Lactic Acidosis in Patients with Solid Cancer

Abstract

Significance:

Cancer-associated tissue-specific lactic acidosis stimulates and mediates tumor invasion and metastasis and is druggable. Rarely, malignancy causes systemic lactic acidosis, the role of which is poorly understood.

Recent Advances:

The understanding of the role of lactate has shifted dramatically since its discovery. Long recognized as only a waste product, lactate has become known as an alternative metabolism substrate and a secreted nutrient that is exchanged between the tumor and the microenvironment. Tissue-specific lactic acidosis is targeted to improve the host body's anticancer defense and serves as a tool that allows the targeting of anticancer compounds. Systemic lactic acidosis is associated with poor survival. In patients with solid cancer, systemic lactic acidosis is associated with an extremely poor prognosis, as revealed by the analysis of 57 published cases in this study. Although it is considered a pathology worth treating, targeting systemic lactic acidosis in patients with solid cancer is usually inefficient.

Critical Issues:

Research gaps include simple questions, such as the unknown nuclear pH of the cancer cells and its effects on chemotherapy outcomes, pH sensitivity of glycosylation in cancer cells, in vivo mechanisms of response to acidosis in the absence of lactate, and overinterpretation of in vitro results that were obtained by using cells that were not preadapted to acidic environments.

Future Directions:

Numerous metabolism-targeting anticancer compounds induce lactatemia, lactic acidosis, or other types of acidosis. Their potential to induce acidic environments is largely overlooked, although the acidosis might contribute to a substantial portion of the observed clinical effects. Antioxid. Redox Signal. 37, 1130–1152.

Introduction

Nearly two centuries ago, in 1843, the German physician and chemist Johann Joseph Scherer (Fig. 1a) demonstrated the postmortal presence of lactic acid in human blood under pathological conditions (191). Later, in 1851, Scherer provided the first proof of the presence of lactic acid in the blood of a leukemia patient. This patient, who died from leukemia, was autopsied by Rudolf Virchow. Virchow offered Scherer blood from this patient for analysis. Scherer concluded that the blood contained “formic acid, acetic acid, and lactic acid, as also found by me previously in spleen fluids” (Ameisensäure, Essigsäure und Milchsäure, die gleichfalls von mir schon früher als in der Milzflüssigkeit vorkommend bezeichnet wurden) (192). This was the first mention of the presence of lactic acid in the blood of a cancer patient. Later, in the 1850s and 1860s, Carl Folwarczny (Fig. 1b) from Vienna and Friedrich Mosler (Fig. 1c) and Wilhelm Körner (Fig. 1d) from Giessen independently confirmed that lactic acid is present in the blood of living leukemia patients (75, 152).

FIG. 1.

Authors of the first independent evidence of lactate in human blood. (a) German physician and chemist Johann Joseph Scherer. (b) Austrian physician and chemist Carl Folwarczny. (c) German internal medicine specialist Friedrich Mosler. (d) German-Italian chemist Wilhelm Körner. The figures were reprinted from (5, 40, 125, 217).

However, the causative link between leukemia and the presence of lactic acid in blood appeared controversial (125). Indeed, in 1878, Georg Solomon from Berlin provided evidence of the presence of lactic acid in the blood of patients with other pathologic conditions, including pernicious anemia, congestive heart failure, chronic obstructive pulmonary disease, pleuritis, pericarditis, pneumonia, and a variety of solid tumors (188).

A century ago, in 1925, S. W. Clausen from St. Louis (MO) identified lactic acid accumulation as a cause of acid-base disorder (38). More recently, in 1978, the Canadian-American physiologist Peter A. Stewart from Providence (RI) postulated the physicochemical approach to acid-base physiology, which suggests that lactate has an acidifying effect similar to that of chloride. Lactate, therefore, causes a decrease in the strong ion difference, which can be calculated as [Na⁺] + [K⁺] + [Ca²⁺] + [Mg²⁺] - [Cl⁻] - [lactate] (156). Thus, according to the electroneutrality law, lactate causes a proportionate increase in [H⁺] and therefore acidosis (186). For every 1 mM increase in lactate, the standard base excess decreases by one unit (104). Currently, lactic acidosis is recognized as the most common form of metabolic acidosis. Metabolic acidosis is a condition in which the pH of the arterial blood is ≤7.35, whereas alkalosis is characterized by a pH of the arterial blood ≥7.45 (139). Under physiological conditions, the pH of human arterial blood is in the range of 7.35–7.40 and the pH of human venous blood is in the range of 7.20–7.35 (88).

In addition to metabolic acidosis, several other types of acidosis exist, including diabetic acidosis (due to the accumulation of ketones), hyperchloremic acidosis (due to loss of sodium bicarbonate), and renal tubular acidosis (due to limited secretion of acids into the urine). Another unrelated type of acidosis is respiratory acidosis, which occurs when CO₂ is not eliminated from the body and carbonic acid accumulates in the blood. A decrease in the intracellular pH of brain cells is characteristic of epilepsy and MELAS (mitochondrial myopathy, encephalopathy with lactic acidosis, and stroke episodes) (4). Acidosis is often associated with pain and increased nociception, as the primary nociceptors are acid-stimulated ion channels (211).

To diagnose systemic lactic acidosis, serum lactic acid levels should be greater than 5 mM, whereas normal serum lactic acid levels are less than 2 mM (139). Critically ill patients with lactic acidosis have a mortality rate of greater than 50% (94, 207). Patients with cancer accompanied by systemic lactic acidosis have a mortality rate of greater than 80% (77, 198). Multiple types of lactic acidosis are recognized based on its origin. Type A lactic acidosis emerges due to anaerobic conditions typically due to insufficient oxygen delivery to tissues, which inhibits oxidative phosphorylation.

Type A typically manifests in patients with ischemic bowel syndrome, sepsis, cardiogenic shock, and hypovolemia. Type B lactic acidosis manifests despite aerobic conditions and is found in well-ventilated patients. Type B typically manifests in patients with hematologic malignancies, human immunodeficiency virus infection, diabetes mellitus, liver disease, thiamine deficiency, and hereditary mitochondrial enzymatic deficiencies and as a side effect of treatment with various compounds, including metformin (69). Type D-lactic acidosis is caused by excessive production of D-lactic acid by proliferating intestinal bacteria and is commonly noted in patients with short bowel syndrome or other forms of gastrointestinal malabsorption (138).

Systemic Lactic Acidosis in Patients with Cancer

Cancer-associated systemic lactic acidosis mostly manifests in patients with aggressive lymphomas and leukemias (e.g., 66, 198). Only sporadic cases have been reported from a broad range of other cancer types (52). Systemic lactic acidosis caused by solid malignancies is, however, associated with high mortality due to advanced disease progression and high tumor burden. The causes of tumor-induced lactic acidosis are unclear. The possible explanations include excessive lactate generation by glycolytic tumors (110, 153); severe depletion of thiamine, which leads to lactic acidosis (225), or the effect of liver metastases that impair pyruvate metabolism (52), which corresponds to the fact that the majority of the reported patients with solid tumors associated with lactic acidosis have liver metastases (Fig. 2). This finding likely stems from the fact that, under physiological conditions, ∼80% of lactate is metabolized by gluconeogenesis in the liver, and the remainder is metabolized in the kidneys. However, the relationship is not valid vice versa, and the presence of liver metastasis does not suggest that the patient will display lactic acidosis. Note also that lactic acidosis is rarely observed in patients with severe liver diseases, such as cirrhosis and fulminant hepatic failure (173). Therefore, lactic acidosis should not be simply attributed to liver dysfunction due to the presence of metastasis. Kidneys may replace certain components of liver function, which is true particularly for subjects with serum lactate concentrations above 6–10 mM (6, 128).

