One of the most unique characteristics of cancer metabolism is activated aerobic glycolysis, which is called the "Warburg effect", and is a hallmark of cancer. An acidic tumor microenvironment (TME) resulting from activated anaerobic glycolysis is associated with cancer progression, multi-drug resistance, and immune escape. This article delves into the relationship between alkaline diets, cancer research, and the potential for therapeutic intervention.
The Warburg Effect and Acidic Tumor Microenvironment
Activation of aerobic glycolysis, also known as the “Warburg effect”, is a characteristic feature of cancer metabolism and a hallmark of cancer. Cancer cells require rapid adenosine triphosphate (ATP) generation to maintain their energy state, increase macromolecule biosynthesis, and maintain an appropriate cellular redox state for their survival and growth. Activated aerobic glycolysis produces reduced nicotinamide adenine dinucleotide phosphate, which is necessary to maintain redox balance, and also acts as an antioxidant to protect against reactive oxygen species that are generated during rapid cancer growth. Therefore, aerobic glycolysis, which is a shift from ATP generation by oxidative phosphorylation to ATP generation by glycolysis, is observed even under normal oxygen concentrations. The constant increase in aerobic glycolysis is considered to be an adaptation to the hypoxia that occurs as precancerous lesions become increasingly distant from the blood supply. However, recent reports indicate that the glycolytic phenotype is an important component of the metabolic reprogramming of cancer cells that occurs early in carcinogenesis, i.e., before the development of tissue hypoxia. Aerobic glycolysis can be caused by genetic instability, mutations, abnormal gene expression, or altered signaling pathways. Increased lactate production owing to increased glycolysis leads to acidosis of the extracellular tumor microenvironment (TME). Moreover, the systemic extrusion of H+ by different proton transporters, and the neutralization of protons in cancer cells by bicarbonate anions from the chloride bicarbonate exchanger are the main mechanism for reversing the pH gradient in cancer cells.
The acidic TME is a critical factor in cancer progression. There are numerous lines of evidence that pH gradient reversal, intracellular alkalization, and extracellular acidification are commonly seen in malignant tumors and are associated with the progression, metastasis, and multidrug resistance (MDR) of cancer cells. A direct cause and effect association among the degree of MDR, decrease in external tumor pH (pHe), and increase in internal tumor pH (pHi) has been reported, and the reversed pH gradient of cancer cells is known as a key factor in driving the progression of malignancy and resistance to conventional therapies. An in vitro study of human lung tumor cells demonstrated that a close to 2,000-fold increase in doxorubicin resistance was observed when the pHi increases from 7.0 to 7.4. Furthermore, a decrease in pHe and increase in pHi mediated by proton-extruding mechanisms is responsible for not only the maintenance of MDR but also protection against the induction of apoptosis. P-glycoprotein, a drug efflux transporter, is regulated in a pH-dependent manner, and a decrease in pH of the TME has the potential to enhance its efflux function. Moreover, the uptake of weakly basic chemotherapeutic drugs by tumors is highly affected by the pH of the TME and the ionization properties of the drug. That is, an acidic TME reduces the cellular uptake of weakly basic chemotherapeutic drugs, such as anthracyclines (doxorubicin, daunorubicin, mitoxantrone, etc.) because weakly basic chemotherapeutic drugs become trapped in extracellular compartments owing to being positively charged in acidic conditions. Characteristics of the TME, such as having an acidic pH, being hypoxic, and lacking nutrients, are associated with cancer stem cells that demonstrate self-renewal and multilineage potential, leading to heterogeneity within the tumor and contributing to treatment resistance and clinical relapse. It is also known that the acidic TME is associated with a decreased anti-cancer immune response. Lactic acid in the TME suppresses immune cells, such as dendritic cells, natural killer cells, cytotoxic T cells, and macrophages, resulting in the inhibition of antitumor immune responses, and cancer immune escape. In summary, reversal of the pH gradient of the TME of cancer cells leads to MDR and reduced cancer immunity, resulting in resistance to cancer therapy.
