Combination of nutritional ketosis and hyperoxygenation therapy—promising ground for integrative cancer treatment: a systematic review

Santhosh John

1Ayush Medical Officer (Naturopathy & Yoga), National Health Mission, Department of Health and Family welfare, Government of India.

Abstract Though the cancer is a multifactorial disease, where various types of cancers exhibit varying mechanisms,pathways, genetic and cellular defects, the study of tumor micro-environment confirms that upregulated glycolysis and hypoxia are the part and parcel of almost every cancer subtypes.Therefore, targeting them with nutritional ketosis and hyper-oxygenation therapies could create an unfavourable environment for cancers to thrive.The aim of this review is to study the significance of these interventions in the integrative cancer treatment.Extensive search has been carried out through the online scientific database like PubMed and other medical journals with the search words, ‘cancer metabolism’, ‘tumor micro environment’, ‘hypoxia and tumor’, ‘ketosis and cancer treatment’,‘hyperbaric oxygen therapy and cancer’and ‘ozone therapy and cancer’.All biomolecule studies, preclinical and clinical studies,received as search results are reviewed.In addition,a nutritional book,named‘Healing with Whole Foods:Asian Traditions and Modern Nutrition’by Paul Pitchford is also referred.These studies recommend the use of various therapeutic approaches like ketogenic diet, ketone supplementation, hyperbaric oxygen therapy and intravenous ozone therapy, individually or in combination with standard therapies, based on its antitumor effects,safety, tolerability, its ability to potentiate the radio and chemo therapy, while decreasing its side effects and its efficiency to improve the quality of life.Rewardingly, when combined, the synergistic action of nutritional ketosis and hyperoxygenation therapies elicited profound, supra additive anti-cancer effects.As per present studies, these therapies are safe to include in an Integrative cancer treatment,though large clinical trials are needed to systematize its clinical usage.

Key words:Cancer treatment,Naturopathy,Nutritional ketosis,Hyperoxygenation therapies

Background

Cancer is a multifactorial disease, where various types of cancers exhibit varying mechanisms, pathways,genetic and cellular defects.However, there are two phenomena, which are common to almost all cancers,either causative and/or developmental,namely hypoxia and upregulated glycolysis[1,2].

Hypoxia is the absence of enough oxygen in the tissues, is a critical hallmark of solid tumors, which involves increased tumor survival, angiogenesis,glycolytic metabolism, metastasis, resistance to standard treatments and mortality rate [3, 4, 7–14].By histopathological study of vascular insufficiency,direct oxygen measurements in tumors, and by physiological imaging and mapping, the presence of hypoxia in human tumors has been strongly demonstrated [5, 6]by clinicians and researchers.

Glycolytic metabolism is a consistent feature of most tumor cells across all tissue types.In 1930, Otto Warburg (Nobel Laureate) observed that all cancers express high rates of fermentation, which cause cancers to rely heavily on glucose for energy [15, 16].Mitochondrial defects, overexpression of glycolytic genes and oncogenic mutations in the tumor microenvironment (TME) contribute to the increased glucose consumption by cancer cells [20–26].18-fluorodeoxyglucose positron-emission tomography scans are the widespread diagnostic tool for cancer,which works by utilizing the glycolytic metabolism of cancer cells[17–19].

Therapeutically targeting hypoxia and upregulated glycolysis, along with other standard therapies can be more effective, speedy and preventive of recurrence.Though there are many preclinical studies are coming up recently to target glycolysis and hypoxia,Nutritional Ketosis and Hyper oxygenation therapies are chosen, as these already existing non-toxic interventions can be employed effectively in an integrative medicine clinical set up.

Therapies

Following four methods are mainly considered to target tumor hypoxia;

(i) Deliver O2to tumour tissues.Hyperoxygenation therapies like hyperbaric oxygen therapy, ozone therapy or treatment with blood substitutes helps to deliver more O2to the tumour cells.Blood carries the O2and delivers to each cell.To enhance the O2delivery, blood substitutes, which have the property to bind with O2and transport it efficiently, are used in treatment.The O2carrying property of haemoglobin and perfluorocarbon makes them preferable choices[27,28].

