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Mechanism of action of lonidamine in the 9L brain tumor model involves inhibition of lactate efflux and intracellular acidification

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Abstract

Malignant gliomas have been associated with a high rate of glycolytic activity which is believed necessary to sustain cellular function and integrity. Since lonidamine (LND) is believed to reduce tumor glucose utilization by inhibition of the mitochondrially-bound glycolytic enzyme hexokinase (HK), 31P magnetic resonance spectroscopy (MRS) was used to noninvasively follow the effects of LND on both tumor pH and the high-energy phosphate metabolites; ATP, phosphocreatine (PCr) and inorganic phosphate (Pi) in subcutaneous rat 9L gliosarcomas. 31P tumor spectra acquired in 5 min intervals pre- and post LND administration of 50 and 100 mg/kg, i.p. revealed an acidotic pH shift of − 0.25 and − 0.45 pH units, respectively within 30 min post administration. The ATP/Pi ratio of 9L tumors decreased to 40% of control and Pi levels increased to 280% of control over a 3 hr period. LND exerted no effect on tumor blood flow and mean arterial blood pressure. Brain and muscle metabolite levels and pH were also unaffected by LND. In vitro measurements of cultured 9L tumor cell intra- and extracellular lactate, pentose phosphate pathway (PPP) and hexokinase (HK) activities suggest that the mode of action of LND involves inhibition of lactate efflux and intracellular acidification. The selective reduction of tumor energy metabolites and pH by LND may be exploitable for sensitizing gliomas to radiation, chemotherapy or hyperthermia.

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References

  1. Rhodes CG, Wise RJS, Gibbs JM, Frackowiak RSJ, Hatazawa J, Palmer AJ, Thomas DGT, Jones T: In vivo disturbance of the oxidative metabolism of glucose in human cerebral gliomas. Ann Neurol 14: 614–626, 1983

    Google Scholar 

  2. Di Chiro G, Brooks RA, Patronas HJ, Bairmain D, Kornblith PL, Smith BH, Mansi L, Barker J: Issues in the in vivo measurement of glucose metabolism of central nervous system tumors. Ann Neurol 15 (suppl): S138–S146, 1984

    Google Scholar 

  3. Weinhouse S: Glycolysis, respiration, and anomalous gene expression in experimental hepatomas: G.H.A. Clowes memorial lecture. Cancer Res 32: 2007–2016, 1972

    Google Scholar 

  4. Bustamante E, Pedersen PL: High aerobic glycolysis of rat hepatoma cells in culture: role of mitochondrial hexokinase. Proc Natl Acad Sci USA 74: 3735–3739, 1977

    Google Scholar 

  5. Parry DM, Pedersen PL: Intracellular localization and properties of particulate hexokinase in the Novikoff ascites tumor. Evidence for an outer mitochondrial membrane location. J Biol Chem 258: 10904–10912, 1983

    Google Scholar 

  6. Oudard S, Poirson F, Miccoli L, Bourgeois Y, Vassault A, Poisson M, Magdelenat H, Dutrillaux B, Poupon M-F: Mitochondria-bound hexokinase as target for therapy of malignant gliomas. Int J Cancer 62: 216–222, 1995

    Google Scholar 

  7. Arora KK, Pedersen PL: Functional significance of mitochondrial bound hexokinase in tumor cell metabolism. Evidence for preferential phosphorylation of glucose by intramitochondrially generated ATP. J Biol Chem 263: 17422–17428, 1988

    Google Scholar 

  8. Floridi A, Paggi MG, Marcante ML, Silvestrini B, Caputo A, De Martino C: Lonidamine, a selective inhibitor of aerobic glycolysis of murine tumor cells. J Natl Cancer Inst 66: 497–499, 1981

    Google Scholar 

  9. Floridi A, Paggi MG, D'Altri S, De Martino C, Marcante ML, Silvestrini B, Caputo A: Effect of lonidamine on energy metabolism in Ehrlich ascites tumor cells. Cancer Res 41: 4661–4666, 1981

    Google Scholar 

  10. Hahn GM, Van Kersen I, Silvestrini B: Inhibition of the recovery from potential lethal damage by lonidamine. Br J Cancer 50: 657–6601, 1984