FIG. 2.

Analysis of the survival of patients with cancer who manifested systemic lactic acidosis. (a) Canonical correspondence analysis of the effects of seven environmental variables on survival. The environmental variables included tissue location of the tumor (lung, breast, pheochromocytomas, and neuroendocrine tumors excluding tumors of the pancreas and other tumors), the presence of liver metastases, and treatments applied (i.v. sodium bicarbonate and thiamine). Survival was stratified into three categories: death in less than 1 week, death in one to 10 weeks, and survival for more than 10 weeks or complete remission. Axis 1 explains 60.2% of the variability (eigenvalue 0.165), and Axis 2 explains 39.8% of the variability (eigenvalue 0.109). N = 57. Source data are provided in Supplementary Table S1. (b) Time trends in the use of bicarbonate therapy in patients with solid cancer who manifested systemic lactate acidosis. The cases are stratified into individual decades and reflect whether the treated patient survived the period of at least 10 weeks after lactic acidosis onset. (c) Volcano plot of Pearson correlation coefficients and associated p-values for the comparison of survival during the period of at least 10 weeks after lactic acidosis onset. Significant correlations are identified with arrows.

Cancer-associated lactic acidosis is occasionally resolved with the regression of the tumor, including its metastases, as reported by Rice & Schwartz (177) or, more recently, by Imperiale et al. (115). However, successfully resolved lactic acidosis cases are mostly associated with neuroendocrine tumors, particularly with pheochromocytochroma. Pheochromocytochroma is a rare tumor of the adrenal medulla that is highly hormonally active and often secretes catecholamines, metanephrines, or methoxytyramine. Catecholamines activate adrenergic receptors. The α agonism of catecholamines increases blood glucose levels (by decreasing insulin secretion) and glycogenolysis.

The β agonism of catecholamines increases blood glucose levels (by increasing glucagon and adrenocorticotropic hormone secretion as cortisol decreases tissue uptake of glucose) and increases lipolysis (100). Catecholamines also induce vasoconstriction, which results in peripheral tissue ischemia and thus may induce anaerobic glycolysis in peripheral tissues. Importantly, catecholamines are more effective in glycogenolysis and glycolysis stimulation than in gluconeogenesis stimulation. The difference in increases in glycogenolysis and gluconeogenesis is significant (approximately three orders of magnitude). This difference is responsible for the excessive production of lactate in many patients with pheochromocytochromas, particularly in epinephrine-secreting pheochromocytomas. Increased lactate is commonly observed in patients with pheochromocytochroma and can be further increased both during and after surgery. A common complication of adrenalectomy in patients with pheochromocytomas is intraoperative transient lactic acidosis. This transient lactic acidosis is caused by catecholamines, particularly epinephrine, released from the tumors during resection (213). Consistent with the earlier findings, extrinsic epinephrine infusion (but not norepinephrine infusion) causes an increase in plasma lactate (135). Postoperative increases in lactate are also common in surgically treated patients with pheochromocytomas. In a study of 145 surgically treated patients with pheochromocytoma from Beijing, China, 26% of the patients developed moderate postoperative hyperlactatemia (serum lactate 2.5–5.0 mM) and an additional 15% of patients developed severe hyperlactatemia or lactic acidosis (serum lactate >5.0 mM) (237). Therefore, lactic acidosis in patients with pheochromocytoma is caused by different mechanisms compared with lactic acidosis in patients with other solid malignancies.

The pathogenesis of the onset of systemic lactic acidosis also differs between solid tumors and lymphomas. Sillos et al. reported that 43 out of 53 examined hematologic malignancies associated with systemic lactic acidosis manifested liver involvement, and 20 cases manifested hypoglycemia (198). To briefly touch on the options for systemic lactic acidosis treatment in patients with hematologic malignancies, there is no consensus regarding treatment. Only aggressive cytotoxic therapy is effective, as it leads to neoplasm remission and consequently to lactic acidosis resolution within 1–3 days after the initiation of chemotherapy as long as the patient is responsive to chemotherapy (30, 77). The administration of i.v. bicarbonate seems to be ineffective. Renal replacement therapy may be useful in a fraction of patients with renal dysfunction. Finally, i.v. insulin has been proposed to serve as an alternative lactic acidosis treatment in patients with hematologic malignancies. However, this treatment is also ineffective (198). In the following sections of this review, we focus mostly on lactic acidosis that is associated with solid tumors.

The mechanisms of wound healing resemble those exploited by proliferating tumors. This finding was reported in 1924 by Montrose T. Burrows (23), although it became famous only after Harold F. Dvorak coined the phrase “tumors are wounds that do not heal” in the mid-1980s (65). Elevated systemic lactate predicts poor survival in patients with trauma, similar to that described earlier for patients with cancer. For example, Odom et al. (157) revealed that arterial lactate >4.0 mM at admission was associated with 20% mortality in patients with trauma.

When these patients were stratified into those in whom arterial lactate decreased by at least 60% during the first 6 h and those in whom arterial lactate decreased by less than 30%, the first group had a mortality rate of 7.5%, whereas the latter group had a mortality rate of 30% (157). Therefore, systemic lactic acidosis is associated with poor prognosis in patients with both cancer and trauma.

Tissue-Specific Lactic Acidosis in Solid Cancer

Cancer-associated tissue-specific lactic acidosis has many parallels with wound-induced tissue-specific lactic acidosis. Wounds are characterized by transient ischemia-driven tissue acidification, which resolves as soon as the wound heals and the vascular supply is reinstated (8). The physiological effects of wound acidification are unclear; some studies suggest increased production of inflammatory cytokines by the surrounding endothelial or stromal cells (58).

These factors induce angiogenesis. Then, acidosis is resolved, and inflammation disappears. However, in the tumor environment, acidification never resolves. Thus, regarding tissue-specific acidosis, the tumors clearly resemble wounds that do not heal. Because acidification never resolves, T cells are unable to be activated unless the extracellular pH is artificially increased (166). Therefore, tissue-specific lactic acidosis in cancer is a potential target of future therapies exploiting ways to improve the host body's own anticancer defense.

Aerobic glycolysis, which is characteristic of proliferating tumor cells, leads to the overproduction of lactate and acidification of the tumor extracellular environment to pH 6.5–6.9 (83, 92, 112, 210, 215, 221, 234). Tumor-associated acidosis can be detected very early in tumor development and stimulates and mediates tumor invasion and metastasis (49, 85, 86, 150). Similarly, tumors with metastatic spread have repeatedly been shown to have increased tissue-specific lactate content in the tumor compared with a series of tumors of the same type but without metastatic spread (Fig. 3 [20, 226–228]).

FIG. 3.

Differences between lactate content in tumors with and without metastatic spread. Source data were retrieved from (20, 226 –228).

