and improving quality of life indicators. Additionally, omega-3 FAs have been found to have a positive impact on cancer cachexia [97].

3.8. Berberine

3.9. Atorvastatin

3.10. Disulfiram

Disulfiram (DSF) inhibits aldehyde dehydrogenase, leading to acetaldehyde accumulation and unpleasant effects when alcohol is consumed, making it an anti-alcoholism drug; however, it has been repurposed as a potent cancer treatment, showing anti-tumor effects in preclinical studies and recent success in treating seven types of cancer in humans [451].

3.11. Cimetidine

3.12. Mistletoe

The European white-berry mistletoe (Viscum album L.) is commonly used in continental Europe as an adjunctive treatment for cancer patients, with mistletoe extracts administered subcutaneously or intravenously to reduce disease- and treatment-related symptoms and improve quality of life [463].

3.13. Ashwagandhia

Ashwagandha (Withania somnifera, WS), historically employed in Mediterranean and Ayurvedic medicine, functions as both a functional food and medicinal plant with potential anticancer attributes [472]. Its active compounds, including withanolides and alkaloids, underpin its pharmacological effects [142].

3.14. Phosphodiesterase 5 Inhibitors

Selective phosphodiesterase 5 inhibitors, including sildenafil, tadalafil, and vardenafil, are widely used in the treatment of erectile dysfunction and pulmonary arterial hypertension [477]. These drugs may also be effective cancer treatments [478].

3.15. Itraconazole

Itraconazole, a well-established antifungal agent inhibiting lanosterol 14α-demethylase, has demonstrated potential as an anticancer agent through mechanisms unrelated to its antifungal effects.

4. Potential Adjunctive Therapies

Adjunctive therapies demonstrate some potential for use in the treatment of cancer. These are summarized in and the associated infographic Figure 2.

4.1. Tumor Treating Fields

Tumor treating fields (TTF) are non-invasive alternating electric fields administered via the Optune^® system, utilizing transdermally transmitted 100–400 kHz AC electric fields through orthogonal transducer arrays to disrupt mitosis [502,503]. This disrupts the mitotic spindle assembly checkpoint and leads to cell-cycle arrest, cell death, or senescence, while also promoting autophagy and immunological effects such as STING pathway activation and enhanced dendritic cell and macrophage activity [503]. Although extensively studied in glioblastoma multiforme (GBM), the use of TTF is being evaluated in NSCLC, pancreatic, and ovarian cancer [503]. In GBM, TTF in combination with maintenance temozolomide demonstrated significantly improved progression-free survival and overall survival [504]. The National Comprehensive Cancer Network (NCCN) recommends the use of TTF combined with temozolomide for both newly diagnosed and recurrent glioblastoma patients, suggesting it as an adjunctive treatment option [505,506]. Compliance is crucial as TTF’s therapeutic effects are limited to actively dividing cancer cells during its application [502].

4.2. Photodynamic Therapy

Photodynamic therapy (PDT) involves tissue destruction through visible light when combined with a photosensitizer and oxygen [507]. When exposed to light, sensitizer molecules transition to high-energy states, interacting with oxygen to produce reactive oxygen species that induce cell death through apoptosis, necrosis, and autophagy [508]. Historical use of light for therapeutic purposes dates back thousands of years, particularly combined with reactive chemicals to treat conditions like vitiligo, psoriasis, and skin cancer. Sunlight, encompassing ultraviolet-B (UVB) and near-infrared (NIR) radiation, offers significant health benefits including vitamin D synthesis and mitochondrial melatonin production [509,510]. However, modern lifestyles lead to deficient NIR exposure [510]. NIR-A radiation, with deep tissue penetration, demonstrated efficacy during the 1918 influenza pandemic, and recent studies link sun avoidance to higher all-cause mortality rates [511,512]. PDT, widely used by dermatologists for actinic keratoses and nonmelanoma skin cancers, holds potential for broader applications, including solid tumors, achieved through preferentially accumulated sensitizers activated by light [507,508]. Topical photosensitizers such as 5-aminolevulinic acid or methyl aminolevulinate are commonly employed for cutaneous indications, while visceral tumors require agents like porfimer sodium [347,507]. PDT’s efficacy in experimental cancer cell destruction is proven, yet clinical evidence supporting its benefits in non-cutaneous malignancies is limited [347,361,513,514]. PDT’s role in non-cutaneous cancer and photobiomodulation necessitates further assessment. To enhance mitochondrial function, regular midday sun exposure is recommended (at least three times a week), ideally through brisk walks [347].

4.3. Hyperbaric Oxygen

Hypoxia is a critical hallmark of solid tumors, associated with enhanced cell survival, angiogenesis, glycolytic metabolism, and metastasis [515]. Hyperbaric oxygen treatment (HBOT) has been employed for centuries to address hypoxia-related disorders, enhancing plasma oxygen levels and tissue delivery of oxygen [515]. HBOT induces hyperoxia and elevated reactive oxygen species (ROS), overwhelming cancer cell defenses and triggering cell death [516,517]. This process involves intricate signaling through protein kinases and receptors such as RAGE, CXCR2, TLR3, and TLR4 [518]. Despite limited direct impact on cancer growth, HBOT may synergize with other treatments; for instance, a ketogenic diet combined with HBOT exhibited significant anticancer effects [12]. Hypoxia contributes to chemoresistance, and HBOT as an adjuvant has demonstrated enhanced effects both in vitro and in vivo, although certain chemotherapeutic agents might interact negatively [515]. Radiotherapy combined with HBOT serves therapeutic and radiosensitizing purposes, particularly for head and neck tumors [515]. A recent Cochrane review cautioned that while HBOT might improve local tumor control and mortality for head and neck tumors, its benefits should be interpreted cautiously due to unusual fractionation schemes [519]. While HBOT holds promise as an anticancer intervention, particularly in combination with other modalities, clinical data supporting its efficacy remain limited [520].

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