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Cancer and Metastasis Reviews

, Volume 38, Issue 1–2, pp 205–222 | Cite as

Causes, consequences, and therapy of tumors acidosis

  • Smitha R. Pillai
  • Mehdi Damaghi
  • Yoshinori Marunaka
  • Enrico Pierluigi Spugnini
  • Stefano FaisEmail author
  • Robert J. GilliesEmail author
Article

Abstract

While cancer is commonly described as “a disease of the genes,” it is also associated with massive metabolic reprogramming that is now accepted as a disease “Hallmark.” This programming is complex and often involves metabolic cooperativity between cancer cells and their surrounding stroma. Indeed, there is emerging clinical evidence that interrupting a cancer’s metabolic program can improve patients’ outcomes. The most commonly observed and well-studied metabolic adaptation in cancers is the fermentation of glucose to lactic acid, even in the presence of oxygen, also known as “aerobic glycolysis” or the “Warburg Effect.” Much has been written about the mechanisms of the Warburg effect, and this remains a topic of great debate. However, herein, we will focus on an important sequela of this metabolic program: the acidification of the tumor microenvironment. Rather than being an epiphenomenon, it is now appreciated that this acidosis is a key player in cancer somatic evolution and progression to malignancy. Adaptation to acidosis induces and selects for malignant behaviors, such as increased invasion and metastasis, chemoresistance, and inhibition of immune surveillance. However, the metabolic reprogramming that occurs during adaptation to acidosis also introduces therapeutic vulnerabilities. Thus, tumor acidosis is a relevant therapeutic target, and we describe herein four approaches to accomplish this: (1) neutralizing acid directly with buffers, (2) targeting metabolic vulnerabilities revealed by acidosis, (3) developing acid-activatable drugs and nanomedicines, and (4) inhibiting metabolic processes responsible for generating acids in the first place.

Keywords

Cancer Microenvironment acidity Exosomes Anti-acidic therapy 

Notes

Funding

This work was supported by the Anticancer Fund (RJG), US PHS NIH grants R01 CA077575 (RJG), U54 CA193489 (RJG), and the Florida Health grant 8BC04 (SRP/RJG); the Italian Ministry of Health (SF); and Grants-in-Aid from Japan Society of the Promotion of Science, JSPS KAKENHI grant numbers JP15K15034 and 18H03182 (YM).

Compliance with ethical standards

Conflict of interest

Dr. Gillies reports a COI with Helix Biopharma, with whom he is a consultant and investor.