The mechanisms include remodeling of the extracellular matrix (67), angiogenesis stimulation by vascular endothelial growth factor release (240), suppression of T cell activity, and induction of macrophage phenotypic switch toward the M2 phenotype (26, 132, 166). In response to the acidic environment within the tumor, infiltrating T cells suppress interferon-γ translation and can be activated by simply increasing the extracellular pH (166). Cancer cells stressed by acidic environments may adapt by increasing genomic instability (89) and epigenetic changes (123).

The difficulty of treating tissue-specific lactic acidosis can be illustrated by the fact that the increase in systemic lactate is not projected within hours in the interstitial fluid (Fig. 4) (205). Therefore, the organism is capable of compensating for large-scale systemic changes in lactate, and these changes minimally affect tissue-specific lactate levels.

FIG. 4.

Lactate monitoring in Sprague–Dawley rats using subcutaneous dorsally implanted needle electrodes. Intravenous Na lactate was administered via the tail vein. The curves represent blood lactate and continuously monitored tissue lactate. The shading represents the period of i.v. lactate infusion. Reprinted from Spehar-Délèze et al. (205).

Treatment of Solid Cancer-Associated Systemic Lactic Acidosis

The treatment of lactic acidosis associated with solid tumors often consists of intravenous sodium bicarbonate (NaHCO₃). However, the effect of sodium bicarbonate treatment on the survival of patients with solid tumors (neuroendocrine tumors excluded) is negligible. In total, PubMed-indexed papers (Supplementary Table S1) reported 29 patients with solid tumors (neuroendocrine tumors excluded) who were treated with sodium bicarbonate. Seven of these patients (24%) survived over 2 months after lactic acidosis onset. In contrast, according to the same papers, 21 patients with the same diagnosis were not treated with sodium bicarbonate; of these, two patients (10%) survived over 2 months after lactic acidosis onset. Therefore, the difference was too small to provide evidence-based support for the prosurvival effects of sodium bicarbonate treatment of patients with solid tumors of other than neuroendocrine origin; the odds ratio was 0.39 (95% CI: 0.07–2.09, z = 1.092, p > 0.05).

This finding corresponds to the fact that treatment with sodium bicarbonate is considered controversial since it may induce CO₂ accumulation in tissues and thus further promote acidosis and worsen treatment outcomes (120). In addition, lactate production itself can be stimulated by sodium bicarbonate therapy (76), which corresponds to the results from experimental animals with phenformin-induced lactic acidosis that were treated with bicarbonate. In this model, blood lactate increased, liver and erythrocyte pH declined, and mortality did not change (7).

The administration of bicarbonate represents the most common form of direct neutralization of lactic acidosis. Although sodium bicarbonate administration has limited prosurvival effects when treating systemic lactic acidosis, the results are more promising when targeting tumor pH and metastasis formation. In experimental studies in animal models, orally administered sodium bicarbonate effectively suppressed tumor metastatic activity and increased tumor pH, whereas it did not affect systemic pH (142, 143, 170, 182, 199).

Consistent with the earlier findings, orally administered alkaline solution Basenpulver (Pascoe, Germany), which is a mixture of sodium bicarbonate and carbonate salts, controlled melanoma growth in a mouse model (10). This effect is likely mediated by pH neutralization and is not connected to lactate itself, as it can be achieved by buffers lacking sodium bicarbonate (109, 176). Of high clinical interest are, however, the effects of pH neutralization on metastasis formation, as invasion and metastasis account for greater than 90% of cancer-associated mortality. Classical migrastatics usually target actin polymerization and contractility (80). However, in this case, pH neutralization likely plays a role. In addition to the examples mentioned earlier, the administration of neutralization buffers did not affect the already established primary tumor but both prevented cancer onset (108) and completely inhibited metastasis formation (9, 111). Therefore, a similar extent of metastasis rate reduction can be achieved not only with bicarbonate but also with buffers based on tris(hydroxyethyl)aminomethane (TRIS, pK_a = 7.8) or 2-imidazole-1-yl-3-ethoxycarbonylpropionic acid (IEPA, pK_a = 6.9) (107, 109). Conflicting results have arisen from a study on local bicarbonate infusion in patients with advanced hepatocarcinoma, which revealed effects on the tumor but no inhibition of extrahepatic metastases (31).

In addition to bicarbonate, other buffers targeting tissue and/or systemic acidity have been developed and include, for example, urease or HCl absorbers. An example of the treatment that employs urease consisting of the immunoconjugate of jack bean urease targeted to CEACAM6 has been developed and is marketed as L-DOS47 (218). This drug acts by converting endogenous urea to two ammonium ions and one bicarbonate anion (59, 172). In contrast to sodium bicarbonate therapy, the phase I/II dose escalation study of L-DOS47 revealed that the cancer patients tolerated its administration to a sufficient extent (59, 172). The best example of the second of the abovementioned active compounds, HCl absorbers, is the drug veverimer (TRC101). In its primary application, veverimer is administered orally to treat metabolic acidosis by binding HCl in the gastrointestinal tract. It increases systemic bicarbonate in patients with chronic kidney disease who manifest metabolic acidosis and successfully passed a phase III study in these patients (25, 232, 233). However, data on veverimer are still lacking from patients with cancer and/or diabetes.

Another alternative to sodium bicarbonate treatment involves the use of dichloroacetate, which indirectly activates pyruvate dehydrogenase and therefore depletes cellular pyruvate levels. Consequently, dichloroacetate decreases the amount of pyruvate available for lactate production. Mechanistically, dichloroacetate inhibits mitochondrial pyruvate dehydrogenase kinase, thereby maintaining this enzyme unphosphorylated and catalytically active. Despite promising preclinical results (159) and the use of dichloroacetate to treat congenital mitochondrial disorders in small children (1), the dichloroacetate treatment of patients admitted to critical care units with lactic acidosis did not improve their survival (208). Several clinical trials have targeted the use of dichloroacetate in cancer. Although the phase II trial of dichloroacetate in patients with previously treated advanced non-small-cell lung cancer and breast cancer was preliminarily terminated (82), several trials appeared later with more promising results. In a phase I study of patients with recurrent malignant brain tumors, there were no dose-limiting toxicities, and the compound was well tolerated (64). In a phase II study of patients with multiple myeloma, dichloroacetate concentrations, tolerability, and disease outcomes were correlated with individual glutathione S-transferase ζ 1 (GSTZ1) genotypes (219).

Perhaps closer to practical use could be the employment of dichloroacetate as a radiosensitizer, as recently reported in high-grade gliomas (42). Moreover, it is necessary to keep in mind that dichloroacetate is metabolized differently by adults and children. Age-dependent differences in dichloroacetate metabolism and elimination cause its lower toxicity in children (197).

Previous proposals for the treatment of cancer-associated systemic lactic acidosis include the reduction of tumor burden (99), hemodialysis (77, 169), or thiamine supplementation (214). The suggestion for thiamine supplementation stems from the fact that thiamine deficiency is an uncommon but well-documented cause of hyperlactatemia in beriberi disease (124, 201). Among the patients with solid tumors listed in Supplementary Table S1, six were treated with thiamine. Two died within a week, two survived up to 10 weeks, and the other two survived over 10 weeks after lactic acidosis onset. Therefore, there is insufficient evidence of the benefits of thiamine supplementation to resolve fatalities in patients with cancer-associated systemic lactic acidosis.

