The regulation of pH in tumours involves the interplay of several proteins, including: the carbonic anhydrases (EC 188.8.131.52) CA2, CA9 and CA12; the vacuolar ATPase (V-ATPase); anion exchangers AE1, AE2 and AE3; Na+/HCO3− co-transporters (NBCs); electroneutral Na+-driven Cl−/HCO3− exchanger (NDCBE); the monocarboxylate transporters MCT1, MCT2, MCT3 and MCT4; and Na+/H+ exchanger 1, among others.
The concerted action of these proteins maintains a slightly alkaline intracellular pH (pHi) and an acidic extracellular pH (pHe) within the tumours, which favours the growth and spread of the primary tumour, leading to the formation of metastases.
The inhibition of one or more of these pH regulators with specific inhibitors causes both pHi and pHe values to return to normal, with the consequent impairment of tumour growth. This property represents an antitumour mechanism that is not exploited by the classical anticancer drugs.
The inhibition of CA9 and/or CA12 with sulphonamide- or coumarin-based small-molecule inhibitors reverses the effects of tumour acidification, leading to inhibition of cancer cell growth in both primary tumours and metastases. Some of these compounds are in preclinical development. This effect can also be exploited for the imaging and treatment of tumours that overexpress CA9 or CA12. The same effect has been observed with antibodies targeting CA9 (and, more recently, also CA12). Some of these antibodies (for example, cG250) are in Phase III clinical development as antitumour and diagnostic agents.
Some sulphonamides also inhibit anion exchangers, whereas proton pump inhibitors of the omeprazole type show antitumour effects by inhibiting V-ATPase, thus interfering with other tumour pH regulators.
Potent, specific and non-toxic compounds as well as antibodies that interfere with these proteins may represent valuable new antitumour drugs.
Changes in pHi towards basic values lead to the production of splice isoforms of extracellular matrix components at the tumour site, which are ideal targets for antibody-based pharmacodelivery strategies.
The high metabolic rate of tumours often leads to acidosis and hypoxia in poorly perfused regions. Tumour cells have thus evolved the ability to function in a more acidic environment than normal cells. Key pH regulators in tumour cells include: isoforms 2, 9 and 12 of carbonic anhydrase, isoforms of anion exchangers, Na+/HCO3− co-transporters, Na+/H+ exchangers, monocarboxylate transporters and the vacuolar ATPase. Both small molecules and antibodies targeting these pH regulators are currently at various stages of clinical development. These antitumour mechanisms are not exploited by the classical cancer drugs and therefore represent a new anticancer drug discovery strategy.
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Research in our laboratories is financed by a European Union grant of the Seventh Framework Programme (Metoxia; C.T.S.), the ETH Zürich (D.N.), the Swiss National Science Foundation (D.N.), the SwissBridge Foundation (D.N.) and the Stammbach Foundation (D.N.).
Claudiu T. Supuran is an inventor on patents of carbonic anhydrase inhibitors, and Dario Neri is an inventor on patents of fibronectin and tenascin antibodies. Dario Neri is also a co-founder and shareholder of Philogen.
- Warburg effect
The ability of cancer cells to predominantly produce energy by a high rate of glycolysis followed by lactic acid fermentation in the cytosol, rather than by glycolysis followed by oxidation of pyruvate in the mitochondria, as most normal cells do.
- Orthotopic tumours
Tumours that occur at the normal place in the body in an animal model of cancer (for example, mouse orthotopic mammary tumours develop in the mammary gland of the animal).
A temporary structural–functional complex formed between sequential enzymes or proteins of a metabolic pathway. It is held together by non-covalent interactions and structural elements of the cell, such as integral membrane proteins and proteins of the cytoskeleton.
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Neri, D., Supuran, C. Interfering with pH regulation in tumours as a therapeutic strategy. Nat Rev Drug Discov 10, 767–777 (2011). https://doi.org/10.1038/nrd3554
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