References

  1. 1.
    Hinton, A., Sennoune, S. R., Bond, S., Fang, M., Reuveni, M., Sahagian, G. G., Jay, D., Martinez-Zaguilan, R., & Forgac, M. (2009). Function of a subunit isoforms of the V-ATPase in pH homeostasis and in vitro invasion of MDA-MB231 human breast cancer cells. The Journal of Biological Chemistry, 284, 16400–16408.  https://doi.org/10.1074/jbc.M901201200.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Toyomura, T., Oka, T., Yamaguchi, C., Wada, Y., & Futai, M. (2000). Three subunit a isoforms of mouse vacuolar H(+)-ATPase. Preferential expression of the a3 isoform during osteoclast differentiation. The Journal of Biological Chemistry, 275, 8760–8765.Google Scholar
  3. 3.
    Boedtkjer, E., Moreira, J. M. A., Mele, M., Vahl, P., Wielenga, V. T., Christiansen, P. M., Jensen, V. E. D., Pedersen, S. F., & Aalkjaer, C. (2013). Contribution of Na+,HCO3 -cotransport to cellular pH control in human breast cancer: a role for the breast cancer susceptibility locus NBCn1 (SLC4A7). International Journal of Cancer, 132, 1288–1299.  https://doi.org/10.1002/ijc.27782.PubMedGoogle Scholar
  4. 4.
    Lee, S., Mele, M., Vahl, P., Christiansen, P. M., Jensen, V. E. D., & Boedtkjer, E. (2015). Na+,HCO3 -cotransport is functionally upregulated during human breast carcinogenesis and required for the inverted pH gradient across the plasma membrane. Pflügers Archiv, 467, 367–377.  https://doi.org/10.1007/s00424-014-1524-0.PubMedGoogle Scholar
  5. 5.
    Lee, S., Axelsen, T. V., Andersen, A. P., Vahl, P., Pedersen, S. F., & Boedtkjer, E. (2016). Disrupting Na+,HCO3 -cotransporter NBCn1 (Slc4a7) delays murine breast cancer development. Oncogene, 35, 2112–2122.  https://doi.org/10.1038/onc.2015.273.PubMedGoogle Scholar
  6. 6.
    Ames, S., Pastorekova, S., & Becker, H. M. (2018). The proteoglycan-like domain of carbonic anhydrase IX mediates non-catalytic facilitation of lactate transport in cancer cells. Oncotarget, 9, 27940–27957.  https://doi.org/10.18632/oncotarget.25371.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Mahon, B. P., Bhatt, A., Socorro, L., Driscoll, J. M., Okoh, C., Lomelino, C. L., Mboge, M. Y., Kurian, J. J., Tu, C., Agbandje-McKenna, M., Frost, S. C., & McKenna, R. (2016). The structure of carbonic anhydrase IX is adapted for low-pH catalysis. Biochemistry, 55, 4642–4653.  https://doi.org/10.1021/acs.biochem.6b00243.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Lee, S. H., McIntyre, D., Honess, D., Hulikova, A., Pacheco-Torres, J., Cerdán, S., Swietach, P., Harris, A. L., & Griffiths, J. R. (2018). Carbonic anhydrase IX is a pH-stat that sets an acidic tumour extracellular pH in vivo. British Journal of Cancer, 119, 622–630.  https://doi.org/10.1038/s41416-018-0216-5.PubMedGoogle Scholar
  9. 9.
    Bartosova, M., et al. (2002). Expression of carbonic anhydrase IX in breast is associated with malignant tissues and is related to overexpression of c-erbB2. The Journal of Pathology, 197, 314–321.  https://doi.org/10.1002/path.1120.PubMedGoogle Scholar
  10. 10.
    Shiozaki, A., Hikami, S., Ichikawa, D., Kosuga, T., Shimizu, H., Kudou, M., Yamazato, Y., Kobayashi, T., Shoda, K., Arita, T., Konishi, H., Komatsu, S., Kubota, T., Fujiwara, H., Okamoto, K., Kishimoto, M., Konishi, E., Marunaka, Y., & Otsuji, E. (2018). Anion exchanger 2 suppresses cellular movement and has prognostic significance in esophageal squamous cell carcinoma. Oncotarget, 9, 25993–26006.  https://doi.org/10.18632/oncotarget.25417.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Anemone, A., Consolino, L., Arena, F., Capozza, M., & Longo, D. V. (2019). Imaging tumor acidosis: a survey of the available techniques for mapping in vivo tumor pH. Cancer Metastasis Rev.  https://doi.org/10.1007/s10555-019-09782-9.
  12. 12.
    Gillies, R. J., Brown, J. S., Anderson, A. R. A., & Gatenby, R. A. (2018). Eco-evolutionary causes and consequences of temporal changes in intratumoural blood flow. Nature Reviews. Cancer, 18, 576–585.  https://doi.org/10.1038/s41568-018-0030-7.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Wang, L. X., Liu, K., Lin, G. W., & Zhai, R. Y. (2012). Solitary necrotic nodules of the liver: histology and diagnosis with CT and MRI. Hepatitis Monthly, 12, e6212.  https://doi.org/10.5812/hepatmon.6212.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Heidenreich, A., Ravery, V., & European Society of Oncological, U. (2004). Preoperative imaging in renal cell cancer. World Journal of Urology, 22, 307–315.  https://doi.org/10.1007/s00345-004-0411-2.PubMedGoogle Scholar
  15. 15.
    Mohlin, S., Wigerup, C., Jogi, A., & Pahlman, S. (2017). Hypoxia, pseudohypoxia and cellular differentiation. Experimental Cell Research, 356, 192–196.  https://doi.org/10.1016/j.yexcr.2017.03.007.PubMedGoogle Scholar
  16. 16.
    Barathova, M., Takacova, M., Holotnakova, T., Gibadulinova, A., Ohradanova, A., Zatovicova, M., Hulikova, A., Kopacek, J., Parkkila, S., Supuran, C. T., Pastorekova, S., & Pastorek, J. (2008). Alternative splicing variant of the hypoxia marker carbonic anhydrase IX expressed independently of hypoxia and tumour phenotype. British Journal of Cancer, 98, 129–136.  https://doi.org/10.1038/sj.bjc.6604111.PubMedGoogle Scholar
  17. 17.
    Gatenby, R. A., & Gillies, R. J. (2004). Why do cancers have high aerobic glycolysis? Nature Reviews. Cancer, 4, 891–899.  https://doi.org/10.1038/nrc1478.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Longo, D. L., Bartoli, A., Consolino, L., Bardini, P., Arena, F., Schwaiger, M., & Aime, S. (2016). In vivo imaging of tumor metabolism and acidosis by combining PET and MRI-CEST pH imaging. Cancer Research, 76, 6463–6470.  https://doi.org/10.1158/0008-5472.CAN-16-0825.PubMedGoogle Scholar
  19. 19.
    Helmlinger, G., Yuan, F., Dellian, M., & Jain, R. K. (1997). Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nature Medicine, 3, 177–182.Google Scholar
  20. 20.
    Hashim, A. I., Zhang, X., Wojtkowiak, J. W., Martinez, G. V., & Gillies, R. J. (2011). Imaging pH and metastasis. NMR in Biomedicine, 24, 582–591.  https://doi.org/10.1002/nbm.1644.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Swietach, P., Vaughan-Jones, R. D., Harris, A. L., & Hulikova, A. (2014). The chemistry, physiology and pathology of pH in cancer. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 369, 20130099.  https://doi.org/10.1098/rstb.2013.0099.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Gatenby, R. A., & Gawlinski, E. T. (1996). A reaction-diffusion model of cancer invasion. Cancer Research, 56, 5745–5753.PubMedGoogle Scholar
  23. 23.
    Stubbs, M., McSheehy, P. M., Griffiths, J. R., & Bashford, C. L. (2000). Causes and consequences of tumour acidity and implications for treatment. Molecular Medicine Today, 6, 15–19.Google Scholar
  24. 24.
    Halestrap, A. P., & Wilson, M. C. (2012). The monocarboxylate transporter family--role and regulation. IUBMB Life, 64, 109–119.  https://doi.org/10.1002/iub.572.PubMedGoogle Scholar
  25. 25.
    Faubert, B., Li, K. Y., Cai, L., Hensley, C. T., Kim, J., Zacharias, L. G., Yang, C., Do, Q. N., Doucette, S., Burguete, D., Li, H., Huet, G., Yuan, Q., Wigal, T., Butt, Y., Ni, M., Torrealba, J., Oliver, D., Lenkinski, R. E., Malloy, C. R., Wachsmann, J. W., Young, J. D., Kernstine, K., & DeBerardinis, R. J. (2017). Lactate metabolism in human lung tumors. Cell, 171, 358–371 e359.  https://doi.org/10.1016/j.cell.2017.09.019.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Nelson, S. J., Kurhanewicz, J., Vigneron, D. B., Larson, P. E. Z., Harzstark, A. L., Ferrone, M., van Criekinge, M., Chang, J. W., Bok, R., Park, I., Reed, G., Carvajal, L., Small, E. J., Munster, P., Weinberg, V. K., Ardenkjaer-Larsen, J. H., Chen, A. P., Hurd, R. E., Odegardstuen, L. I., Robb, F. J., Tropp, J., & Murray, J. A. (2013). Metabolic imaging of patients with prostate cancer using hyperpolarized [1-(1)(3)C]pyruvate. Science Translational Medicine, 5, 198ra108.  https://doi.org/10.1126/scitranslmed.3006070.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Puppulin, L., Hosogi, S., Sun, H., Matsuo, K., Inui, T., Kumamoto, Y., Suzaki, T., Tanaka, H., & Marunaka, Y. (2018). Bioconjugation strategy for cell surface labelling with gold nanostructures designed for highly localized pH measurement. Nature Communications, 9, 5278.  https://doi.org/10.1038/s41467-018-07726-5.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Morita, T., Nagaki, T., Fukuda, I., & Okumura, K. (1992). Clastogenicity of low pH to various cultured mammalian cells. Mutation Research, 268, 297–305.Google Scholar