Several compounds known as glycolytic agents stimulate the shift of cancer cells from aerobic glycolysis to oxidative phosphorylation. Melatonin, the hormone responsible for the synchronization of circadian rhythms, also functions as an inhibitor of aerobic glycolysis in cancer cells. The mechanism involves the downregulation of pyruvate dehydrogenase kinase. Melatonin suppresses the proliferative activity of cancer cells, stimulates apoptosis, and has migrastatic activity. Under a standard light:dark cycle, lactate levels are subject to circadian fluctuations.

Due to the effects of melatonin on pyruvate dehydrogenase kinase, irregularities in circadian rhythms cause constitutive elevation of lactate levels (14, 174) (Fig. 5). The effects of melatonin on lactic acidosis and its reactive oxygen species (ROS) scavenging function could contribute to the effects of melatonin treatment of patients who undergo chemotherapy with tamoxifen or doxorubicin (50, 238).

FIG. 5.

Lactate release dependence on circadian rhythms. The tumor-bearing rats were exposed to a standard light:dark cycle (control; alternating white and black bars at the bottom) or dim LAN (alternating white and gray bars at the bottom). The two groups of rats differed in plasma melatonin rhythms (a), glucose uptake rhythms (b), estimated tumor weight (c), and lactate release rhythms (d). In the control group, the highest levels of glucose uptake and lactate release occurred during the day. In the LAN group, both glucose uptake and lactate release remained elevated throughout both the light and dark periods, which likely indicates that the tumors were using cytosolic glucose oxidation to produce ATP. Reprinted from Blask et al. (14). Asterisks indicate significant differences as revealed by Student`s t-test at p < 0.01 (*) and p < 0.05 (**). LAN, light at night.

Use of Tissue Lactic Acidosis for Ion Trapping

Under physiological conditions, the extracellular interstitial pH is ∼7.3, and the intracellular pH of the cellular cytoplasm is ∼7.2. When acidosis is induced locally, the pH can be reduced to 6.7 in the interstitial fluid, whereas it remains at 7.0–7.1 in the cytoplasm in vivo (236) (Fig. 6 for experimentally induced acidosis of the cell growth medium [164, 204]). Therefore, the pH gradient is reversed from −0.1 to +0.3–0.4. Importantly, some chemotherapeutics are attracted by the less acidic pH of the cells in acidic environments. The mechanism consists of the entrapment of a nonionized membrane-permeable form of the compound, which is then converted intracellularly to a charged compound that cannot cross biological membranes.

FIG. 6.

Changes in intracellular pH in response to changes in extracellular pH. In the cholangiocarcinoma SKC cell line, the intracellular pH (measured using BCECF dye) remained at ∼7.4 when the medium pH was in the range of 7.0–7.4 but started to decrease when the medium pH was less than 7.0. For example, when the pH of the medium was 6.0, the intracellular pH was 6.7. The data are shown as the measured data points (closed circles) combined with the model for different cell radii. Equilibrium was reached at ΔpHi/Δt<10⁻⁵; the volume of the environment was set at V = 10¹² μm³ = 1 mL. Reprinted from Piasentin et al. (164). BCECF, 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein.

This phenomenon leads to the exclusion of weak base chemotherapeutics from more alkaline environments and the sequestration of weak acids (236). The majority of anticancer compounds fulfill the earlier criteria and have ionizable species under physiological conditions; importantly, these include many commonly used chemotherapeutic agents (Table 1). When tumor acidity is targeted in parallel to the standard treatment regimen, the therapeutic efficacy of chemotherapeutics that are subject to ion trapping may substantially change. Typically, weakly basic compounds enhance their efficacy with a buffer-induced increase in tumor pH, whereas weakly acidic compounds display decreased activity (87, 142, 170, 222).

Table 1.

Examples of Chemotherapeutic Agents That Are Subject to Ion Trapping

Group (effect)	Compound
Weak bases (decreased uptake)	Ifosfamide/Cyclophosphamide Erlotinib/Lapatinib/Gefitinib Tamoxifen
Weak acids (increased uptake)	Fluorouacil Capcitabine Pemetrexed
Complex ionization (decreased uptake)	Doxorubicin/Daunorubicin Imatinib Melphelan
Complex ionization (increased uptake)	Gemcitabine Irinotecan Sunitinib

The groups of compounds that are sorted according to their dissociation in aqueous solutions are indicated. The effect (shown in brackets) denotes the effects of the higher acidity of the tumor environment. Note that the therapy designed to neutralize tumor acidity would completely reverse these effects. Adapted from Gillies et al. (88).

Use of Tissue Lactic Acidosis for Compound Activation

Several groups of compounds are activated only in acidic environments, that is, typically in the localized areas of tumor-induced lactic acidosis. These include nanoparticles that release their cargo in acidic environments, proton pump inhibitors, and carbonic anhydrase IX inhibitors.

A pH gradient can be employed to deliver cargo to compartments with different pH values. The main approaches used for cargo delivery in the pH gradient consist of pH-sensitive micelles, acid-based linkers, pHLIP (pH-low insertion peptides) MMAE (monomethyl auristatin E) conjugates, and AuNS-pHLIP-Ce6 particles (where AuNS stay for gold nanoshells and Ce6 stays for chlorin e6). Regarding the micelles, pH-responsive amphiphilic micelles were reported to deliver curcumin selectively to acidic environments, where the acid-triggered hydrolysis of the acetal group to two hydroxyl groups increases the hydrophilicity of the micelle core and causes swelling of the micelles accompanied by cargo release (249).

Other functional pH-responsive nanoparticles were designed to encapsulate doxorubicin into poly-L-histidine-based polymeric micelles that are destabilized in an acidic cancer cell environment (57, 118). Another example is the pH-sensitive conjugates of doxorubicin with methacrylamide copolymers (37). As a last example, nanoparticles of polyethylene glycol-conjugated doxorubicin that also encapsulated curcumin are stable at neutral pH but release both doxorubicin and curcumin in an acidic environment (248). Regarding acid-based linkers (e.g., hydrazine), examples include the conjugation of trastuzumab via acid-cleavable thiomaleamic acid (29). Regarding the pHLIP-MMAE conjugates and the AuNS-pHLIP-cargo particles, these were extensively reviewed (e.g., 116, 178). pHLIPs are 35- to 37-amino acid peptides that can facilitate the internalization of nanomaterials at low pH; when conjugated to the microtubule inhibitor MMAE, they show potent anticancer activity in vivo (22). The AuNS have a core-shell structure consisting of a silica core surrounded by a thin gold shell and are then conjugated to pHLIP and a cargo, such as the Ce6 photosensitizer. Although pHLIP is responsible for the delivery of the cargo into the cell, laser irradiation is used to unload and dequench from AuNS. This reaction uses the photothermal effect of AuNS and leads to enhanced photodynamic ablation of target cancer cells (244). pH-mediated intracellular cargo delivery has been subject to rapid development in recent years and is definitively of use in multiple future clinical applications. However, this topic exceeds the scope of this review.