Neutralizing the Acidic TME: Alkalizing Agents
Several in vitro and in vivo studies reported that neutralization of the acidic TME by alkalizing agents, such as bicarbonate, resulted in the suppression of cancer progression and a potential benefit for anti-cancer drug responses. Several studies have been reported on buffer therapies that neutralize the acidic TME of cancer cells. Alkalizing agents, such as bicarbonate, are commonly used in in vitro and in vivo studies. A mathematical simulation study showed that oral bicarbonate consumption as a systemic pH buffer increases the pH of the external TME and inhibits tumor invasion. In mouse models of metastatic breast cancer, it was reported that bicarbonate administration increased the pH of the TME, resulting in the suppression of metastasis and improvements of survival rates. It was also reported that alkalization of the acidic TME improves the anticancer immune response. As described above, the effects of anti-programmed cell death 1 therapy in mouse models of melanoma have been shown to be enhanced by alkalization through bicarbonate consumption. A prospective clinical trial in healthy volunteers was conducted for investigation of the safety of the long-term consumption of sodium bicarbonate for cancer care, and demonstrated that 90 days of sodium bicarbonate consumption (median 0.17 g/kg/day) was feasible and safe, and an increase in urine pH as a surrogate marker for buffering effect was observed following bicarbonate intake.
Dietary Alkalization: Fruits, Vegetables, and Urine pH
In clinical settings, alkalizing effects were achieved not only by alkalizing agents, but also by a following a particular diet. An epidemiological study demonstrated that more fruits and vegetables and less meat and dairy products are associated with an increase in urine pH, which may reflect the alkalizing effect on the body.
Read also: Plant-Based Alkaline Wellness
It is known that diet is associated with cancer risk. The World Cancer Research Fund/American Institute for Cancer Research reported their recommendations associated with food intake to reduce cancer risk as follows: ‘Eat a diet rich in wholegrains, vegetables, fruit and beans’ and ‘Limit consumption of red and processed meat’. Although the benefit of an alkaline diet on cancer risk still remains unclear, a case-control study reported that a diet with a high acid load may increase lung cancer risk. However, to our knowledge, there are no studies to date regarding the association between food intake and pH of the TME. On the other hand, the acid-base load on the body can be affected by food. In a study investigating the effects of food on urine pH, the acid and base precursors in food were quantified and the potential renal acid load was calculated to predict net renal acid excretion, and the potential renal acid load of meat was calculated as +9.5 mEq, whereas that of fruit was −3.1 mEq and vegetables was −2.8 mEq. An epidemiological study showed that an alkaline diet consisting of high fruit and vegetable and low meat intake had a significant association with an increase in urine pH.
Clinical Evidence and Alkalization Therapy
Although pH regulation of the acidic TME is considered to be a potential target of cancer therapy, research on the effects of alkalizing agents and proton transport inhibitors on cancer are mainly limited to in vivo and in vitro studies, and there are few clinical reports regarding alkalization therapy for cancer treatment.
First, a retrospective study investigated the effects of an alkaline diet on advanced or recurrent non-small cell lung cancer patients with epidermal growth factor receptor (EGFR) mutations, who were treated with EGFR-tyrosine kinase inhibitor (TKI). All patients in this study were given instructions to follow an alkaline diet as part of their routine clinical care. In this study, the mean urine pH (n = 11) was significantly increased after an alkaline diet, which was defined as that with a large amount of vegetables and fruits and minimal amount of meat and dairy products. Although the average dosage of EGFR-TKI administered to the patients was less than the standard dosage (56% ± 22% of the standard dosage), the median PFS was 19.5 (n = 11, range = 3.1-33.8) months. It is known that the median PFS reported in publications of a similar population treated with EGFR-TKI alone was 10.9-13.1 months.
Second, a retrospective study was conducted to investigate the effects of alkalization therapy performed concurrently with chemotherapy on recurrent or metastatic pancreatic cancer patients. A total of 28 patients with advanced pancreatic cancer who agreed to receive alkalization therapy, were treated with alkalization therapy, consisting of an alkaline diet with oral sodium bicarbonate (3.0−5.0 g/day). We found that alkalization therapy significantly increased the mean urine pH. A significantly prolonged median OS was observed in patients with a urine pH of higher than 7.0, compared with patients with a urine pH of 7.0 or lower (n = 28, 16.1 vs. 4.7 months; p< 0.05). Moreover, a retrospective case-control study was conducted to investigate the effects of alkalization therapy on chemotherapy outcomes in recurrent or metastatic pancreatic cancer patients. Patients in the alkalization group (alkalization therapy plus chemotherapy, n = 36), which included patients from the above retrospective study, were compared with patients in the control group (chemotherapy only, n = 89). The median OS was significantly longer in the alkalization group than in the control group (15.4 vs. ). In addition, the median OS of patients with an increased urine pH (pH > 7.0) in the alkalization group (n = 13) was significantly longer than that of the control group (n = 89) (25.1 vs. ). These studies suggest that alkalization therapy may be associated with more favorable outcomes in advanced pancreatic cancer patients treated with chemotherapy.