  29. 29.
    Gillies, R. J., Verduzco, D., & Gatenby, R. A. (2012). Evolutionary dynamics of carcinogenesis and why targeted therapy does not work. Nature Reviews. Cancer, 12, 487–493.  https://doi.org/10.1038/nrc3298.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Corbet, C., Draoui, N., Polet, F., Pinto, A., Drozak, X., Riant, O., & Feron, O. (2014). The SIRT1/HIF2alpha axis drives reductive glutamine metabolism under chronic acidosis and alters tumor response to therapy. Cancer Research, 74, 5507–5519.  https://doi.org/10.1158/0008-5472.CAN-14-0705.PubMedGoogle Scholar
  31. 31.
    Zhang, H. Y., Hormi-Carver, K., Zhang, X., Spechler, S. J., & Souza, R. F. (2009). In benign Barrett’s epithelial cells, acid exposure generates reactive oxygen species that cause DNA double-strand breaks. Cancer Research, 69, 9083–9089.  https://doi.org/10.1158/0008-5472.CAN-09-2518.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Delikatny, E. J., Chawla, S., Leung, D. J., & Poptani, H. (2011). MR-visible lipids and the tumor microenvironment. NMR in Biomedicine, 24, 592–611.  https://doi.org/10.1002/nbm.1661.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Glunde, K., Guggino, S. E., Solaiyappan, M., Pathak, A. P., Ichikawa, Y., & Bhujwalla, Z. M. (2003). Extracellular acidification alters lysosomal trafficking in human breast cancer cells. Neoplasia, 5, 533–545.Google Scholar
  34. 34.
    Damaghi, M., Tafreshi, N. K., Lloyd, M. C., Sprung, R., Estrella, V., Wojtkowiak, J. W., Morse, D. L., Koomen, J. M., Bui, M. M., Gatenby, R. A., & Gillies, R. J. (2015). Chronic acidosis in the tumour microenvironment selects for overexpression of LAMP2 in the plasma membrane. Nature Communications, 6, 8752.  https://doi.org/10.1038/ncomms9752.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Rothberg, J. M., Bailey, K. M., Wojtkowiak, J. W., Ben-Nun, Y., Bogyo, M., Weber, E., Moin, K., Blum, G., Mattingly, R. R., Gillies, R. J., & Sloane, B. F. (2013). Acid-mediated tumor proteolysis: contribution of cysteine cathepsins. Neoplasia, 15, 1125–1137.Google Scholar
  36. 36.
    Rozhin, J., Sameni, M., Ziegler, G., & Sloane, B. F. (1994). Pericellular pH affects distribution and secretion of cathepsin B in malignant cells. Cancer Research, 54, 6517–6525.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Wojtkowiak, J. W., Rothberg, J. M., Kumar, V., Schramm, K. J., Haller, E., Proemsey, J. B., Lloyd, M. C., Sloane, B. F., & Gillies, R. J. (2012). Chronic autophagy is a cellular adaptation to tumor acidic pH microenvironments. Cancer Research, 72, 3938–3947.Google Scholar
  38. 38.
    Walton, Z. E., Patel, C. H., Brooks, R. C., Yu, Y., Ibrahim-Hashim, A., Riddle, M., Porcu, A., Jiang, T., Ecker, B. L., Tameire, F., Koumenis, C., Weeraratna, A. T., Welsh, D. K., Gillies, R., Alwine, J. C., Zhang, L., Powell, J. D., & Dang, C. V. (2018). Acid suspends the circadian clock in hypoxia through inhibition of mTOR. Cell, 174, 72–87 e32.  https://doi.org/10.1016/j.cell.2018.05.009.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Logozzi, M., Angelini, D. F., Iessi, E., Mizzoni, D., di Raimo, R., Federici, C., Lugini, L., Borsellino, G., Gentilucci, A., Pierella, F., Marzio, V., Sciarra, A., Battistini, L., & Fais, S. (2017). Increased PSA expression on prostate cancer exosomes in in vitro condition and in cancer patients. Cancer Letters, 403, 318–329.  https://doi.org/10.1016/j.canlet.2017.06.036.PubMedGoogle Scholar
  40. 40.
    Parolini, I., Federici, C., Raggi, C., Lugini, L., Palleschi, S., de Milito, A., Coscia, C., Iessi, E., Logozzi, M., Molinari, A., Colone, M., Tatti, M., Sargiacomo, M., & Fais, S. (2009). Microenvironmental pH is a key factor for exosome traffic in tumor cells. The Journal of Biological Chemistry, 284, 34211–34222.  https://doi.org/10.1074/jbc.M109.041152.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Ratajczak, J., Wysoczynski, M., Hayek, F., Janowska-Wieczorek, A., & Ratajczak, M. Z. (2006). Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication. Leukemia, 20, 1487–1495.  https://doi.org/10.1038/sj.leu.2404296.PubMedGoogle Scholar
  42. 42.
    Ban, J. J., Lee, M., Im, W., & Kim, M. (2015). Low pH increases the yield of exosome isolation. Biochemical and Biophysical Research Communications, 461, 76–79.  https://doi.org/10.1016/j.bbrc.2015.03.172.PubMedGoogle Scholar
  43. 43.
    Logozzi, M., Mizzoni, D., Angelini, D., di Raimo, R., Falchi, M., Battistini, L., & Fais, S. (2018). Microenvironmental pH and exosome levels interplay in human cancer cell lines of different histotypes. Cancers (Basel), 10.  https://doi.org/10.3390/cancers10100370.
  44. 44.
    Busco, G., Cardone, R. A., Greco, M. R., Bellizzi, A., Colella, M., Antelmi, E., Mancini, M. T., Dell'Aquila, M. E., Casavola, V., Paradiso, A., & Reshkin, S. J. (2010). NHE1 promotes invadopodial ECM proteolysis through acidification of the peri-invadopodial space. The FASEB Journal, 24, 3903–3915.  https://doi.org/10.1096/fj.09-149518.Google Scholar
  45. 45.
    Boedtkjer, E., Bentzon, J. F., Dam, V. S., & Aalkjaer, C. N.+. (2016). HCO3 -cotransporter NBCn1 increases pHi gradients, filopodia and migration of smooth muscle cells and promotes arterial remodeling. Cardiovascular Research, 111, 227–239.  https://doi.org/10.1093/cvr/cvw079.PubMedGoogle Scholar
  46. 46.
    Lloyd, M. C., Alfarouk, K. O., Verduzco, D., Bui, M. M., Gillies, R. J., Ibrahim, M. E., Brown, J. S., & Gatenby, R. A. (2014). Vascular measurements correlate with estrogen receptor status. BMC Cancer, 14, 279.  https://doi.org/10.1186/1471-2407-14-279.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Lloyd, M. C., Cunningham, J. J., Bui, M. M., Gillies, R. J., Brown, J. S., & Gatenby, R. A. (2016). Darwinian dynamics of intratumoral heterogeneity: not solely random mutations but also variable environmental selection forces. Cancer Research, 76, 3136–3144.  https://doi.org/10.1158/0008-5472.CAN-15-2962.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Estrella, V., Chen, T., Lloyd, M., Wojtkowiak, J., Cornnell, H. H., Ibrahim-Hashim, A., Bailey, K., Balagurunathan, Y., Rothberg, J. M., Sloane, B. F., Johnson, J., Gatenby, R. A., & Gillies, R. J. (2013). Acidity generated by the tumor microenvironment drives local invasion. Cancer Research, 73, 1524–1535.  https://doi.org/10.1158/0008-5472.CAN-12-2796.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Gatenby, R. A., Gawlinski, E. T., Gmitro, A. F., Kaylor, B., & Gillies, R. J. (2006). Acid-mediated tumor invasion: a multidisciplinary study. Cancer Research, 66, 5216–5223.  https://doi.org/10.1158/0008-5472.CAN-05-4193.Google Scholar
  50. 50.
    Pilon-Thomas, S., Kodumudi, K. N., el-Kenawi, A. E., Russell, S., Weber, A. M., Luddy, K., Damaghi, M., Wojtkowiak, J. W., Mulé, J. J., Ibrahim-Hashim, A., & Gillies, R. J. (2016). Neutralization of tumor acidity improves antitumor responses to immunotherapy. Cancer Research, 76, 1381–1390.  https://doi.org/10.1158/0008-5472.CAN-15-1743.PubMedGoogle Scholar
  51. 51.
    Lardner, A. (2001). The effects of extracellular pH on immune function. Journal of Leukocyte Biology, 69, 522–530.PubMedGoogle Scholar
  52. 52.
    Calcinotto, A., Filipazzi, P., Grioni, M., Iero, M., de Milito, A., Ricupito, A., Cova, A., Canese, R., Jachetti, E., Rossetti, M., Huber, V., Parmiani, G., Generoso, L., Santinami, M., Borghi, M., Fais, S., Bellone, M., & Rivoltini, L. (2012). Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes. Cancer Research, 72, 2746–2756.  https://doi.org/10.1158/0008-5472.CAN-11-1272.PubMedGoogle Scholar