Proton pump inhibitors (omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole) are tetracyclic sulfonamides that are activated by protonation to become sulfhydryl reagents (165). Clinically relevant support for the use of proton pump inhibitors in cancer therapy stems from the meta-analysis of treatment outcomes of 596 patients with previously untreated head and neck squamous cell carcinoma (158). This study revealed the beneficial effects of proton pump inhibitors and histamine receptor-2 antagonists alone and the potentiation of their effects when used in combination. Similarly, the combination of proton pump inhibitor (esomeprazole) pretreatment with neoadjuvant chemotherapy potentiated the effects of chemotherapy in patients with resected osteosarcomas, particularly in the chondroblastic variant of the disease (74). Further, in patients with breast cancer, patients treated with cisplatin and paclitaxel benefited from proton pump inhibitor (esomeprazole) administration before therapy and during the year after therapy. The time to progression and overall survival increased, particularly in triple-negative patients (230). The beneficial effects of a proton pump inhibitor were also demonstrated in chemotherapy-treated patients with refractory gastrointestinal cancer (68). The mechanism of the anticancer action of proton pump inhibitors is only partially understood. In addition to anti-acidic effects at the gastric level, they may affect the ATPases expressed by the cancer cells (209, 242), and they also affect signaling through dopamine and serotonin receptors (28). An observational case–control study suggested that prior use of proton pump inhibitors was less common in breast cancer patients than in matched controls, and this relationship was dose dependent (33). The advantage of proton pump inhibitors is in their well-known safety profiles; in nongastroenterological cancers, they display both preventive effects and the ability to potentiate the effects of chemotherapy.

Mitochondrial carbonic anhydrases are involved not only in tumorigenesis but also in de novo lipogenesis and are considered promising antiobesity drugs, thereby representing another as-yet little explored link between the treatment of systemic metabolic diseases and cancer (194). Carbonic anhydrases IX and XII (CA9 and CA12) are exofacial enzymes that contribute to extracellular acidosis and are negative prognostic markers that are associated with invasion and metastasis (51). CA9 and CA12 are sensitive to oxygen levels and were reported to be in an active conformation in hypoxic tumors but in a closed inactive conformation in well-oxygenated tissues (62). CA inhibitors typically contain a sulfonamide, coumarin, or sulfocoumarin group that targets the active site (130). When targeting exofacial anhydrases, such as CA9 and CA12, strongly hydrophilic or halogenated groups are usually attached to the respective sulfonamides to prevent internalization (113). Selective CA9 and CA12 sulfonamide-based inhibitors often bind to only CA9 and CA12 at the surface of hypoxic cells (and reverse tumor acidification) but avoid binding to normoxic cells in less acidic environments (212). A phase I clinical trial of sulfonamide SLC-0111 (U-104), which involved 17 patients with 10 solid cancer types at untreatable stages, revealed stable disease in two of these 17 patients, including one with sarcoma of the spine and another with colorectal cancer (148). The future of CA inhibitors involves the potentiation of the action of currently used drugs.

Cells growing in acidic medium can be selectively targeted with devimistat (CPI-613) alone or in combination with tetracycline, but these effects are lactate independent (126). Devimistat is an inhibitor of the pyruvate dehydrogenase complex and α-ketoglutarate dehydrogenase complex. Tetracycline, an antibacterial antibiotic, serves as an inhibitor of mitochondrial proteosynthesis that disturbs mitochondrial proteostasis and metabolic activity and induces changes in gene expression (32). A phase III open-label trial of devimistat in combination with cytarabine and mitoxantrone in patients with relapsed acute myeloid leukemia was terminated due to lack of efficacy (NCT03504410; ARMADA 2000).

Another phase III open-label trial of devimistat in combination with modified folfirinox in patients with metastatic adenocarcinoma of the pancreas failed to meet the primary end point of overall survival (NCT03504423; AVENGER 500) (185). Further research should identify the conditions that limit devimistat action in vivo.

Treatment of Solid Cancer-Associated Tissue-Specific Lactic Acidosis

Tissue-specific lactate levels can be affected by targeting lactate dehydrogenase (LDH). LDH catalyzes the conversion of pyruvate to lactate, and its increased expression was observed, for example, in a series of head and neck cancers and in cancers of the gastrointestinal tract (184). The suppression of LDH led to an increase in ROS production and to apoptosis of the cancer cells in vitro (133). Consistent with these observations, LDHA inactivation led to a decrease in carcinogenesis and cancer progression in mouse cancer models (239). It seems that the simultaneous inhibition of LDHA and LDHB works better than the suppression of LDHA alone (220, 245).

Multiple LDH inhibitors are available, but most of them suffer from low potency and high off-target effects. When oxamate, a specific LDH inhibitor, was applied, paclitaxel-resistant breast cancer cells exhibited increased sensitivity to the applied chemotherapy (250). However, oxamate is used in the millimolar range and therefore has never entered clinical trials (144, 220). LDH can also be inhibited by quinolone-3-sulfonamides, which have anticancer activity but suffer from poor bioavailability (13, 239). Similarly, the LDH inhibitors 2-amino-5-aryl pyrazine and 2-thio-6-oxo-1,6-dihydropyrimidine work well against the pure enzyme but have only limited activity in cancer cells (60, 71). More promising is the LDH inhibitor GNE-140, which inhibits the pancreatic cancer cell line MIA PaCa-2, colorectal cancer cell line LS174T, and mouse melanoma cell line B16-F10 in vitro and has IC₅₀ values of 3 and 5 nM for LDHA and LDHB, respectively (17, 245). Other LDH inhibitors, including galloflavin (70, 145), FX11 (133), pyrazole (171), and N-hydroxyindole-2-carboxylate (134), also decreased cancer cell proliferation, but none of these agents were used under clinical settings. 1,4-Triazole-containing compounds display potent inhibitory activity against LDH but were not tested in cells (3). The saffron derivative crocetin (91) and the flavonoid oroxylin A (231) also affect LDH activity, but they affect a much broader scale of proteins. In addition, gossypol (AT-101) decreases LDH levels, but it is not selective, as it blocks NADH binding not only to LDH but also to other NADH-dependent enzymes (56). Among clinically approved drugs, the antiepileptic drug stiripentol (187) and the nonsteroidal anti-inflammatory drugs diclofenac and lumiracoxib (21) show LDH inhibitory properties. Representative cancer drugs that target metabolic pathways, including LDH, are provided in Table 2.

Table 2.

Representative Anticancer Drugs That Target Glycolysis, Mitochondrial Metabolism, Lipid Synthesis, and Nucleic Acid Synthesis

