The chronic administration of drugs that inhibit the regulation of intracellular pH: in vitro and anti-tumour effects

Yamagata, Masayo; Tannock, I. F.

doi:10.1038/bjc.1996.254

Cited by 75 publications

(67 citation statements)

References 16 publications

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“…Both cariporide (80 mM) and S3705 (40 mM) failed to show toxicity to cells grown in monolayers at doses that inhibited pHi regulation, even at relatively low levels of extracellular pH. This is consistent with previous results for EIPA and DIDS which only become toxic at low pHe if the cells are first acidified by using an ionophore such as nigericin (Newell et al, 1992;Yamagata and Tannock, 1996). Thus cariporide and S3705 are unlikely to be directly toxic to cells in solid tumours, despite the tendency of the microenvironment to be acidic; they might however enhance the activity of agents that cause intracellular acidification (Newell et al, 1992;Yamagata and Tannock, 1996), but this was not evaluated directly.…”

Section: Discussionsupporting

confidence: 90%

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Cytostatic potential of novel agents that inhibit the regulation of intracellular pH

Wong

Hw²,

Tannock

2002

Br J Cancer

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Cells within the acidic extracellular environment of solid tumours maintain their intracellular pH (pHi) through the activity of membrane-based ion exchange mechanisms including the Na + /H + antiport and the Na + -dependent Cl 7 /HCO 3 7 exchanger. Inhibition of these regulatory mechanisms has been proposed as an approach to tumour therapy. Previously available inhibitors of these exchangers were toxic (e.g. 4,4-diisothiocyanstilbene-2,2-disulphonic acid), and/or non-specific (e.g. 5-N-ethyl-Nisopropyl amiloride). Using two human (MCF7, MDA-MB231) and one murine (EMT6) breast cancer cell lines, we evaluated the influence of two new agents, cariporide (an inhibitor of the Na + /H + antiport) and S3705 (an inhibitor of the Na + -dependent Cl 7 /HCO 3 7 exchanger) on the regulation of intracellular pH (pHi). The cytotoxicity of the two agents was assessed by using clonogenic assays. Our results suggest that cariporide has similar efficacy and potency to 5-N-ethyl-Nisopropyl amiloride for inhibition of Na + /H + exchange while S3705 is more potent and efficient than 4,4-diisothiocyanstilbene-2,2-disulphonic acid in inhibiting Na+-dependent Cl 7 /HCO3 7 exchange. The agents inhibited the growth of tumour cells when they were incubated at low pHe (7.0 -6.8), but were non-toxic to cells grown at doses that inhibited the regulation of pHi. Our results indicate that cariporide and S3705 are selective cytostatic agents under in vitro conditions that reflect the slightly acidic microenvironment found in solid tumours.

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Section: Discussionsupporting

confidence: 90%

“…This agent provides partial non-reversible inhibition of the exchanger and is toxic to cells in vitro at 0.4 mM and quite toxic in vivo (Yamagata and Tannock, 1996). More recently, investigators from the Aventis Pharmaceutical Company have developed a new inhibitor of the Na + -dependent Cl 7 /HCO3 7 exchanger, known as S3705 (unpublished data).…”

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confidence: 99%

Cytostatic potential of novel agents that inhibit the regulation of intracellular pH

Wong

Hw²,

Tannock

2002

Br J Cancer

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“…DIDS is an inhibitor of these transporters, but owing to its toxicity it cannot be used as a therapeutic agent 79 . Another inhibitor of these HCO 3 -transporters -S3705 -has been reported and evaluated for the inhibition of proliferation and apoptosis of the human cholangiocarcinoma cell lines HUH-28 and Mz-ChA-1 80 ; the structure of S3705, however, has not been disclosed.…”