  53. 53.
    Grundstrom, S., Dohlsten, M., & Sundstedt, A. (2000). IL-2 unresponsiveness in anergic CD4+ T cells is due to defective signaling through the common gamma-chain of the IL-2 receptor. Journal of Immunology, 164, 1175–1184.Google Scholar
  54. 54.
    Wells, A. D., Walsh, M. C., Sankaran, D., & Turka, L. A. (2000). T cell effector function and anergy avoidance are quantitatively linked to cell division. Journal of Immunology, 165, 2432–2443.Google Scholar
  55. 55.
    Demotte, N., Stroobant, V., Courtoy, P. J., van der Smissen, P., Colau, D., Luescher, I. F., Hivroz, C., Nicaise, J., Squifflet, J. L., Mourad, M., Godelaine, D., Boon, T., & van der Bruggen, P. (2008). Restoring the association of the T cell receptor with CD8 reverses anergy in human tumor-infiltrating lymphocytes. Immunity, 28, 414–424.  https://doi.org/10.1016/j.immuni.2008.01.011.PubMedGoogle Scholar
  56. 56.
    Dvorak, H. F. (1986). Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. The New England Journal of Medicine, 315, 1650–1659.  https://doi.org/10.1056/NEJM198612253152606.Google Scholar
  57. 57.
    Ashby, B. S. (1966). pH studies in human malignant tumours. Lancet, 2, 312–315.Google Scholar
  58. 58.
    Dong, L., Li, Z., Leffler, N. R., Asch, A. S., Chi, J. T., & Yang, L. V. (2013). Acidosis activation of the proton-sensing GPR4 receptor stimulates vascular endothelial cell inflammatory responses revealed by transcriptome analysis. PLoS One, 8, e61991.  https://doi.org/10.1371/journal.pone.0061991.PubMedPubMedCentralGoogle Scholar
  59. 59.
    Silva, A. S., Yunes, J. A., Gillies, R. J., & Gatenby, R. A. (2009). The potential role of systemic buffers in reducing intratumoral extracellular pH and acid-mediated invasion. Cancer Research, 69, 2677–2684.  https://doi.org/10.1158/0008-5472.CAN-08-2394.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Ibrahim Hashim, A., Cornnell, H. H., Coelho Ribeiro, M. L., Abrahams, D., Cunningham, J., Lloyd, M., Martinez, G. V., Gatenby, R. A., & Gillies, R. J. (2011). Reduction of metastasis using a non-volatile buffer. Clinical & Experimental Metastasis, 28, 841–849.  https://doi.org/10.1007/s10585-011-9415-7.Google Scholar
  61. 61.
    Robey, I. F., Baggett, B. K., Kirkpatrick, N. D., Roe, D. J., Dosescu, J., Sloane, B. F., Hashim, A. I., Morse, D. L., Raghunand, N., Gatenby, R. A., & Gillies, R. J. (2009). Bicarbonate increases tumor pH and inhibits spontaneous metastases. Cancer Research, 69, 2260–2268.  https://doi.org/10.1158/0008-5472.CAN-07-5575.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Ibrahim-Hashim, A., Cornnell, H. H., Abrahams, D., Lloyd, M., Bui, M., Gillies, R. J., & Gatenby, R. A. (2012). Systemic buffers inhibit carcinogenesis in TRAMP mice. The Journal of Urology, 188, 624–631.  https://doi.org/10.1016/j.juro.2012.03.113.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Ibrahim-Hashim, A., Robertson-Tessi, M., Enriquez-Navas, P. M., Damaghi, M., Balagurunathan, Y., Wojtkowiak, J. W., Russell, S., Yoonseok, K., Lloyd, M. C., Bui, M. M., Brown, J. S., Anderson, A. R. A., Gillies, R. J., & Gatenby, R. A. (2017). Defining cancer subpopulations by adaptive strategies rather than molecular properties provides novel insights into intratumoral evolution. Cancer Research, 77, 2242–2254.  https://doi.org/10.1158/0008-5472.CAN-16-2844.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Pilot, C., Mahipal, A., & Gillies, R. J. (2018). Buffer therapy → buffer diet. Journal of Nutrition & Food Sciences, 8, 684–688.Google Scholar
  65. 65.
    Tian, B., Wong, W. Y., Hegmann, E., Gaspar, K., Kumar, P., & Chao, H. (2015). Production and characterization of a camelid single domain antibody-urease enzyme conjugate for the treatment of cancer. Bioconjugate Chemistry, 26, 1144–1155.  https://doi.org/10.1021/acs.bioconjchem.5b00237.PubMedGoogle Scholar
  66. 66.
    Ramlau, R., et al. (2017). Phase I/II dose escalation study of L-DOS47 as a monotherapy in non-squamous non-small cell lung cancer patients. Journal of Thoracic Oncology, 12, S1017–S1072.Google Scholar
  67. 67.
    Bushinsky, D. A., Hostetter, T., Klaerner, G., Stasiv, Y., Lockey, C., McNulty, S., Lee, A., Parsell, D., Mathur, V., Li, E., Buysse, J., & Alpern, R. (2018). Randomized, controlled trial of TRC101 to increase serum bicarbonate in patients with CKD. Clinical Journal of the American Society of Nephrology, 13, 26–35.  https://doi.org/10.2215/CJN.07300717.PubMedGoogle Scholar
  68. 68.
    Kazokaite, J., Aspatwar, A., Parkkila, S., & Matulis, D. (2017). An update on anticancer drug development and delivery targeting carbonic anhydrase IX. PeerJ, 5, e4068.  https://doi.org/10.7717/peerj.4068.PubMedPubMedCentralGoogle Scholar
  69. 69.
    Boyd, N. H., Walker K., Fried J., Hackney J. R., McDonald P. C., Benavides G. A., Spina R., Audia A., Scott S. E., Libby C. J., Tran A. N., Bevensee M. O., Griguer C., Nozell S., Gillespie G. Y., Nabors B., Bhat K. P., Bar E. E., Darley-Usmar V., Xu B., Gordon E., Cooper S. J., Dedhar S., Hjelmeland A. B.. (2017) Addition of carbonic anhydrase 9 inhibitor SLC-0111 to temozolomide treatment delays glioblastoma growth in vivo. JCI Insight 2, doi: https://doi.org/10.1172/jci.insight.92928.
  70. 70.
    Harguindey, S., et al. (2013). Cariporide and other new and powerful NHE1 inhibitors as potentially selective anticancer drugs - an integral molecular/biochemical/metabolic/clinical approach after one hundred years of cancer research. Journal of Translational Medicine, 11, 282.  https://doi.org/10.1186/1479-5876-11-282.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Polanski, R., Hodgkinson, C. L., Fusi, A., Nonaka, D., Priest, L., Kelly, P., Trapani, F., Bishop, P. W., White, A., Critchlow, S. E., Smith, P. D., Blackhall, F., Dive, C., & Morrow, C. J. (2014). Activity of the monocarboxylate transporter 1 inhibitor AZD3965 in small cell lung cancer. Clinical Cancer Research, 20, 926–937.  https://doi.org/10.1158/1078-0432.CCR-13-2270.PubMedGoogle Scholar
  72. 72.
    Beloueche-Babari, M., Wantuch, S., Casals Galobart, T., Koniordou, M., Parkes, H. G., Arunan, V., Chung, Y. L., Eykyn, T. R., Smith, P. D., & Leach, M. O. (2017). MCT1 inhibitor AZD3965 increases mitochondrial metabolism, facilitating combination therapy and noninvasive magnetic resonance spectroscopy. Cancer Research, 77, 5913–5924.  https://doi.org/10.1158/0008-5472.CAN-16-2686.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Noble, R. A., Bell, N., Blair, H., Sikka, A., Thomas, H., Phillips, N., Nakjang, S., Miwa, S., Crossland, R., Rand, V., Televantou, D., Long, A., Keun, H. C., Bacon, C. M., Bomken, S., Critchlow, S. E., & Wedge, S. R. (2017). Inhibition of monocarboxyate transporter 1 by AZD3965 as a novel therapeutic approach for diffuse large B-cell lymphoma and Burkitt lymphoma. Haematologica, 102, 1247–1257.  https://doi.org/10.3324/haematol.2016.163030.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Draoui, N., Schicke, O., Seront, E., Bouzin, C., Sonveaux, P., Riant, O., & Feron, O. (2014). Antitumor activity of 7-aminocarboxycoumarin derivatives, a new class of potent inhibitors of lactate influx but not efflux. Molecular Cancer Therapeutics, 13, 1410–1418.  https://doi.org/10.1158/1535-7163.MCT-13-0653.PubMedGoogle Scholar
  75. 75.
    Doherty, J. R., Yang, C., Scott, K. E. N., Cameron, M. D., Fallahi, M., Li, W., Hall, M. A., Amelio, A. L., Mishra, J. K., Li, F., Tortosa, M., Genau, H. M., Rounbehler, R. J., Lu, Y., Dang, C. V., Kumar, K. G., Butler, A. A., Bannister, T. D., Hooper, A. T., Unsal-Kacmaz, K., Roush, W. R., & Cleveland, J. L. (2014). Blocking lactate export by inhibiting the Myc target MCT1 disables glycolysis and glutathione synthesis. Cancer Research, 74, 908–920.  https://doi.org/10.1158/0008-5472.CAN-13-2034.PubMedGoogle Scholar
  76. 76.
    Marchiq, I., & Pouyssegur, J. (2016). Hypoxia, cancer metabolism and the therapeutic benefit of targeting lactate/H(+) symporters. J Mol Med (Berl), 94, 155–171.  https://doi.org/10.1007/s00109-015-1307-x.Google Scholar