Target	Drug	Development stage
GLUT1	WZB117, BAY-876	Preclinical
Hexokinases	2-deoxyglucose	Phase II (results unpublished, not registered at clinicaltrials.gov; another phase II study, NCT00633087, preliminarily terminated)
Pyruvate kinase M2 (PKM2)	TEPP-46	Preclinical
LDHA	Quinoline, 3-sulfonamides, FX11, PSTMB	Preclinical
MCT1	AZD3965	Phase I (NCT01791595)
Pyruvate dehydrogenase (PDH) & α-ketoglutarate dehydrogenase	CPI-613	Phase III (NCT03504423 active; NCT03504410 terminated)
Electron transport chain complex I	Metformin	Phase III (several active studies, e.g., NCT01697566)
	IACS-010759	Phase I (NCT03291938 completed)
Mutant isocitrate dehydrogenase 1 (IDH1)	AG-120, BAY1436032, LY3410738, FT-2102	Phase III (NCT02989857 completed)
	BAY1436032	Phase I (NCT03127735 completed)
	LY3410738	Phase I (NCT04603001 and NCT05205447 completed)
	FT-2102	Phase I/II (NCT03684811 active)
Mutant isocitrate dehydrogenase 2 (IDH2)	AG-221	Phase III (NCT02577406 active)
Thymidylate synthase (TS)	5-fluorouracil, capecitabine, pemetrexed, raltitrexed	Clinically approved
Dihydrofolate reductase (DHFR)	Methotrexate, pemetrexed	Clinically approved
Glycinamide ribonucleotide formyltransferase (GARFT)	Pemetrexed	Clinically approved
Dihydroorotate dehydrogenase (DHORD)	Brequinar	Phase I/II (NCT03760666 completed)
	Leflunomide	Phase III (NCT00004071 and NCT00003293 completed)
Ribonucleotide reductase (RNR)	Gemcitabine, clofarabine, fludarabine, cladribine, cytarabine	Clinically approved
T-phosphoribosyl-1-pyro-phosphatase (PRPP) amidotransferase	Mercaptopurine, thioguanine	Clinically approved
AcetylCoA carboxylase (ACC)	NDI-010976 (ND-630, GS-0976, or firsocostat)	Phase II for NASH (NCT03449446 and NCT02856555 completed)
	MK4074	Phase I (NCT01431521 completed)
Choline kinase	TCD-717 (RSM932A)	Phase I (NCT01215864 completed)
	MN58b	Preclinical
Fatty acid synthase (FASN)	TVB-2640	Phase II (NCT03032484 active)
	TVB-3664	Preclinical
HMG-CoA reductase	Simvastatin	Phase III (NCT01099085 completed)
CPT1	Etomoxir	Clinically approved
	Perhexiline	Preclinical

Adapted from Schmidt et al. (193), updated. The data on the status of clinical studies as published at clinicaltrials.gov as of January 30, 2022.

Tissue-specific lactate levels can also be affected by targeting monocarboxylate transporters (MCT)1 (SLC16A1) and MCT4. MCT1 was proposed as a therapeutic target that is responsible for enhanced lactate transport during metastasis formation. The evidence was derived from patient-derived xenotransplant models of metastatic melanoma. Recently, melanoma patient-derived xenotransplant models were stratified based on their efficiency of metastasis formation and analyzed by in vivo metabolomics to determine how they exploit isotopically labeled nutrients (216). The study found heterogeneity in MCT1 expression within efficiently metastasizing xenotransplants, which could explain why only some of the circulating tumor cells can give rise to metastasis, whereas other cells are unable to induce metastasis (216).

MCT1 inhibitors with anticancer activity in vitro and in vivo include α-cyano-4-hydroxycinnamic acid analogs (27) and 7-aminocarboxycoumarine derivatives (61). Another MCT1 inhibitor, AZD3965, has potent anticancer properties in small cell lung cancer cell lines and their xenografts (167). The outcomes of the AZD3965 phase I clinical trial were reported at the most recent ASCO meeting. AZD3965 can be safely administered at 10 mg twice a day, but monotherapy led to complete response in only one patient and stable disease in another patient out of a total of six examined patients (96).

MCT1 facilitates lactate uptake, whereas MCT4 (SLC16A3) is responsible for the efflux of lactate along with a proton, thereby inducing extracellular acidification of the cancer microenvironment (131). Increased MCT4 expression and its translocation to the cell membrane promote lactate efflux to maintain the intracellular pH and cause extracellular acidification (79). MCT4 renders cancer cells resistant to treatment with 5-fluorouracil in multiple colorectal and gastric cancer cell lines (121).

The MCT4 inhibitors include bindarit (78) and diclofenac (which was already mentioned earlier given its anti-LDH activity) (190). Simultaneous inhibition of MCT4 and MCT1 was reported for AZ93 (146), syrosingopine (12), and the clinically approved indazole lonidamine (154).

Lactate-sensing receptor G-protein coupled receptor 81 (GPR81, also called hydroxycarboxylic acid receptor 1 [HCAR-1]) is expressed by some populations of cancer cells and immune cells. When GPR81 expression was suppressed in cancer cells, the cells expressed less PD-L1 (73), exhibited decreased proliferation and metastatic activity, and prevented lactate-induced expression of lactate metabolism genes (183). GPR81 activation also promoted chemoresistance (224). A putative GPR81 antagonist, 3-hydroxybutyrate, was reported (196), but GPR81 inhibition needs to be explored in more detail in the future.

Other less explored treatment options consist of the inhibition of proton transport through the plasma membrane. The best examples include inhibitors of the Na⁺/H⁺ exchanger (see also the chapter on the Use of tissue lactic acidosis for compound activation). For example, omeprazole reduced the expression of MMP-9 and invasiveness of the tumor and reduced the formation of lung metastases after i.v. injection of pretreated cancer cells (117).

In addition, the molecular pathways that are activated by low pH are considered therapeutic targets. For example, the inhibition of Ca²⁺- or proton-activated TRPM5 channels by acidic pH decreased MMP-9 expression and reduced metastatic potential in an in vivo melanoma model (140). In addition, the blockade of the pH-dependent voltage-gated sodium channel Na_v1.5 by phenytoin has inhibitory effects on the migration and invasion of cancer cells (241).

Hypoxia-inducible factor 1α (HIF1α) is a member of the heterodimeric transcription factor complex. Its α subunit is degraded in the presence of oxygen, whereas the β subunit (HIF1β) is stable. In the presence of hypoxia, HIFs are stabilized and promote the expression of pyruvate dehydrogenase and genes that are responsible for the transport and phosphorylation of glucose. Pyruvate dehydrogenase inhibits pyruvate oxidation and shunts glucose metabolism toward lactate as an adaptation to hypoxic conditions (122). For an overview of HIF1α inhibitors, please refer to other reviews (e.g., 136).

Hyperlactemia and Acidity in Diabetes

Many patients with cancer manifest type 2 diabetes as a comorbidity. Diabetes is well known as a factor that contributes to cancer onset and progression, but it appears unclear as to whether the diabetes-associated increase in hyperlactemia could play a pathogenic role in cancer onset and progression. Patients with type 1 and type 2 diabetes mellitus have lactate levels that are 0.3–1.0 mM higher than those of individuals without diabetes (98). Hyperlactemia is particularly prominent when diabetic ketoacidosis is manifested, particularly due to the combination of hypovolemia and altered carbohydrate metabolism. The lactate levels in diabetic ketoacidosis reach 3.5 mM (95% CI: 1.2–8.3 mM) (46). The decrease in pH of the interstitial fluid in patients with type 2 diabetes explains part of diabetes-causing insulin resistance. The insulin receptor has a lower affinity for insulin under low values of interstitial fluid pH (101). In contrast, the effects of diabetes on acidity are much better understood. Type 2 diabetes manifests as mitochondrial dysfunction, which affects the distribution of acid load. The three main mechanisms of effects on acid load consist of the overproduction of lactate due to the impaired tricarboxylic acid (TCA) cycle, increased renal acid load and net endogenous acid production due to intake of high amounts of protein (175), and production of ketone bodies that are consumed in muscle and brain tissues for ATP synthesis (90).

