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

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          Abstract

          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 −/HCO 3 − 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-N-isopropyl 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 −/HCO 3 − 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-N-isopropyl 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 −/HCO3 − 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.

          British Journal of Cancer (2002) 37, 238–245. doi: 10.1038/sj.bjc.6600424 www.bjcancer.com

          © 2002 Cancer Research UK

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          The relevance of tumour pH to the treatment of malignant disease.

          J.L. Wike-Hooley, J. Haveman, H.S. Reinhold (1984)
          The wide range of tumour pH values that have been determined in human tumours is shown in Fig. 4. It can be seen that tumour pH values may be very low, or may fall in the same range as the values found in normal tissues. This means that pH-mediated modification of therapeutic effectiveness will be patient specific, rather than a general phenomenon. That the pH of the cellular environment might influence the effectiveness of various therapeutic agents is not a new idea. The data published in this field to date concerning such effects have been discussed extensively and are summarized in Table IV. Here we can see that low pH leads to decreased cell survival following treatment with hyperthermia, radiotherapy combined with hyperthermia, radiosensitizers and various chemotherapeutic agents. Conversely, low pH affords some protection against radiation and some drugs. Most of these data were, of necessity, derived from in vitro studies. In vivo studies are in most cases not feasible due to the difficulty of isolating the effect of one selected factor. Low tumour pH is, in vivo, generally assumed to be closely interlinked with tissue hypoxia and low blood-flow levels, each of which may individually influence the experimental outcome. Moreover, most of the aforementioned in vitro studies were conducted under well-oxygenated conditions. As previously mentioned, euoxic cells can, under certain conditions, maintain a pH gradient over the cell membrane. This collapses with the onset of hypoxia, leading to intracellular acidification. Low oxygen levels have been shown to be characteristic of many tumours. Within these limitations it is thus evident that tumour pH values could have far-reaching consequences for therapy. If the in vitro findings should prove to be relevant to the clinical situation various applications are possible. Pre-selection of patients less likely to respond to certain (toxic) chemotherapeutic agents, or conversely selection of agents that are more likely to be effective in the pH range of the tumour to be treated are two examples. Alternatively, the exploitation of low tumour pH values is a possibility. Agents that form or release toxic derivatives in areas of low pH, e.g., pH-sensitive liposomes, will work selectively in such areas. Tumour selective therapy may also be possible in patients with higher tumour pH values if the tumour pH can be lowered. This has been achieved experimentally by the administration of hyperthermia at temperatures above 42 degrees C, or by the administration of glucose.(ABSTRACT TRUNCATED AT 400 WORDS)
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            Changes in intramitochondrial and cytosolic pH: early events that modulate caspase activation during apoptosis.

            Shigemi Matsuyama, Quinn L. Deveraux, Roger Y. Tsien … (2000)
            Mitochondria trigger apoptosis by releasing caspase activators, including cytochrome c (cytC). Here we show, using a pH-sensitive green fluorescent protein (GFP), that mitochondria-dependent apoptotic stimuli (such as Bax, staurosporine and ultraviolet irradiation) induce rapid, Bcl-2-inhibitable mitochondrial alkalinization and cytosol acidification, followed by cytC release, caspase activation and mitochondrial swelling and depolarization. These events are not induced by mitochondria-independent apoptotic stimuli, such as Fas. Activation of cytosolic caspases by cytC in vitro is minimal at neutral pH, but maximal at acidic pH, indicating that mitochondria-induced acidification of the cytosol may be important for caspase activation; this finding is supported by results obtained from cells using protonophores. Cytosol acidification and cytC release are suppressed by oligomycin, a FoF1-ATPase/H +-pump inhibitor, but not by caspase inhibitors. Ectopic expression of Bax in wild-type, but not FoF1/H+-pump-deficient, yeast cells similarly results in mitochondrial matrix alkalinization, cytosol acidification and cell death. These findings indicate that mitochondria-mediated alteration of intracellular pH may be an early event that regulates caspase activation in the mitochondrial pathway for apoptosis.
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              Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation.

              F. Yuan, G Helmlinger, M Dellian … (1997)
              The partial pressure of oxygen (pO2) and pH play critical roles in tumor biology and therapy. We report here the first combined, high-resolution (< or = 10 microns) measurements of interstitial pH and pO2 profiles between adjacent vessels in a human tumor xenograft, using fluorescence ratio imaging and phosphorescence quenching microscopy. We found (1) heterogeneity in shapes of pH and pO2 profiles; (2) a discordant relation between local pH profiles and corresponding pO2 profiles, yet a strong correlation between mean pH and pO2 profiles; (3) no correlation between perivascular pH/pO2 and nearest vessel blood flow; and (4) well-perfused tumor vessels that were hypoxic and, consequently, large hypoxic areas in the surrounding interstitium. Such multiparameter measurements of the in vivo microenvironment provide unique insights into biological processes in tumors and their response to treatment.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Br J Cancer
                Title: British Journal of Cancer
                Publisher: Nature Publishing Group
                ISSN (Print): 0007-0920
                ISSN (Electronic): 1532-1827
                Publication date (Electronic): 02 July 2002
                Publication date (Print): 15 July 2002
                Volume: 87
                Issue: 2
                Pages: 238-245
                Affiliations
                [1 ]Department of Medical Biophysics, Princess Margaret Hospital/Ontario Cancer Institute, University of Toronto, Toronto, M5G 2M9, Canada
                [2 ]Aventis Pharma Deutschland GmbH, Industriepark Höchst, 65926 Frankfurt/Main, Germany
                [3 ]Department of Medical Oncology and Hematology and the Division of Experimental Therapy, Princess Margaret Hospital, University of Toronto, Toronto, M5G 2M9, Canada
                Author notes
                [* ]Author for correspondence: ian.tannock@ 123456uhn.on.ca
                Article
                Publisher Item ID: 6600424
                DOI: 10.1038/sj.bjc.6600424
                PMC ID: 2376112
                PubMed ID: 12107849
                SO-VID: fcde782d-c4cf-4cd7-9110-460c2f0de87f
                Copyright © Copyright 2002, Cancer Research UK
                History
                Date received : 01 February 2002
                Date revision received : 26 April 2002
                Date accepted : 26 April 2002
                Categories
                Subject: Experimental Therapeutics

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: na+-dependent cl−/hco3− exchanger,cariporide,intracellular ph,na+/h+ antiport,s3705
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: na+-dependent cl−/hco3− exchanger, cariporide, intracellular ph, na+/h+ antiport, s3705

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