  77. 77.
    Benjamin, D., Robay, D., Hindupur, S. K., Pohlmann, J., Colombi, M., el-Shemerly, M. Y., Maira, S. M., Moroni, C., Lane, H. A., & Hall, M. N. (2018). Dual inhibition of the lactate transporters MCT1 and MCT4 is synthetic lethal with metformin due to NAD+ depletion in cancer cells. Cell Reports, 25, 3047–3058 e3044.  https://doi.org/10.1016/j.celrep.2018.11.043.PubMedPubMedCentralGoogle Scholar
  78. 78.
    Mele, L., Paino, F., Papaccio, F., Regad, T., Boocock, D., Stiuso, P., Lombardi, A., Liccardo, D., Aquino, G., Barbieri, A., Arra, C., Coveney, C., la Noce, M., Papaccio, G., Caraglia, M., Tirino, V., & Desiderio, V. (2018). A new inhibitor of glucose-6-phosphate dehydrogenase blocks pentose phosphate pathway and suppresses malignant proliferation and metastasis in vivo. Cell Death & Disease, 9, 572.  https://doi.org/10.1038/s41419-018-0635-5.Google Scholar
  79. 79.
    Cremon, C., Stanghellini, V., Barbaro, M. R., Cogliandro, R. F., Bellacosa, L., Santos, J., Vicario, M., Pigrau, M., Alonso Cotoner, C., Lobo, B., Azpiroz, F., Bruley des Varannes, S., Neunlist, M., DeFilippis, D., Iuvone, T., Petrosino, S., di Marzo, V., & Barbara, G. (2017). Randomised clinical trial: the analgesic properties of dietary supplementation with palmitoylethanolamide and polydatin in irritable bowel syndrome. Alimentary Pharmacology & Therapeutics, 45, 909–922.  https://doi.org/10.1111/apt.13958.Google Scholar
  80. 80.
    Indraccolo, U., Indraccolo, S. R., & Mignini, F. (2017). Micronized palmitoylethanolamide/trans-polydatin treatment of endometriosis-related pain: a meta-analysis. Annali dell’Istituto Superiore di Sanità, 53, 125–134.  https://doi.org/10.4415/ANN_17_02_08.CrossRefPubMedGoogle Scholar
  81. 81.
    Hitosugi, T., Zhou, L., Elf, S., Fan, J., Kang, H. B., Seo, J. H., Shan, C., Dai, Q., Zhang, L., Xie, J., Gu, T. L., Jin, P., Alečković, M., LeRoy, G., Kang, Y., Sudderth, J. A., DeBerardinis, R. J., Luan, C. H., Chen, G. Z., Muller, S., Shin, D. M., Owonikoko, T. K., Lonial, S., Arellano, M. L., Khoury, H. J., Khuri, F. R., Lee, B. H., Ye, K., Boggon, T. J., Kang, S., He, C., & Chen, J. (2012). Phosphoglycerate mutase 1 coordinates glycolysis and biosynthesis to promote tumor growth. Cancer Cell, 22, 585–600.  https://doi.org/10.1016/j.ccr.2012.09.020.PubMedPubMedCentralGoogle Scholar
  82. 82.
    Liberti, M. V., Dai, Z., Wardell, S. E., Baccile, J. A., Liu, X., Gao, X., Baldi, R., Mehrmohamadi, M., Johnson, M. O., Madhukar, N. S., Shestov, A. A., Chio, I. I. C., Elemento, O., Rathmell, J. C., Schroeder, F. C., McDonnell, D. P., & Locasale, J. W. (2017). A predictive model for selective targeting of the Warburg effect through GAPDH inhibition with a natural product. Cell Metabolism, 26, 648–659 e648.  https://doi.org/10.1016/j.cmet.2017.08.017.PubMedPubMedCentralGoogle Scholar
  83. 83.
    Harriman, G., Greenwood, J., Bhat, S., Huang, X., Wang, R., Paul, D., Tong, L., Saha, A. K., Westlin, W. F., Kapeller, R., & Harwood, H. J., Jr. (2016). Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats. Proceedings of the National Academy of Sciences of the United States of America, 113, E1796–E1805.  https://doi.org/10.1073/pnas.1520686113.PubMedPubMedCentralGoogle Scholar
  84. 84.
    Kim, C. W., Addy, C., Kusunoki, J., Anderson, N. N., Deja, S., Fu, X., Burgess, S. C., Li, C., Ruddy, M., Chakravarthy, M., Previs, S., Milstein, S., Fitzgerald, K., Kelley, D. E., & Horton, J. D. (2017). Acetyl CoA carboxylase inhibition reduces hepatic steatosis but elevates plasma triglycerides in mice and humans: a bedside to bench investigation. Cell Metabolism, 26, 576.  https://doi.org/10.1016/j.cmet.2017.08.011.PubMedGoogle Scholar
  85. 85.
    Kall, S. L., Delikatny, E. J., & Lavie, A. (2018). Identification of a unique inhibitor-binding site on choline kinase alpha. Biochemistry, 57, 1316–1325.  https://doi.org/10.1021/acs.biochem.7b01257.PubMedGoogle Scholar
  86. 86.
    Lacal, J. C., & Campos, J. M. (2015). Preclinical characterization of RSM-932A, a novel anticancer drug targeting the human choline kinase alpha, an enzyme involved in increased lipid metabolism of cancer cells. Molecular Cancer Therapeutics, 14, 31–39.  https://doi.org/10.1158/1535-7163.MCT-14-0531.PubMedGoogle Scholar
  87. 87.
    Kumar, M., Arlauckas, S. P., Saksena, S., Verma, G., Ittyerah, R., Pickup, S., Popov, A. V., Delikatny, E. J., & Poptani, H. (2015). Magnetic resonance spectroscopy for detection of choline kinase inhibition in the treatment of brain tumors. Molecular Cancer Therapeutics, 14, 899–908.  https://doi.org/10.1158/1535-7163.MCT-14-0775.PubMedPubMedCentralGoogle Scholar
  88. 88.
    Mazarico, J. M., Sanchez-Arevalo Lobo, V. J., Favicchio, R., Greenhalf, W., Costello, E., Carrillo-de Santa Pau, E., Marques, M., Lacal, J. C., Aboagye, E., & Real, F. X. (2016). Choline kinase alpha (CHKalpha) as a therapeutic target in pancreatic ductal adenocarcinoma: expression, predictive value, and sensitivity to inhibitors. Molecular Cancer Therapeutics, 15, 323–333.  https://doi.org/10.1158/1535-7163.MCT-15-0214.PubMedGoogle Scholar
  89. 89.
    Zaytseva, Y. Y., Rychahou, P. G., le, A. T., Scott, T. L., Flight, R. M., Kim, J. T., Harris, J., Liu, J., Wang, C., Morris, A. J., Sivakumaran, T. A., Fan, T., Moseley, H., Gao, T., Lee, E. Y., Weiss, H. L., Heuer, T. S., Kemble, G., & Evers, M. (2018). Preclinical evaluation of novel fatty acid synthase inhibitors in primary colorectal cancer cells and a patient-derived xenograft model of colorectal cancer. Oncotarget, 9, 24787–24800.  https://doi.org/10.18632/oncotarget.25361.PubMedPubMedCentralGoogle Scholar
  90. 90.
    Wang, B. Y., Zhang, J., Wang, J. L., Sun, S., Wang, Z. H., Wang, L. P., Zhang, Q. L., Lv, F. F., Cao, E. Y., Shao, Z. M., Fais, S., & Hu, X. C. (2015). Intermittent high dose proton pump inhibitor enhances the antitumor effects of chemotherapy in metastatic breast cancer. Journal of Experimental & Clinical Cancer Research, 34, 85.  https://doi.org/10.1186/s13046-015-0194-x.Google Scholar
  91. 91.
    Spugnini, E. P., Buglioni, S., Carocci, F., Francesco, M., Vincenzi, B., Fanciulli, M., & Fais, S. (2014). High dose lansoprazole combined with metronomic chemotherapy: a phase I/II study in companion animals with spontaneously occurring tumors. Journal of Translational Medicine, 12, 225.  https://doi.org/10.1186/s12967-014-0225-y.PubMedPubMedCentralGoogle Scholar
  92. 92.
    Walsh, M., Fais, S., Spugnini, E. P., Harguindey, S., Abu Izneid, T., Scacco, L., Williams, P., Allegrucci, C., Rauch, C., & Omran, Z. (2015). Proton pump inhibitors for the treatment of cancer in companion animals. Journal of Experimental & Clinical Cancer Research, 34, 93.  https://doi.org/10.1186/s13046-015-0204-z.Google Scholar
  93. 93.
    Upreti, M., Jyoti, A., & Sethi, P. (2013). Tumor microenvironment and nanotherapeutics. Transl Cancer Res, 2, 309–319.  https://doi.org/10.3978/j.issn.2218-676X.2013.08.11.CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Barkey, N. M., Preihs, C., Cornnell, H. H., Martinez, G., Carie, A., Vagner, J., Xu, L., Lloyd, M. C., Lynch, V. M., Hruby, V. J., Sessler, J. L., Sill, K. N., Gillies, R. J., & Morse, D. L. (2013). Development and in vivo quantitative magnetic resonance imaging of polymer micelles targeted to the melanocortin 1 receptor. Journal of Medicinal Chemistry, 56, 6330–6338.  https://doi.org/10.1021/jm4005576.PubMedGoogle Scholar
  95. 95.
    Cheng, R., Meng, F., Deng, C., Klok, H. A., & Zhong, Z. (2013). Dual and multi-stimuli responsive polymeric nanoparticles for programmed site-specific drug delivery. Biomaterials, 34, 3647–3657.  https://doi.org/10.1016/j.biomaterials.2013.01.084.PubMedGoogle Scholar
  96. 96.
    Zhu, L., & Torchilin, V. P. (2013). Stimulus-responsive nanopreparations for tumor targeting. Integr Biol (Camb), 5, 96–107.  https://doi.org/10.1039/c2ib20135f.Google Scholar
  97. 97.