Effects of Acidosis on Cancer Cells

Cancer cells display multiple metabolic adaptations to growth in acidic environments. At the genomic level, acidosis contributes to genomic instability, particularly chromosome breaks and translocations (151). Acidosis is also commonly associated with the switch from glucose addiction (common in cells in tissue culture) to respiration fueled by glutamine or beta oxidation of fatty acids (44); the hexokinases that catalyze the first reaction of glycolysis substantially decrease their activity at acidic pH (200). Stronger oxidative flux leads to higher levels of ROS (44) and high levels of acetyl-CoA nonenzymatically acetylate respiratory complex I, which inhibits beta oxidation (247). Sirtuin-mediated histone deacetylation, which inhibits ACC2, thereby reversing fatty acid synthase inhibition and promoting fatty acid synthesis in parallel with beta oxidation, is common (55). Further research should also explore the function of rapid and reversible induction of adiposomes in response to acidosis (55).

The cells that face acidosis increase lysosomogenesis and redistribute lysosomes from a perinuclear space to the plasma membrane, where they can release their contents, including proteases and protons, to the extracellular space. The redistribution of lysosomes prevents lysosome-associated membrane protein 2 from acid hydrolysis (48), induces autophagy (235), and separates the mammalian target of rapamycin complex from the Ras homolog enriched in the brain and other parts of its regulatory complex (229). The secretion of protons to the surrounding stroma is characteristic of invading tumors (67, 84) and could, therefore, stimulate tumor invasion by the activation of proteases, including lysosome-released cathepsins. Moreover, invadopodia and the invading edge of the tumor, in general, contain proton-exporting proteins, such as NHE1 or NBCn1 coupled to CA9 (15, 24). In response to acidosis, cancer cells also release increased amounts of extracellular vesicles (161). The NHE1 inhibitor cariporide is currently in preclinical use to treat cancer (97) and has passed phase I-III trials for other diagnoses (149).

Acidosis-exposed cells need to reprogram their metabolic pathways. Glyceraldehyde phosphate dehydrogenase (GAPDH) and glucose-6-phosphate dehydrogenase (G6PDH) are enzymes that are crucial for survival at low pH (163). As a rate-limiting glycolysis enzyme, GAPDH can be targeted by a number of inhibitors, such as arsenate, arsenic trioxide, 3-brompyruvate, iodoacetate, koningic acid, and other compounds (165). G6PDH is a rate-limiting enzyme allowing the entry of glucose-6-phosphate into the PPP pathway. G6PDH can be inhibited by the natural glucoside polydatin (resveratrol precursor), which is well tolerated and has already succeeded in a phase II clinical trial for the treatment of nonneoplastic pathologies (47).

Lactate derived from tumors potently induces arginase-1 (ARG1) in tumor-associated macrophages by means of ERK, STAT3, and HIF-1α stabilization. This mechanism serves as a feedback loop, as the pseudohypoxic activation of HIF-1α in tumor-associated macrophages stimulates angiogenesis and thus supports tumor growth (41). Arginase also stimulates cell growth by the accumulation of polyamines (which could be reversed by N-hydroxyarginine). Typically, ARG1 induction is associated with the differentiation of tumor-associated macrophages into the M2 phenotype, which promotes not only tumor angiogenesis but also the immune tolerance of cancer cells.

Cancer cells that have already adapted to acidic environments are more sensitive to oxidative damage induced by various agents, including hydrogen peroxide, high-dose ascorbate, and photodynamic therapy. However, when high lactate concentrations are present, this sensitization is abrogated. Acidosis itself prevents antioxidant capacity by decreasing the NADPH supply derived from glucose metabolism. The addition of lactate restores NADPH production in the TCA cycle and, therefore, restores the cellular redox balance. In the absence of glucose, cells growing in acidic environments are more sensitive to hydrogen peroxide challenge; this effect can be rescued by the addition of lactate (126).

High rates of glycolysis and high levels of lactate contribute to radioresistance in many tumor types. This relationship functions as a positive feedback loop, as radiation itself promotes lactate production (243). Radioresistance linked to lactate metabolism has been linked to LDH, MCT1, MCT4, and MPC, as shown in a number of preclinical studies and several clinical studies (Table 3). The mechanisms are unclear and are possibly related to the decrease in ROS levels (103). To date, gossypol (AT-101) is the only lactate metabolism drug that entered phase I/II trials for its radiosensitizing effects. However, the phase I/II trial NCT00561197 was terminated. The trial NCT00390403, which was only a phase I trial, was completed in 2009, but the results have never been published.

Table 3.

Studies That Have Exploited Lactate Metabolism to Improve Cancer Radiotherapy Outcomes

Target	Inhibitor	Model	Result	Reference
LDH	Oxamate	In vitro—glioblastoma cell lines U87MG and T98G	RD₅₀ decreased	(127)
	Oxamate	In vitro & in vivo—nasopharyngeal carcinoma cell lines CNE-1 and CNE-2	Apoptosis increased, inhibition of clonogenic survival increased, and tumor growth decreased in vivo	(246)
	GSK2837808A	In vivo—pancreatic ductal adenocarcinoma Panc-02, orthotopic	Tumor growth and myeloid-derived suppressor cell activation decreased, and CD8⁺ T cells increased in the tumor	(243)
	Gossypol (AT-101)	Phase I/II study (with docetaxel and 5-fluorouracil)	Terminated	NCT00561197
	Gossypol (AT-101)	Phase I study (with temozolomide)	Completed in 2009, results not reported	NCT00390403
MCT	AR-C122982, AR-C155858, simvastatin, 2-cyano-3-(4-hydroxyphenyl)-2-propenoic acid (CHC)	In vitro—oral squamous cell carcinoma cell line CAL27	Cell proliferation decreased	(18)
	AZD3965	In vitro & in vivo—small cell lung cancer cell line H526, s.c. xenotransplants	Intracellular lactate increased, tumor growth decreased, and survival improved	(16)
MPC	7-aminocarboxycoumarin 2 (7ACC2), UK-5099	In vivo—cervical cancer cell line SiHa, s.c. xenotransplants	Tumor growth decreased	(43)

Adapted from Liu et al. (137).

Lactate derived from tumors was hypothesized to undergird the existence of tumors that are responsive and nonresponsive to uprosertib (GSK2141795), an ATP-competitive pan-Akt inhibitor. Uprosertib has already been assessed in phase II clinical trials (63), but disease regression was observed only in a small subset of patients (2). Uprosertib treatment led to reduced glucose uptake (93). Its action was independent of the presence of lactate, but the inhibition of lactate transport potentiated uprosertib-induced apoptosis. In addition, lactate acidosis conferred uprosertib resistance (11). Akt phosphorylation at Ser473 is changed in cancer cells subjected to acidosis, but additional research is needed to reach a consensus on the direction and extent of changes in Ser473 phosphorylation.

Lactic Acidosis Caused by Anticancer Drugs

Metformin, which has been used as an antidiabetic drug since the 1950s, suppresses cancer progression, improves the survival of patients with cancer (168), and may contribute to cancer prevention (102). Metformin enhances the cytotoxicity of some anticancer compounds (34, 114) but impairs the cytotoxic effects of some chemotherapeutics, such as doxorubicin, by decreasing extracellular pH, which is mediated by MCT4 membrane translocation (202). Metformin also adversely affects the binding kinetics of paclitaxel to tubulin, which is mediated by metformin-induced depletion of intracellular pH (202). Thus, although paclitaxel uptake is not affected by pH changes, its action is affected by changes in intracellular pH, ion concentration, or cellular ATP levels (179). When metformin-pretreated cells were treated with phloretin (dietary MCT inhibitor) or sodium bicarbonate, sensitivity to chemotherapeutics was restored (202). One of the key effects of metformin consists of the inhibition of respiratory complex I activity, which leads to enhanced glycolysis and a subsequent increase in lactate production. Inhibition of GPR81 by its putative antagonist, 3-hydroxybutyrate (to prevent lactate), facilitates the anticancer effects of metformin and contributes to the activation of CD8⁺ T cells (35).