Therapeutic Approaches Targeting the Acidic pH of the TME
There are two main therapeutic approaches that target the acidic pH of the TME. NHE1 is known to play not only an essential role in the survival of normal cells, but also a key role in cancer progression. In normal cells, NHE1 is quiescent in the steady-state resting intracellular pH, and is activated only upon cytosolic acidification. In cancer cells, NHE1 is activated even at resting pH, and the activation of NHE1 directly results in an increase in intracellular pH and a decrease in extracellular pH of cancer cells. NHE1 is a major plasma membrane pump that extrudes intracellular protons from cells, and is associated with tumor growth and progression. There are several NHE1 inhibitors, including derivatives of amiloride, such as 5-(N-ethyl-N-isopropyl) amiloride, 5-(N,N-dimethyl) amiloride, 5-(N,N-hexamethylene) amiloride (HMA), and cariporide. In vitro and in vivo studies using breast cancer cells have reported that cariporide improves doxorubicin sensitivity. It was reported that a patient with metastatic ovarian cancer who was treated with amiloride as a Na+/H+ exchanger inhibitor showed a favorable outcome. However, as NHE1 is widely present in many tissues and plays a fundamental role in important physiological processes, there is a potential risk of life-threatening side effects associated with NHE1 inhibitors.
Read also: Foods for Alkaline Diet
CA acts as a catalyst to reversibly hydrate carbon dioxide to produce bicarbonate and protons, and the overexpression of CA isoforms IX and XII is involved in cancer progression and metastasis. These enzymes contribute to acidification of the extracellular pH of cancer cells. Inhibitors of CA IX and CA XII are considered as potential anticancer agents, and several clinical trials using these inhibitors have been conducted. A study using girentuximab, a chimeric antibody against CA IX, was reported and showed no significant effects on recurrence-free survival in clear cell renal cell carcinoma. The activated glycolysis of cancer cells results in the overproduction of lactate, which is transported out across the cancer cell membrane via the MCT (mainly MCT1). Expression of MCT1 and MCT4 has been reported to be a characteristic of cancer cells and to contribute to tumor invasiveness, and hence these MCTs are potential targets for cancer treatment. V-ATPase is an ATP-dependent proton transporter that expels protons from cancer cells, and V-ATPase activation promotes the progression of cancer. The inhibition of V-ATPase was reported to reduce cancer cell growth and induce apoptosis in several in vivo and in vitro studies. Moreover, proton pump inhibitors (PPIs), which act as H+/K+-ATPases and are used for the treatment of gastric ulcers and gastroesophageal reflux, are also known to inhibit V-ATPase. In vivo and in vitro studies have shown that PPIs induce apoptotic cell death and lead to chemosensitization and reversal of chemoresistance via the inhibition of V-ATPase. Population-based studies also reported that treatment with PPIs may prevent the progression of breast cancer. Although clinical trials are limited, favorable results have been reported in three patients with advanced colorectal cancer treated with chemotherapy in combination with high-dose PPIs.
Complementary Therapies and Cancer
A complementary therapy means you can use it alongside your conventional medical treatment. People often use complementary and alternative therapies to feel more in control. Most alternative therapies have not been through this testing. Talk to your healthcare team if you're considering complementary or alternative therapies. Some types of alternative therapy may not be completely safe. Try to eat a balanced diet, even if you are thinking about taking a nutritional supplement or trying an alternative diet. Ask to talk to a dietitian at your hospital about these diets or supplements. Also, let the dietitian know if you have problems with eating.
Common Diets and Cancer
There are many types of diets. Some claim to cure cancer or have certain benefits.
Gerson Therapy
People who use Gerson therapy believe that changes to diet and nutrient intake can help to treat cancer and other conditions. Gerson therapy aims to rid the body of toxins and strengthen the immune system. Gerson therapy may not be the best diet for you to follow when you are ill and already undernourished.