    Castaneda, L., et al. (2013). Acid-cleavable thiomaleamic acid linker for homogeneous antibody-drug conjugation. Chem Commun (Camb), 49, 8187–8189.  https://doi.org/10.1039/c3cc45220d.Google Scholar
  98. 98.
    Lambert, J. M., & Morris, C. Q. (2017). Antibody-drug conjugates (ADCs) for personalized treatment of solid tumors: a review. Advances in Therapy, 34, 1015–1035.  https://doi.org/10.1007/s12325-017-0519-6.PubMedPubMedCentralGoogle Scholar
  99. 99.
    Rinaldi, F., Hanieh, P. N., del Favero, E., Rondelli, V., Brocca, P., Pereira, M. C., Andreev, O. A., Reshetnyak, Y. K., Marianecci, C., & Carafa, M. (2018). Decoration of nanovesicles with pH (low) insertion peptide (pHLIP) for targeted delivery. Nanoscale Research Letters, 13, 391.  https://doi.org/10.1186/s11671-018-2807-8.PubMedPubMedCentralGoogle Scholar
  100. 100.
    Tang, H., Zhao, W., Yu, J., Li, Y., & Zhao, C. (2018). Recent development of pH-responsive polymers for cancer nanomedicine. Molecules, 24.  https://doi.org/10.3390/molecules24010004.
  101. 101.
    Wyatt, L. C., Lewis, J. S., Andreev, O. A., Reshetnyak, Y. K., & Engelman, D. M. (2018). Applications of pHLIP technology for cancer imaging and therapy: (trends in biotechnology 35, 653-664, 2017). Trends in Biotechnology, 36, 1300.  https://doi.org/10.1016/j.tibtech.2017.11.005.PubMedGoogle Scholar
  102. 102.
    Wyatt, L. C., Moshnikova, A., Crawford, T., Engelman, D. M., Andreev, O. A., & Reshetnyak, Y. K. (2018). Peptides of pHLIP family for targeted intracellular and extracellular delivery of cargo molecules to tumors. Proceedings of the National Academy of Sciences of the United States of America, 115, E2811–E2818.  https://doi.org/10.1073/pnas.1715350115.PubMedPubMedCentralGoogle Scholar
  103. 103.
    Burns, K. E., Robinson, M. K., & Thevenin, D. (2015). Inhibition of cancer cell proliferation and breast tumor targeting of pHLIP-monomethyl auristatin E conjugates. Molecular Pharmaceutics, 12, 1250–1258.  https://doi.org/10.1021/mp500779k.PubMedPubMedCentralGoogle Scholar
  104. 104.
    Antosh, M. P., Wijesinghe, D. D., Shrestha, S., Lanou, R., Huang, Y. H., Hasselbacher, T., Fox, D., Neretti, N., Sun, S., Katenka, N., Cooper, L. N., Andreev, O. A., & Reshetnyak, Y. K. (2015). Enhancement of radiation effect on cancer cells by gold-pHLIP. Proceedings of the National Academy of Sciences of the United States of America, 112, 5372–5376.  https://doi.org/10.1073/pnas.1501628112.PubMedPubMedCentralGoogle Scholar
  105. 105.
    Yu, M., Guo, F., Wang, J., Tan, F., & Li, N. (2015). Photosensitizer-loaded pH-responsive hollow gold nanospheres for single light-induced photothermal/photodynamic therapy. ACS Applied Materials & Interfaces, 7, 17592–17597.  https://doi.org/10.1021/acsami.5b05763.Google Scholar
  106. 106.
    Yu, M., Guo, F., Wang, J., Tan, F., & Li, N. (2016). A pH-driven and photoresponsive nanocarrier: remotely-controlled by near-infrared light for stepwise antitumor treatment. Biomaterials, 79, 25–35.  https://doi.org/10.1016/j.biomaterials.2015.11.049.PubMedGoogle Scholar
  107. 107.
    Persi, E., Duran-Frigola, M., Damaghi, M., Roush, W. R., Aloy, P., Cleveland, J. L., Gillies, R. J., & Ruppin, E. (2018). Systems analysis of intracellular pH vulnerabilities for cancer therapy. Nature Communications, 9, 2997.  https://doi.org/10.1038/s41467-018-05261-x.PubMedPubMedCentralGoogle Scholar
  108. 108.
    Rahier, N. J., Molinier, N., Long, C., Deshmukh, S. K., Kate, A. S., Ranadive, P., Verekar, S. A., Jiotode, M., Lavhale, R. R., Tokdar, P., Balakrishnan, A., Meignan, S., Robichon, C., Gomes, B., Aussagues, Y., Samson, A., Sautel, F., & Bailly, C. (2015). Anticancer activity of koningic acid and semisynthetic derivatives. Bioorganic & Medicinal Chemistry, 23, 3712–3721.  https://doi.org/10.1016/j.bmc.2015.04.004.Google Scholar
  109. 109.
    Kumagai, S., Narasaki, R., & Hasumi, K. (2008). Glucose-dependent active ATP depletion by koningic acid kills high-glycolytic cells. Biochemical and Biophysical Research Communications, 365, 362–368.  https://doi.org/10.1016/j.bbrc.2007.10.199.PubMedGoogle Scholar
  110. 110.
    Peng, X., Gong, F., Chen, Y., Jiang, Y., Liu, J., Yu, M., Zhang, S., Wang, M., Xiao, G., & Liao, H. (2014). Autophagy promotes paclitaxel resistance of cervical cancer cells: involvement of Warburg effect activated hypoxia-induced factor 1-alpha-mediated signaling. Cell Death & Disease, 5, e1367.  https://doi.org/10.1038/cddis.2014.297.Google Scholar
  111. 111.
    Du, Q. H., Peng, C., & Zhang, H. (2013). Polydatin: a review of pharmacology and pharmacokinetics. Pharmaceutical Biology, 51, 1347–1354.  https://doi.org/10.3109/13880209.2013.792849.PubMedGoogle Scholar
  112. 112.
    Jones, N. P., & Schulze, A. (2012). Targeting cancer metabolism--aiming at a tumour’s sweet-spot. Drug Discovery Today, 17, 232–241.  https://doi.org/10.1016/j.drudis.2011.12.017.PubMedGoogle Scholar
  113. 113.
    Shi, J., Kantoff, P. W., Wooster, R., & Farokhzad, O. C. (2017). Cancer nanomedicine: progress, challenges and opportunities. Nature Reviews. Cancer, 17, 20–37.  https://doi.org/10.1038/nrc.2016.108.PubMedGoogle Scholar
  114. 114.
    Uthaman, S., Huh, K. M., & Park, I. K. (2018). Tumor microenvironment-responsive nanoparticles for cancer theragnostic applications. Biomater Res, 22, 22.  https://doi.org/10.1186/s40824-018-0132-z.PubMedPubMedCentralGoogle Scholar
  115. 115.
    Sun, X., du, R., Zhang, L., Zhang, G., Zheng, X., Qian, J., Tian, X., Zhou, J., He, J., Wang, Y., Wu, Y., Zhong, K., Cai, D., Zou, D., & Wu, Z. (2017). A pH-responsive yolk-like nanoplatform for tumor targeted dual-mode magnetic resonance imaging and chemotherapy. ACS Nano, 11, 7049–7059.  https://doi.org/10.1021/acsnano.7b02675.PubMedGoogle Scholar
  116. 116.
    Tsuchikama, K., & An, Z. (2018). Antibody-drug conjugates: recent advances in conjugation and linker chemistries. Protein & Cell, 9, 33–46.  https://doi.org/10.1007/s13238-016-0323-0.Google Scholar
  117. 117.
    Jain, N., Smith, S. W., Ghone, S., & Tomczuk, B. (2015). Current ADC linker chemistry. Pharmaceutical Research, 32, 3526–3540.  https://doi.org/10.1007/s11095-015-1657-7.PubMedPubMedCentralGoogle Scholar
  118. 118.
    Lambert, J. M., & Berkenblit, A. (2018). Antibody-drug conjugates for cancer treatment. Annual Review of Medicine, 69, 191–207.  https://doi.org/10.1146/annurev-med-061516-121357.PubMedGoogle Scholar
  119. 119.
    Reshetnyak, Y. K., Andreev, O. A., Segala, M., Markin, V. S., & Engelman, D. M. (2008). Energetics of peptide (pHLIP) binding to and folding across a lipid bilayer membrane. Proceedings of the National Academy of Sciences of the United States of America, 105, 15340–15345.  https://doi.org/10.1073/pnas.0804746105.PubMedPubMedCentralGoogle Scholar
  120. 120.
    Wyatt, L. C., Lewis, J. S., Andreev, O. A., Reshetnyak, Y. K., & Engelman, D. M. (2017). Applications of pHLIP technology for cancer imaging and therapy. Trends in Biotechnology, 35, 653–664.  https://doi.org/10.1016/j.tibtech.2017.03.014.PubMedPubMedCentralGoogle Scholar
  121. 121.
    Izumi, H., Torigoe, T., Ishiguchi, H., Uramoto, H., Yoshida, Y., Tanabe, M., Ise, T., Murakami, T., Yoshida, T., Nomoto, M., & Kohno, K. (2003). Cellular pH regulators: potentially promising molecular targets for cancer chemotherapy. Cancer Treatment Reviews, 29, 541–549.Google Scholar
  122. 122.
    Taylor, S., Spugnini, E. P., Assaraf, Y. G., Azzarito, T., Rauch, C., & Fais, S. (2015). Microenvironment acidity as a major determinant of tumor chemoresistance: proton pump inhibitors (PPIs) as a novel therapeutic approach. Drug Resistance Updates, 23, 69–78.  https://doi.org/10.1016/j.drup.2015.08.004.PubMedGoogle Scholar
  123. 123.
    De Milito, A., et al. (2010). pH-dependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidity. International Journal of Cancer, 127, 207–219.  https://doi.org/10.1002/ijc.25009.PubMedGoogle Scholar
  124. 124.
    De Milito, A., Marino, M. L., & Fais, S. (2012). A rationale for the use of proton pump inhibitors as antineoplastic agents. Current Pharmaceutical Design, 18, 1395–1406.Google Scholar
  125. 125.