Section: Inhibiting Other Hcomentioning

confidence: 99%

Interfering with pH regulation in tumours as a therapeutic strategy

Neri¹,

Supuran

2011

Nat Rev Drug Discov

1,377

1,269

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The growth of solid tumours is characterized not only by the uncontrolled proliferation of cancer cells but also by changes in the tumour environment that support the growth of the neoplastic mass and the metastatic spread of cancer cells to distant sites 1 . The formation of new blood vessels from pre-existing ones (angiogenesis) provides oxygen and nutrients to the tumour, which are essential for tumour growth 2 . A complex dynamic interplay exists between the expanding neoplastic mass and the tumour environment, which is affected by the metabolic requirements of cancer cells and by their products, such as secreted proteins (for example, extracellular matrix components and proteases) and metabolites.Upregulated glucose metabolism is a hallmark of invasive cancers 3 . In normal cells glucose is converted to glucose-6-phosphate and subsequently to pyruvate, which is then oxidized in the mitochondria to carbon dioxide and water; this releases 38 moles of ATP per mole of glucose 3 . However, inadequate oxygen delivery to some regions of tumours leads to hypoxia, which restricts oxidative phosphorylation. As a consequence, hypoxic tumour cells shift their metabolism towards glycolysis so that the pyruvate generated in the first step of the process is reduced to lactate, generating only 2 moles of ATP per mole of glucose. This is a less energy-efficient process but it does not depend on oxygen. Furthermore, glycolysis often persists even after reoxygenation because the obtained metabolic intermediates (that is, lactate and pyruvate) can be used for the biosynthesis of amino acids, nucleotides and lipids, thus providing a selective advantage to proliferating tumour cells. This explains Warburg's observation of high glucose consumption and high lactate production in tumour tissues 3-5 (known as the Warburg effect).Oncogenic metabolism also generates an excess of protons and carbon dioxide, which are kept in equilibrium with carbonic acid by the enzyme carbonic anhydrase 3-9 . Thus, increased glucose metabolism in tumour cells leads to enhanced acidification of the extracellular milieu, which is frequently accompanied by various levels of hypoxia. This phenotype confers a substantial Darwinian growth advantage to tumour cells over normal cells, which undergo apoptosis in response to such an acidic extracellular environment 3 .Tumour cells have evolved various mechanisms to cope with the acidic and hypoxic stress mentioned above. They eliminate acidic catabolites by ion transporters and pumps to preserve a slightly alkaline intracellular pH (pH i ), which is optimal for cell proliferation and tumour survival 3-10 . Acid export leads to a reduction in the extracellular pH (pH e ) to values as low as 6.0 (the usual pH e in tumours is in the range of 6.5-7.0) 3 , which is a salient feature of the tumour microenvironment 3-9 . As well as triggering the overexpression of many proteins involved in glucose metabolism -such as the glucose transporter GLUT1 (also known as SLC2A1) and pH-regulating proteins such as carbonic anhyd...

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“…At low extracellular pH, angiostatin affects EC intracellular pH. The average tumor extracellular pH (5.6-7.6), measured in vivo using magnetic resonance imaging (MRI), is lower and more variable than in normal tissue (7.2-7.6), yet tumor cells have a normal average intracellular pH [Yamagata and Tannock, 1996]. Angiostatin is more potent at low extracellular pH [Wahl and Grant, 2002], thus has enhanced activity in the tumor microenvironment.…”

Section: Other Factors Affecting Regulation Ofmentioning

confidence: 99%

Angiostatin's molecular mechanism: Aspects of specificity and regulation elucidated

Wahl

Kenan

Gonzalez-Gronow

et al. 2005

J of Cellular Biochemistry

114

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Tumor growth requires the development of new vessels that sprout from pre-existing normal vessels in a process known as ''angiogenesis'' [Folkman (1971) N Engl J Med 285:1182-1186. These new vessels arise from local capillaries, arteries, and veins in response to the release of soluble growth factors from the tumor mass, enabling these tumors to grow beyond the diffusion-limited size of approximately 2 mm diameter. Angiostatin, a naturally occurring inhibitor of angiogenesis, was discovered based on its ability to block tumor growth in vivo by inhibiting the formation of new tumor blood vessels [O'Reilly et al. (1994a) Cold Spring Harb Symp Quant Biol 59:471-482]. Angiostatin is a proteolytically derived internal fragment of plasminogen and may contain various members of the five plasminogen ''kringle'' domains, depending on the exact sites of proteolysis. Different forms of angiostatin have measurably different activities, suggesting that much remains to be elucidated about angiostatin biology. A number of groups have sought to identify the native cell surface binding site(s) for angiostatin, resulting in at least five different binding sites proposed for angiostatin on the surface of endothelial cells (EC). This review will consider the data supporting all of the various reported angiostatin binding sites and will focus particular attention on the angiostatin binding protein identified by our group: F 1 F O ATP synthase. There have been several developments in the quest to elucidate the mechanism of action of angiostatin and the regulation of its receptor. The purpose of this review is to describe the highlights of research on the mechanism of action of angiostatin, its' interaction with ATP synthase on the EC surface, modulators of its activity, and issues that should be explored in future research related to angiostatin and other anti-angiogenic agents.

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The chronic administration of drugs that inhibit the regulation of intracellular pH: in vitro and anti-tumour effects

Cited by 75 publications

References 16 publications

Cytostatic potential of novel agents that inhibit the regulation of intracellular pH

Cytostatic potential of novel agents that inhibit the regulation of intracellular pH

Interfering with pH regulation in tumours as a therapeutic strategy

Angiostatin's molecular mechanism: Aspects of specificity and regulation elucidated

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