Other biguanides, such as phenformin, have similar or even stronger effects on lactate production. Multiple events of severe lactic acidosis in patients with diabetes were behind the withdrawal of phenformin from the U.S. market in 1977 and the delay of approval of metformin until 1995. In contrast to phenformin, lactic acidosis associated with therapeutic doses of metformin is much less frequent, and some authors concluded that the observed association could be coincidental (189) and that lactate levels are similar among patients with type 2 diabetes regardless of the use of metformin therapy (54).

In addition to metformin, a number of different drugs have been reported as putative causative agents of elevated lactate levels. As summarized by Smith et al. (203), there are a number of drugs that rarely but repeatedly induce hyperlactatemia or lactic acidosis. These include propofol, an anesthetic commonly used in cancer surgery (36), and oxaliplatin, a classical anticancer drug (53). Incidental cases of elevated lactate were also reported for the chronic lymphocytic leukemia treatment agent fludarabine (206), the chemotherapeutics carboplatin (19), the EGFR inhibitor erlotinib (162), and the nitrosourea-based chemotherapeutic agent streptozocin (155). The putative mechanisms of these agents differ. Erlotinib causes type B1 lactic acidosis through the induction of hepatic injury. In contrast, oxaliplatin and streptozocin cause type B2 lactic acidosis and act through alterations in glucose metabolism favoring the accumulation of lactate relative to pyruvate. Other type B2 lactic acidosis-causing agents include carboplatin, which mediates the inhibition of mitochondrial protein synthesis and function, and propofol, which causes the inhibition of the mitochondrial electron transport chain (203).

Research Gaps

Previous research has addressed pH gradients in the serum, interstitial fluid, and cytoplasm. However, whether changes in nuclear pH play a role has not been assessed. Under physiological conditions, the nucleus has a slightly more alkaline pH than the cytoplasm, and various studies agree on the range of 7.55–7.88 (39, 147, 195). The activity of transcription factors, the DNA replication apparatus, and DNA-dependent protein kinases that are responsible for nonhomologous end joining repair are pH sensitive (106, 223), and many pH-sensitive chemotherapeutics act in the nucleus. Therefore, it remains to be tested whether changes in nuclear pH affect chemotherapy outcomes and whether the nuclear pH of cancer cells differs from the nuclear pH of nontransformed cells.

Another pH-dependent process, which is minimally understood in the context of cancer-associated lactate acidosis, is O-glycosylation in the Golgi apparatus. Glycosylation is pH sensitive (141, 181), and the more alkaline Golgi pH in cancer cells compared with nontransformed cells (180, 181) could explain the repeatedly reported pH-dependent glycosylation changes in cancer cells (95, 129). Altered glycosylation promotes carcinogenesis and metastasis (95), but the effects of lactic acidosis and its treatments on O-glycosylation in cancer cells remain poorly understood.

The next questions stem from the fact that cells, including cancer cells, respond differently to acidosis in the presence and absence of lactate in vitro. It is more difficult for cancer cells to survive in an acidic medium in the absence of lactate, particularly because the pentose phosphate pathway is blocked by the absence of lactate (81). Relevant metabolomic studies from patients or at least from patient-derived xenograft models are lacking.

Many studies, including very recent studies, have based their conclusions on cancer cell lines grown in vitro under standard cell culture conditions. However, this methodology requires the cells to be grown for a long time in alkaline growth media. When such cells are switched to acidic medium, they typically slow their growth. This does not reflect the situation in vivo, where the cancer cells have already adapted to acidic conditions or even contribute to their maintenance (165). Therefore, any reports on growth inhibition by acidic conditions in vitro must be taken with extreme caution.

Interestingly, one of the least understood research topics is the sources and sinks of lactate in lactic acidosis. Detailed metabolomic tracing studies are lacking. However, the first data are available from healthy animals under various conditions and for several cancer types. In mice on a carbohydrate diet that were fasted for 8 h, circulating glucose was made from lactate, alanine, and glycerol in an approximately equal balance (Fig. 7a). Glucose serves as the dominant precursor of lactate, and lactate serves as a dominant precursor of alanine. Lactate and glucose serve equally as precursors of circulating glycerol, but glycerol is mainly synthesized from stored triglycerides. Glucose, alanine, and other amino acids serve as lactate precursors, but only glucose is the predominant direct contributor (Fig. 7b). In contrast to glucose, amino acids are first converted to circulating glucose by gluconeogenesis and then only to lactate. These metabolic relationships are only marginally unaltered in fed mice as long as we focus on the sources of lactate, alanine, and glutamine. The Cori cycle and triglyceride cycle are unaltered in the fed state. When the mice are maintained on a ketogenic diet, glycerol emerges as a direct lactate precursor, and alanine is no longer a major gluconeogenic precursor. Other primary sources of the circulating metabolites remain the same, and lactate cycling persists despite the near complete lack of dietary carbohydrates (105). Regarding lactate metabolism in cancer, acetate is used as a metabolic fuel in a number of cancer cell types, including breast cancer (119, 160) and non-small-cell lung cancer (72). However, lactate metabolism exhibits heterogeneity between and within tumors (72). Some other tumors, such as clear cell renal cell carcinomas, display a low labeled lactate to 3-phosphoglycerate ratio after [U-¹³C]glucose infusion (45), suggesting that clear cell renal cell carcinomas do not prefer lactate as their metabolic source. How lactate metabolism differs among cancer types remains to be elucidated.

FIG. 7.

Sources of circulating glucose (a) and lactate (b) in mice under 8-h fasting, standard diet, and ketogenic diet conditions. Adapted from Hui et al. (105).

Conclusions

The field's understanding of the role of lactate has shifted dramatically since its discovery. Long recognized as only a waste product, lactate was subsequently recognized as an alternative metabolic substrate and a secreted nutrient that is exchanged between the tumor and the environment. Most recently, tissue-specific lactic acidosis has been employed in a number of anticancer drug-targeting strategies. In contrast to tissue-specific lactic acidosis, systemic lactic acidosis is associated with poor prognosis; in the case of patients with solid cancer, it is associated with extremely poor prognosis.

Despite attempts at various treatments for solid cancer-associated systemic lactic acidosis, the currently most frequently used bicarbonate and thiamine therapies are inefficient, and patients usually die within days of solid cancer-associated systemic lactic acidosis onset. The only exceptions are patients with neuroendocrine tumors, particularly pheochromocytomas, in which lactic acidosis usually regresses spontaneously after tumor resection. Numerous metabolism-targeting anticancer compounds induce lactatemia, lactic acidosis, or other types of acidosis. Their potential to cause acidic environments is largely overlooked; however, these agents could explain a substantial portion of the observed clinical effects.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

The study was supported by the Charles University project Cooperatio 39.

Supplementary Material

Supplementary Table S1

Abbreviations Used

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