(ii)Promote tumor blood flow.Another strategy is to increase the blood flow in the vessels, which supplies to the tumor.When hyaluronidase is administered in tumor blood vessels, it is found that it can increase the density of blood vessels and perfusion inside the tumor,which in turn reduced the tumour hypoxia by delivering more O2[29–32].

(iii) Produce O2in situ.Reactive Oxygen species(ROS)are found highly increased in the TME.H2O2is the highly expressed ROS.Decomposition of H2O2,produces O2in the site.Nanoparticles with catalytic property (Platinum, Cerium Oxide, Ferroferric Oxide,Calcium Peroxide and Manganese Dioxide) or nano enzymes (Catalase) are capable of decomposing H2O2,thus produce O2locally to treat hypoxia in TME[33–35].

(iv) Reduce the O2consumption by cancer cells.An opposite approach is, reducing the O2consumption of cancer cells.Metformin, commonly used anti hyperglycaemic drug can reduce the O2consumption by inhibiting cellular respiration through metabolic reprogramming,undergoes clinical trials[36–42].

As far as concerned with glycolysis, amongst many approaches, mainly two approaches, mentioned below are studied with great interest.However, targeting the glucose metabolism with drugs seems faint due to their efficacy or safety concern[43,44].

(i) Blocking the glucose transporters (GLUTs).Increased uptake of glucose by tumor cells happens through glucose transporters.So by blocking them,fuel pathway of tumor cells can be compromised,eventually leads to cancer cell death.Several agents such as Phloretin, Glutor, STF-31 etc.acts as GLUT inhibitors show anti-tumor effects in preclinical studies,however, blocking the GLUTs of tumor cells selectively is still perceived as difficult job.

(ii)Targeting the glycolytic enzymes.Next approach is to target the enzymes, which are responsible for glycolysis, such as Hexokinase, Glyceraldehyde 3-phosphate dehydrogenase, phosphofructokinase,Pyruvate kinase-M2, Lactate dehydrogenase, Isocitrate dehydrogenase etc.So far,many agents are searched to target these various glycolytic enzymes with good results.At the same time, there are limitations to use them clinically, as some of these agents are still in preclinical stage, some express high toxicity and some are inefficient to target the tumor glycolysis,selectively.

Alternatively, a nutritional approach to limit the glucose supply to the cancer cells like nutritional ketosis, invited the attention of many researchers and there are many studies conducted in this principle with great results[45].

Nutritional ketosis

Ketosis is a metabolic condition of the body when it is deprived of carbohydrates, in which ketone bodies are the primary source of energy, instead of glucose.Cancer cells mainly rely on glucose for their energy and the same time, normal cells including brain cells can survive with ketone bodies in the absence of glucose.Thus elimination of carbohydrates can slow down the tumor growth and progression.As we know insulin is an anabolic hormone associated with glucose metabolism, it contributes to the tumour growth.Therefore, reducing carbohydrates lowers insulin, thus helps in slow down the tumor growth [46, 47].In addition to lowering the blood glucose level, through several other mechanisms, nutritional ketosis can limit the growth of the tumor, protects healthy cells from damage by chemotherapy or radiation, accelerates chemotherapeutic toxicity toward cancer cells [48, 53,54]and lowers inflammation which acts as a precursor to cancer[55].A dietary regimen called Ketogenic Diet(KD) and Ketone supplements are efficient in producing nutritional ketosis in the system.

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.During those days,ketone bodies are only found in the peoples who are on starvation or on a diet extremely low in carbohydrates for a prolonged period.To induce therapeutic ketosis,other than starvation/fasting, a new diet regimen-“ketogenic diet” was developed.The traditional KD is a 4:1 formulation of fat content to carbohydrate plus protein.KD delivers 90% calories from fat, 8% from protein and only 2%from carbohydrate[49–52].

Studies in mice models with cerebral tumor and malignant gliomas when treated with ketosis,enhanced the survival rate and reduced the tumor growth and tumor energy metabolism.The inflammation and angiogenesis found in the TME and the process of apoptosis are greatly influenced by ketosis, which results in the reduction of tumor growth.It is found that ketosis stimulate some complex interactions amongst a number of gene networks that regulate the important intracellular signalling cascades and cellular homeostatic mechanisms for tumor reduction in addition to lowering blood glucose[56–58].The above results are reobserved in the animal studies of prostate cancer, colon cancer and gastric cancer [59–62].Ketosis potentiated the chemotherapy effects,concurrently healed the side effects of chemotherapy in normal cells[63].

