Disrupting proton dynamics and energy metabolism for cancer therapy

Abstract

Intense interest in the 'Warburg effect' has been revived by the discovery that hypoxia-inducible factor 1 (HIF1) reprogrammes pyruvate oxidation to lactic acid conversion; lactic acid is the end product of fermentative glycolysis. The most aggressive and invasive cancers, which are often hypoxic, rely on exacerbated glycolysis to meet the increased demand for ATP and biosynthetic precursors and also rely on robust pH-regulating systems to combat the excessive generation of lactic and carbonic acids. In this Review, we present the key pH-regulating systems and synthesize recent advances in strategies that combine the disruption of pH control with bioenergetic mechanisms. We discuss the possibility of exploiting, in rapidly growing tumours, acute cell death by 'metabolic catastrophe'.

The acidic microenvironment as a possible niche of dormant tumor cells

“…The mechanism for long-term internal pH control is represented by promotion in tumor cells of multiple and redundant families of transporters, which release protons and lactate into extracellular environment, such as: Na + /H + exchanger 1 (NHE1), HCO 3 − transporters (Na + / HCO 3 − co-transporters, NBCs and anion exchange protein 1, AE1), proton-linked monocarboxylate transporters (MCT1 and 4), and vacuolar H + -ATPases (V-ATPases) [19]. In addition, carbonic anhydrases IX (CAIX), a hypoxia-inducible effector, participates to the complex machinery responsible of internal pH control favouring export of protons and import of bicarbonate ions [19].…”

Stromal uptake and transmission of acid is a pathway for venting cancer cell-generated acid

“…This result indicates that the myofibroblast transport mechanism has a preference for HCO 3 − over OH − (Fig. 2Bi).…”

“…Indeed, dysregulated pH i has been shown to perturb or even kill cancer cells (3,4). Current models of acid handling in tumors are centered on cancer cell mechanisms, which effectively transfer acidity from cytoplasm to the surrounding milieu.…”

Intraoperative Photodynamic Surgery (iPDS) with Acridine Orange for Musculoskeletal Sarcomas

“…AO has many unique biological activities, as previously reported, such as antitumor activity, photosensitizing FIGURE 1: Chemical structure of acridine orange (AO) AO accumulates especially under acidic conditions, because it is a weak basic dye. Recently, it was reported that most of cancers have an acidic microenvironment (acidic extracellular fluid: pH 6.5-7.0) and numerous large lysosomes with strongly acidic vesicular fluid (pH 3.0-5.0) [16]. We demonstrated that high-grade malignant sarcomas have more acidic microenvironments than benign tumors and normal soft tissues [17].…”

“…We also demonstrated that AO exerts selective cytocidal effects against sarcoma cells both in vitro and in vivo after illumination with visible light or irradiation of low-dose X-rays. It is available clinically for photodynamic therapy (PDT) [16][17][18][19][20][21] or radiodynamic therapy (RDT) [22][23].…”