    Ferrari, S., Perut, F., Fagioli, F., Brach del Prever, A., Meazza, C., Parafioriti, A., Picci, P., Gambarotti, M., Avnet, S., Baldini, N., & Fais, S. (2013). Proton pump inhibitor chemosensitization in human osteosarcoma: from the bench to the patients’ bed. Journal of Translational Medicine, 11, 268.  https://doi.org/10.1186/1479-5876-11-268.PubMedPubMedCentralGoogle Scholar
  126. 126.
    Spugnini, E. P., Baldi, A., Buglioni, S., Carocci, F., Milesi de Bazzichini, G., Betti, G., Pantaleo, I., Menicagli, F., Citro, G., & Fais, S. (2011). Lansoprazole as a rescue agent in chemoresistant tumors: a phase I/II study in companion animals with spontaneously occurring tumors. Journal of Translational Medicine, 9, 221.  https://doi.org/10.1186/1479-5876-9-221.PubMedPubMedCentralGoogle Scholar
  127. 127.
    Ranieri, G., Gadaleta, C. D., Patruno, R., Zizzo, N., Daidone, M. G., Hansson, M. G., Paradiso, A., & Ribatti, D. (2013). A model of study for human cancer: spontaneous occurring tumors in dogs. Biological features and translation for new anticancer therapies. Critical Reviews in Oncology/Hematology, 88, 187–197.  https://doi.org/10.1016/j.critrevonc.2013.03.005.PubMedGoogle Scholar
  128. 128.
    Dobson, J. M. (2013). Breed-predispositions to cancer in pedigree dogs. ISRN Vet Sci, 2013, 941275.  https://doi.org/10.1155/2013/941275.PubMedPubMedCentralGoogle Scholar
  129. 129.
    Johnson, P. J. (1998). Dermatologic tumors (excluding sarcoids). The Veterinary Clinics of North America. Equine Practice, 14, 625–658, viii.Google Scholar
  130. 130.
    Merlo, D. F., Rossi, L., Pellegrino, C., Ceppi, M., Cardellino, U., Capurro, C., Ratto, A., Sambucco, P. L., Sestito, V., Tanara, G., & Bocchini, V. (2008). Cancer incidence in pet dogs: findings of the Animal Tumor Registry of Genoa, Italy. Journal of Veterinary Internal Medicine, 22, 976–984.  https://doi.org/10.1111/j.1939-1676.2008.0133.x.PubMedGoogle Scholar
  131. 131.
    Kosugi, Y., Yamamoto, S., Sano, N., Furuta, A., Igari, T., Fujioka, Y., & Amano, N. (2015). Evaluation of acid tolerance of drugs using rats and dogs controlled for gastric acid secretion. Journal of Pharmaceutical Sciences, 104, 2887–2893.  https://doi.org/10.1002/jps.24401.PubMedGoogle Scholar
  132. 132.
    Chen, C. H., Lee, C. Z., Lin, Y. C., Kao, L. T., & Lin, H. C. (2018). Negative association of proton pump inhibitors with subsequent development of breast cancer: a nationwide population-based study. Journal of Clinical Pharmacology, 59, 350–355.  https://doi.org/10.1002/jcph.1329.PubMedGoogle Scholar
  133. 133.
    Papagerakis, S., Bellile, E., Peterson, L. A., Pliakas, M., Balaskas, K., Selman, S., Hanauer, D., Taylor, J. M. G., Duffy, S., & Wolf, G. (2014). Proton pump inhibitors and histamine 2 blockers are associated with improved overall survival in patients with head and neck squamous carcinoma. Cancer Prevention Research (Philadelphia, Pa.), 7, 1258–1269.  https://doi.org/10.1158/1940-6207.CAPR-14-0002.Google Scholar
  134. 134.
    Falcone, R., Roberto, M., D’Antonio, C., Romiti, A., Milano, A., Onesti, C. E., Marchetti, P., & Fais, S. (2016). High-doses of proton pump inhibitors in refractory gastro-intestinal cancer: a case series and the state of art. Digestive and Liver Disease, 48, 1503–1505.  https://doi.org/10.1016/j.dld.2016.08.126.PubMedGoogle Scholar
  135. 135.
    Casey, J. R., Grinstein, S., & Orlowski, J. (2010). Sensors and regulators of intracellular pH. Nature Reviews. Molecular Cell Biology, 11, 50–61.  https://doi.org/10.1038/nrm2820.PubMedGoogle Scholar
  136. 136.
    Martinez-Zaguilan, R., Lynch, R. M., Martinez, G. M., & Gillies, R. J. (1993). Vacuolar-type H(+)-ATPases are functionally expressed in plasma membranes of human tumor cells. The American Journal of Physiology, 265, C1015–C1029.  https://doi.org/10.1152/ajpcell.1993.265.4.C1015.PubMedGoogle Scholar
  137. 137.
    Sennoune, S. R., Bakunts, K., Martínez, G. M., Chua-Tuan, J. L., Kebir, Y., Attaya, M. N., & Martínez-Zaguilán, R. (2004). Vacuolar H+-ATPase in human breast cancer cells with distinct metastatic potential: distribution and functional activity. American Journal of Physiology. Cell Physiology, 286, C1443–C1452.  https://doi.org/10.1152/ajpcell.00407.2003.Google Scholar
  138. 138.
    Cardone, R. A., Casavola, V., & Reshkin, S. J. (2005). The role of disturbed pH dynamics and the Na+/H+ exchanger in metastasis. Nature Reviews. Cancer, 5, 786–795.  https://doi.org/10.1038/nrc1713.PubMedGoogle Scholar
  139. 139.
    Stock, C., & Pedersen, S. F. (2017). Roles of pH and the Na(+)/H(+) exchanger NHE1 in cancer: from cell biology and animal models to an emerging translational perspective? Seminars in Cancer Biology, 43, 5–16.  https://doi.org/10.1016/j.semcancer.2016.12.001.PubMedGoogle Scholar
  140. 140.
    Mullard, A. (2016). Cancer metabolism pipeline breaks new ground. Nature Reviews. Drug Discovery, 15, 735–737.  https://doi.org/10.1038/nrd.2016.223.PubMedGoogle Scholar
  141. 141.
    Neri, D., & Supuran, C. T. (2011). Interfering with pH regulation in tumours as a therapeutic strategy. Nature Reviews. Drug Discovery, 10, 767–777.  https://doi.org/10.1038/nrd3554.PubMedGoogle Scholar
  142. 142.
    Pouyssegur, J., Franchi, A., & Pages, G. (2001). pHi, aerobic glycolysis and vascular endothelial growth factor in tumour growth. Novartis Found Symp, 240, 186–196; discussion 196–188.PubMedGoogle Scholar
  143. 143.
    Chiche, J., Fur, Y. L., Vilmen, C., Frassineti, F., Daniel, L., Halestrap, A. P., Cozzone, P. J., Pouysségur, J., & Lutz, N. W. (2012). In vivo pH in metabolic-defective Ras-transformed fibroblast tumors: key role of the monocarboxylate transporter, MCT4, for inducing an alkaline intracellular pH. International Journal of Cancer, 130, 1511–1520.  https://doi.org/10.1002/ijc.26125.PubMedGoogle Scholar
  144. 144.
    Reshkin, S. J., et al. (2000). Na+/H+ exchanger-dependent intracellular alkalinization is an early event in malignant transformation and plays an essential role in the development of subsequent transformation-associated phenotypes. The FASEB Journal, 14, 2185–2197.  https://doi.org/10.1096/fj.00-0029com.PubMedGoogle Scholar
  145. 145.
    Provost, J. J., & Wallert, M. A. (2013). Inside out: targeting NHE1 as an intracellular and extracellular regulator of cancer progression. Chemical Biology & Drug Design, 81, 85–101.  https://doi.org/10.1111/cbdd.12035.Google Scholar
  146. 146.
    Commisso, C., Davidson, S. M., Soydaner-Azeloglu, R. G., Parker, S. J., Kamphorst, J. J., Hackett, S., Grabocka, E., Nofal, M., Drebin, J. A., Thompson, C. B., Rabinowitz, J. D., Metallo, C. M., Vander Heiden, M. G., & Bar-Sagi, D. (2013). Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature, 497, 633–637.  https://doi.org/10.1038/nature12138.PubMedPubMedCentralGoogle Scholar
  147. 147.
    Hosogi, S., Miyazaki, H., Nakajima, K. I., Ashihara, E., Niisato, N., Kusuzaki, K., & Marunaka, Y. (2012). An inhibitor of Na(+)/H(+) exchanger (NHE), ethyl-isopropyl amiloride (EIPA), diminishes proliferation of MKN28 human gastric cancer cells by decreasing the cytosolic Cl(−) concentration via DIDS-sensitive pathways. Cellular Physiology and Biochemistry, 30, 1241–1253.  https://doi.org/10.1159/000343315.PubMedGoogle Scholar
  148. 148.
    Kellen, J. A., Mirakian, A., & Kolin, A. (1988). Antimetastatic effect of amiloride in an animal tumour model. Anticancer Research, 8, 1373–1376.PubMedGoogle Scholar
  149. 149.
    Matthews, H., Ranson, M., & Kelso, M. J. (2011). Anti-tumour/metastasis effects of the potassium-sparing diuretic amiloride: an orally active anti-cancer drug waiting for its call-of-duty? International Journal of Cancer, 129, 2051–2061.  https://doi.org/10.1002/ijc.26156.PubMedGoogle Scholar
  150. 150.
    Dimmer, K. S., Friedrich, B., Lang, F., Deitmer, J. W., & Broer, S. (2000). The low-affinity monocarboxylate transporter MCT4 is adapted to the export of lactate in highly glycolytic cells. The Biochemical Journal, 350(Pt 1), 219–227.Google Scholar
  151. 151.