Alkaline Diet
The alkaline diet tries to change the pH of the body through eating mostly alkaline foods. The pH is a number that shows how acidic or alkaline a substance is. A pH of less than 7 is acidic, and greater than 7 is alkaline. People following this diet believe that they can prevent and cure diseases, including cancer, by making the body's pH more alkaline. They argue that cancer prefers an acidic environment. And that certain foods cause that environment. Researchers carried out a systematic review of studies on an alkaline diet in 2016. They found that there was a lack of evidence to say that an alkaline diet can prevent or cure cancer. They also said that an alkaline diet could change the pH of urine to be more alkaline, but not that of the whole body. The body regulates the pH of blood through several internal processes. Despite the alkaline diet being rich in certain vegetables and fruits, it also limits you to certain foods. It is low in protein and dairy, so you have a higher risk of becoming malnourished.
Read also: Foods for an Alkaline Vegan Diet
Ketogenic Diet
The ketogenic diet is a high fat, low carbohydrate, and low or unlimited protein diet. Usually, your body uses glucose (from carbohydrates) for energy. If you don’t have enough carbohydrates, your body breaks down fat and protein to release chemicals called ketones. Early (preclinical) studies showed that some cancer cells can’t use ketones as energy. So, changing the diet to be high in fat and low in carbohydrate will lower glucose levels and starve cancer cells. But these are early studies which are mostly in animals. We need more and better quality research on humans. The ketogenic diet lacks fibre, fruit and vegetables. It can also lead to low levels of calcium, vitamin D and other salts (electrolytes). This diet can cause kidney stones in people with a family history of the condition.
Macrobiotic Diet
The macrobiotic diet aims to avoid foods containing toxins. People following it believe that by eating a simple, healthy diet, we can live in harmony with nature. Many people follow a completely vegan diet with no dairy products or meat. But some people eat small amounts of organic fish and meat. There are no scientific studies to say that a macrobiotic diet can prevent or cure cancer. Many people following the diet will lose weight.
Fasting Diet
A fasting diet is based on not eating for some time, or eating very little, followed by a period of eating normally. This is also called intermittent fasting. Laboratory and animal studies have been looking at the effects of fasting on chemotherapy. These early studies showed that fasting might protect healthy body cells from chemotherapy. Some studies showed that short term fasting during chemotherapy improved quality of life and fatigue. Fasting reduced the number of chemotherapy side effects. But these are early studies. Most of the studies on humans are small and based only on selected people with certain cancers. Health professionals don’t recommend that you fast before or during chemotherapy.
Organic Food
Many people believe that organic food is healthier or has more nutrients. Researchers did a systematic review of studies in 2019. Some of the studies in the review showed a lower incidence of non-Hodgkin lymphoma in people eating an organic diet. But the researchers said that there was not enough evidence to say that an organic diet is beneficial in the long term. There is also no evidence that small amounts of pesticides found in foods increase the risk of cancer. Pesticides can be harmful when not used properly and not within the safe levels as stated by the law. Fruit and vegetables might sometimes contain low levels of chemicals.
Dairy Products
Research studies have looked into the role of dairy products in the development and recurrence of different cancers. Some have suggested that there might be a link between high fat dairy products and cancer survival. Healthcare professionals don’t recommend a dairy free diet to prevent or treat cancer. Try to eat 3 portions of low fat dairy or dairy alternative a day as part of a balanced healthy diet. If you want to use a dairy alternative, make sure it is calcium fortified.
Addressing Misconceptions about Alkaline Diets
"Should you have a more alkaline body instead of acidic? I read that having an alkaline diet can cure cancer." In truth your body regulates its acid/base balance within very tight limits. The pH of your body is very slightly alkaline, and any shifts from the normal pH range are quickly dealt with by your body’s systems. The confusion surrounding this myth may come from the fact that some foods can change the pH of urine, with foods such as meat making it more acidic (lowering the urine pH) and foods such as many fruits and vegetables making urine more alkaline. However, the changing pH of urine is just one of the ways your body uses to keep overall blood pH in a very narrow range. Well designed studies on alkaline diets in people are lacking and there is no good evidence that they can be used to prevent or treat diseases such as cancer.