KD improved the quality of life in patients with advanced metastatic tumor and also improved cancer patients’ quality of sleep, emotional health and mood[64,65].

Ketone supplementation.As discussed earlier, KD,fasting and starvation produce ketones in the blood.Therapeutically ketone supplements like 1,3-butanediol or ketone esters are administered to elevate ketone bodies in the blood without the need of severe dietary restriction.These agents serve as ketogenic precursors and are either enzymatically cleaved or metabolized to produce ketones.Ketone supplements can be administered along with standard diet or with KD.Ketone supplements with KD offer more profound results[66].

Some clinicians raise a concern that physiological ketosis may adversely affect the acid base balance of the body, might result in keto acidosis, but the incidence of non–diabetic keto acidosis is very rare[67].However, during the treatment it is wise to maintain the ketosis level at therapeutic ketosis range(2–7 mmol/L).Therapeutic ketosis at a single stretch more than 6 months is not advisable too[68,69].

Hyperoxygenation therapies

As we discussed earlier about the role of hypoxia in the cancer development, the therapies, which can increase the O2level of the TME can be of great use in treating cancer.Two therapies namely, hyperbaric oxygen therapy and ozone therapy are studied by many researchers in regards to cancer due to its efficacy,safety and wide usage in the health industry.

Hyperbaric oxygen therapy.Hyperbaric oxygen therapy (HBO2T) involves the administration of 100%oxygen at elevated pressure (greater than sea level).HBO2T increases plasma O2saturation, which facilitates oxygen delivery to the tissues, independent of haemoglobin O2saturation[70].

Numerous animal studies confirm the anti-proliferative effect of HBO2T.Both in vivo and in vitro study of murine osteosarcoma exposed to HBO2T,shows significant reduction in tumor volume,metastasis, proliferation and mortality rate.When,HBO2T combined with carboplatin, the chemotherapeutic effect was greatly accelerated [71].In rat model studies of mammary tumors and glioma,the HBO2T reduced the tumor growth, angiogenesis and increased the apoptosis.Mesenchymal-to-epithelial transition, induced by HBO2T, reduced the aggressiveness of the tumor cells.Glycolysis, the signature cancer metabolism has been shifted to oxidative phosphorylation, which results in tumor suppression[72–75].

In a study of nineteen randomised control trials with 2286 patients,HBO2T elicited anti proliferative effects,especially with head and neck and uterine cervix cancers [76].HBO2T enhanced the effects of 5-fluorouracil (5-FU), in a mice study with sarcoma,also enhanced the chemotherapeutic effect of doxorubicin both in vitro and in vivo study of rat model metastatic lung cancer.[77, 78].Most common cancer in woman is the cancer of breast [79].HBO2T proved its strong anti-proliferative effect in mammary tumor as a stand-alone treatment in various animal studies [72, 74, 75, 80–83].HBO2T with Radio Therapy (RT) has shown good result in patients with colon and rectal cancer [84].In vitro studies of leukaemia and prostate cancers, treated with HBO2T elicited profound anti-cancer properties along with improving the drug sensitivity[85–88].

Albeit, there are some misconception that HBO2T may promote tumor growth by increasing angiogenesis and metastasis and produce adverse effects when combined with chemotherapy and radiation.Contrary,an exhaustive review rules out the connection between HBO2T and enhanced angiogenesis and there are no studies to support HBO2T induced metastasis.More studies are needed to consider the relationship between HBO2T and chemotherapy.If RT is given right after(not together) the HBO2T treatment, the anticipated side effects can be prevented[3].

Intravenous ozone therapy.Ozone therapy refers to the process of administering ozone gas into the body to treat a disease or wound.Ozone is a colourless gas made up of three atoms of oxygen (O3).Ozone therapy can be comfortably administered in cancer due to its profound anti-cancer properties[89].