    Amith, S. R., Wilkinson, J. M., & Fliegel, L. (2016). KR-33028, a potent inhibitor of the Na(+)/H(+) exchanger NHE1, suppresses metastatic potential of triple-negative breast cancer cells. Biochemical Pharmacology, 118, 31–39.  https://doi.org/10.1016/j.bcp.2016.08.010.PubMedGoogle Scholar
  152. 152.
    Di Sario, A., et al. (2007). Selective inhibition of ion transport mechanisms regulating intracellular pH reduces proliferation and induces apoptosis in cholangiocarcinoma cells. Digestive and Liver Disease, 39, 60–69.  https://doi.org/10.1016/j.dld.2006.07.013.PubMedGoogle Scholar
  153. 153.
    Lv, C., Yang, X., Yu, B., Ma, Q., Liu, B., & Liu, Y. (2012). Blocking the Na+/H+ exchanger 1 with cariporide (HOE642) reduces the hypoxia-induced invasion of human tongue squamous cell carcinoma. International Journal of Oral and Maxillofacial Surgery, 41, 1206–1210.  https://doi.org/10.1016/j.ijom.2012.03.001.PubMedGoogle Scholar
  154. 154.
    Counillon, L., Bouret, Y., Marchiq, I., & Pouyssegur, J. (2016). Na(+)/H(+) antiporter (NHE1) and lactate/H(+) symporters (MCTs) in pH homeostasis and cancer metabolism. Biochimica et Biophysica Acta, 1863, 2465–2480.  https://doi.org/10.1016/j.bbamcr.2016.02.018.PubMedGoogle Scholar
  155. 155.
    Miranda-Goncalves, V., et al. (2013). Monocarboxylate transporters (MCTs) in gliomas: expression and exploitation as therapeutic targets. Neuro-Oncology, 15, 172–188.  https://doi.org/10.1093/neuonc/nos298.PubMedGoogle Scholar
  156. 156.
    Pinheiro, C., Longatto-Filho, A., Azevedo-Silva, J., Casal, M., Schmitt, F. C., & Baltazar, F. (2012). Role of monocarboxylate transporters in human cancers: state of the art. Journal of Bioenergetics and Biomembranes, 44, 127–139.  https://doi.org/10.1007/s10863-012-9428-1.PubMedGoogle Scholar
  157. 157.
    Manning Fox, J. E., Meredith, D., & Halestrap, A. P. (2000). Characterisation of human monocarboxylate transporter 4 substantiates its role in lactic acid efflux from skeletal muscle. The Journal of Physiology, 529(Pt 2), 285–293.PubMedPubMedCentralGoogle Scholar
  158. 158.
    Ullah, M. S., Davies, A. J., & Halestrap, A. P. (2006). The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1alpha-dependent mechanism. The Journal of Biological Chemistry, 281, 9030–9037.  https://doi.org/10.1074/jbc.M511397200.PubMedGoogle Scholar
  159. 159.
    Mathupala, S. P., Parajuli, P., & Sloan, A. E. (2004). Silencing of monocarboxylate transporters via small interfering ribonucleic acid inhibits glycolysis and induces cell death in malignant glioma: an in vitro study. Neurosurgery, 55, 1410–1419; discussion 1419.Google Scholar
  160. 160.
    Fang, J., Quinones, Q. J., Holman, T. L., Morowitz, M. J., Wang, Q., Zhao, H., Sivo, F., Maris, J. M., & Wahl, M. L. (2006). The H+-linked monocarboxylate transporter (MCT1/SLC16A1): a potential therapeutic target for high-risk neuroblastoma. Molecular Pharmacology, 70, 2108–2115.  https://doi.org/10.1124/mol.106.026245.PubMedGoogle Scholar
  161. 161.
    Halestrap, A. P. (2012). The monocarboxylate transporter family--structure and functional characterization. IUBMB Life, 64, 1–9.  https://doi.org/10.1002/iub.573.PubMedGoogle Scholar
  162. 162.
    Le Floch, R., et al. (2011). CD147 subunit of lactate/H+ symporters MCT1 and hypoxia-inducible MCT4 is critical for energetics and growth of glycolytic tumors. Proceedings of the National Academy of Sciences of the United States of America, 108, 16663–16668.  https://doi.org/10.1073/pnas.1106123108.PubMedPubMedCentralGoogle Scholar
  163. 163.
    Baenke, F., Dubuis, S., Brault, C., Weigelt, B., Dankworth, B., Griffiths, B., Jiang, M., Mackay, A., Saunders, B., Spencer-Dene, B., Ros, S., Stamp, G., Reis-Filho, J. S., Howell, M., Zamboni, N., & Schulze, A. (2015). Functional screening identifies MCT4 as a key regulator of breast cancer cell metabolism and survival. The Journal of Pathology, 237, 152–165.  https://doi.org/10.1002/path.4562.PubMedGoogle Scholar
  164. 164.
    Marchiq, I., Le Floch, R., Roux, D., Simon, M. P., & Pouyssegur, J. (2015). Genetic disruption of lactate/H+ symporters (MCTs) and their subunit CD147/BASIGIN sensitizes glycolytic tumor cells to phenformin. Cancer Research, 75, 171–180.  https://doi.org/10.1158/0008-5472.CAN-14-2260.PubMedGoogle Scholar
  165. 165.
    Martinez-Outschoorn, U. E., Peiris-Pages, M., Pestell, R. G., Sotgia, F., & Lisanti, M. P. (2017). Cancer metabolism: a therapeutic perspective. Nature Reviews. Clinical Oncology, 14, 11–31.  https://doi.org/10.1038/nrclinonc.2016.60.PubMedGoogle Scholar
  166. 166.
    Supuran, C. T., & Winum, J. Y. (2015). Carbonic anhydrase IX inhibitors in cancer therapy: an update. Future Medicinal Chemistry, 7, 1407–1414.  https://doi.org/10.4155/fmc.15.71.Google Scholar
  167. 167.
    McDonald, P. C., Winum, J. Y., Supuran, C. T., & Dedhar, S. (2012). Recent developments in targeting carbonic anhydrase IX for cancer therapeutics. Oncotarget, 3, 84–97.  https://doi.org/10.18632/oncotarget.422.PubMedPubMedCentralGoogle Scholar
  168. 168.
    Pastorek, J., et al. (1994). Cloning and characterization of MN, a human tumor-associated protein with a domain homologous to carbonic anhydrase and a putative helix-loop-helix DNA binding segment. Oncogene, 9, 2877–2888.PubMedGoogle Scholar
  169. 169.
    Supuran, C. T., Scozzafava, A., & Casini, A. (2003). Carbonic anhydrase inhibitors. Medicinal Research Reviews, 23, 146–189.  https://doi.org/10.1002/med.10025.PubMedGoogle Scholar
  170. 170.
    Ilies, M. A., Vullo, D., Pastorek, J., Scozzafava, A., Ilies, M., Caproiu, M. T., Pastorekova, S., & Supuran, C. T. (2003). Carbonic anhydrase inhibitors. Inhibition of tumor-associated isozyme IX by halogenosulfanilamide and halogenophenylaminobenzolamide derivatives. Journal of Medicinal Chemistry, 46, 2187–2196.  https://doi.org/10.1021/jm021123s.PubMedGoogle Scholar
  171. 171.
    Supuran, C. T. (2018). Carbonic anhydrase inhibitors as emerging agents for the treatment and imaging of hypoxic tumors. Expert Opinion on Investigational Drugs, 27, 963–970.  https://doi.org/10.1080/13543784.2018.1548608.Google Scholar
  172. 172.
    Supuran, C. T. (2017). Carbonic anhydrase inhibition and the management of hypoxic tumors. Metabolites, 7.  https://doi.org/10.3390/metabo7030048.
  173. 173.
    Andreucci, E., Peppicelli, S., Carta, F., Brisotto, G., Biscontin, E., Ruzzolini, J., Bianchini, F., Biagioni, A., Supuran, C. T., & Calorini, L. (2017). Carbonic anhydrase IX inhibition affects viability of cancer cells adapted to extracellular acidosis. J Mol Med (Berl), 95, 1341–1353.  https://doi.org/10.1007/s00109-017-1590-9.Google Scholar
  174. 174.
    Lou, Y., McDonald, P. C., Oloumi, A., Chia, S., Ostlund, C., Ahmadi, A., Kyle, A., auf dem Keller, U., Leung, S., Huntsman, D., Clarke, B., Sutherland, B. W., Waterhouse, D., Bally, M., Roskelley, C., Overall, C. M., Minchinton, A., Pacchiano, F., Carta, F., Scozzafava, A., Touisni, N., Winum, J. Y., Supuran, C. T., & Dedhar, S. (2011). Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors. Cancer Research, 71, 3364–3376.  https://doi.org/10.1158/0008-5472.CAN-10-4261.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Smitha R. Pillai
    • 1
  • Mehdi Damaghi
    • 1
  • Yoshinori Marunaka
    • 2
    • 3
    • 4
  • Enrico Pierluigi Spugnini
    • 5
  • Stefano Fais
    • 6
    Email author
  • Robert J. Gillies
    • 1
    Email author
  1. 1.Department of Cancer PhysiologyH. Lee Moffitt Cancer Center and Research InstituteTampaUSA
  2. 2.Research Institute for Clinical PhysiologyKyotoJapan
  3. 3.Research Center for Drug Discovery and Pharmaceutical Development Science, Research Organization of Science and TechnologyRitsumeikan UniversityKusatsuJapan
  4. 4.Department of Molecular Cell PhysiologyKyoto Prefectural University of MedicineKyotoJapan
  5. 5.SAFU, Regina Elena Cancer InstituteRomeItaly
  6. 6.Department of Oncology and Molecular MedicineIstituto Superiore di Sanità (National Institute of Health)RomeItaly

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