Human cell culture studies of lung, breast, uterine,colon tumors and neuroblastoma when treated with O3,exhibited inhibition of tumor cells through apoptosis.O3also potentiates the effect of 5-FU and chemotherapy drugs like cisplatin and etoposide [90,92, 93].In vitro study of ovarian cancer, colon cancer,lung cancer and sarcoma, when treated with O3,decreased the tumor metastasis and proliferation,increased the cytotoxicity of radiation, cisplatin and 5-FU [91, 94, 95].In a rabbit model study with metastatic squamous cell carcinoma,when treated with medical O3/O2gas mixture intra peritoneally has shown complete disappearance of primary tumor along with prevention and/or remission of local and distant metastases[96].In addition,the potentiation of CT and RT by O3could be of higher clinical relevance.Animal studies with rat model sarcoma and tongue cancer,mice model peritoneal cancer, when treated with adjuvant O3therapy, reports super anti-tumor effects along with greater survival rates[97–99].

Some human clinical trials on O3therapy in cancer shown fantastic results.Patients with pelvic tumor,head and neck tumous, non-small cell lung cancer treated with O3with or without RT,shown good results,which includes, improved quality of life, less aggressive tumor behaviour,fast tumor regression with minimal side effects of radiation [101–103].Though there are many modes to administer O3, Intravenous ozone therapy (IOT) can be best adopted in cancer management, as it is effective and extremely safe medical therapy[105].

Combination of nutritional ketosis and hyperoxygenation therapies

As reviewed so far, there are compelling clinical evidences for the efficacy of above-mentioned therapies individually in cancer management.Surprisingly, combining these therapies exhibited potent, synergistic anti-cancer effects by targeting several overlapping metabolic pathways that are critical to cancer progression and are especially prominent in metastatic cells.In a study by Angela Poff,et al.,mice were categorised into 4 groups,which received standard diet, KD, KD together with Ketone supplements, KD, Ketone supplements and hyperbaric oxygen respectively.The mice in the three treatment groups showed a 44.6%, 65.4% and 103.2% increase in mean survival time compared to control.Combination group has shown significant reduction in tumor burden and metastatic spread compared to other groups.This study strongly suggests that combining nutritional ketosis with HBO2T may be an effective non-toxic therapy for the treatment of metastatic cancer.[104].Maurer GD, et al.,who studied the utilisation of ketone bodies by glioma cells, suggest that, along with nutritional ketosis, a co-treatment – an antiangiogenic agent like hyperoxygenation therapy can potentiate the anti-tumor effect by synergistic action [56].In an another study of rabbit squamous cell carcinoma,already quoted under ozone therapy,there is 27%more survival and tumor clearance rate has been recorded in the group treated with the mixture of O3and O2compared to the group treated with O2alone [96].In a double blind control study, 54 critically ill cancer patients with 6 different metastatic tumors(liver cancer,colorectal cancer, kidney cancer, brain metastatic tumors, breast cancer, and lung cancer) were treated with the combination of KD and IOT.After three months, an average of 58%reduction in the tumor size was recorded [105].This study continued with 31 patients for 180 days with an addition of HBO2T and several supplements after 90 days, resulted in 98.8%reduction in the tumor size [69], which warrants the development of non-toxic, non-invasive cancer treatment protocol with the substantial inclusion of above-mentioned therapeutic components.As we notice,the base of this human study is the combination of nutritional ketosis and hyperoxygenation.

Conclusion

Background of this review points out the presence of hypoxia and upregulated glycolysis in almost all cancer subtypes as a common feature.To address the same, various measures are discussed.Amongst them,nutritional ketosis and hyperoxygenation therapies are selected, due to their feasibility to incorporate in the integrative oncology care.Followed by, an exhaustive attempt is made to review many biomolecule,pre-clinical and clinical studies to understand the effects of ketogenic diet, ketone supplementation,hyperbaric oxygen therapy and intravenous ozone therapy upon various cancers.The limiting factor of this review is comparatively less available open accessed human clinical studies in this area.However,these therapies are proved to be anticancerous on their own accord, but the most important clinical observation is that the combination of Nutritional Ketosis and Hyperoxygenation therapies can be a groundbreaking combination therapy to combat cancer,explained in the final part of this review.However,large clinical trials are needed to quantitatively assess the efficacy of this approach and bio molecular studies are warranted to understand the synergistic mechanism of action.Meanwhile these therapies are safe to include in an integrative cancer treatment regimen, as per present studies.