    Google Scholar 

  11. Kim JH, Alfieri A, Kim SH, Young CW, Silvestrini B: Radiosensitization of Meth-A fibrosarcoma in mice by lonidamine. Oncology 41 (Suppl 1): 36–38, 1984

    Google Scholar 

  12. Kim JH, Alfieri A, Kim SH, Young CW: Potentiation of radiation effects on two murine tumors by lonidamine. Cancer Res 46: 1120–1123, 1986

    Google Scholar 

  13. Kim JH, Kim SH, Alfieri A, Young CW, Silvestrini B: Lonidamine: A hyperthermic sensitizer of HeLa cells in culture and of the Meth-A tumor in vivo. Oncology 41: 30–35, 1984

    Google Scholar 

  14. Adwankar MK, Chitinis MP: Modification of tumor cell sensitivity to antineoplastic agents lonidamine and bouvardin (NSC 259968) at elevated temperatures. Neoplasma 2: 217–223, 1986

    Google Scholar 

  15. Floridi A, Gambacurta A, Bgnato A, Bianchi C, Paggi MG, Silvestrini B: Modulation of adriamycin uptake by lonidamine in Ehrlich ascites tumor cells. Exp Mol Pathol 49: 421–431, 1988

    Google Scholar 

  16. Rosbe KW, Brann TW, Holden SA, Tiecher BA, Frei E: Effect of lonidamine on the erythrotoxicity of four alkalating agents in vitro. Cancer Chemother Pharmacol 1: 32–36, 1989

    Google Scholar 

  17. Arancia G, Malorni W, Crateri Trovaluschi P, Isacchi G, Giannela G, De Martino C: Differential effect of lonidamine on the plasma membrane ultrastructure of normal and leukemic human lymphocytes. Exp Mol Pathol 48: 37–47, 1988

    Google Scholar 

  18. Malorni W, Meschini S, Mararrese P, Arancia G: The cytoskeleton as a subcellular target of antineoplastic drug lonidamine. Anticancer Res 12: 2037–2045, 1992

    Google Scholar 

  19. Castilgione S, Kennedy KA, Floridi A, Fiskum G: Nonionophoretic elevation of intracellular Ca2+ by lonidamine. Biochem Pharmacol 46: 330–332, 1993

    Google Scholar 

  20. Ben-Horin H, Tassini M, Vivi A, Navon G, Kaplan O: Mechanism of action of the antineoplastic drug lonidamine: 31P and 13C nuclear magnetic resonance studies. Cancer Res 55: 2814–2821, 1995

    Google Scholar 

  21. Lyons JC, Kim GE, Song CW: Modification of intracellular pH and thermosensitivity. Radiation Res 129: 79–87, 1992

    Google Scholar 

  22. Ben-Yoseph O, Kingsley PB, Camp DM, Robinson TE, Ross BD: Measurement of pentose phosphate pathway activity by microdialysis in vivo and in a single incubation in vitro. Neurosci Protocols 94: 060–02–01–13, 1994

    Google Scholar 

  23. Ross BD, Kingsley PB, Ben-Yoseph O: Measurement of pentose phosphate pathway activity in a single incubation with [1,6-13C2,6,6-2H2]glucose. Biochem J 302: 31–38, 1994

    Google Scholar 

  24. Wilson JE: Rapid purification of mitochondrial hexokinase from rat brain by a single affinity chromatography step on Affi-Gel blue. Prep Biochem 19: 13–21, 1989

    Google Scholar 

  25. Stubbs M, Vanstapel F, Rodrigues LM, Griffiths JR: Phosphate metabolites in rat skin. NMR Biomed 1: 50–55, 1988

    Google Scholar 

  26. De Martino C, Battelli T, Paggi MG, Nista A, Marcante ML, D'Atri S, Malorni W, Gallo M, Floridi A: Effects of lonidamine on murine and human tumor cells in vitro: A morphological and biochemical study. Oncology 41 (Suppl 1): 15– 29, 1984

    Google Scholar 

  27. Spencer TL, Lehninger AL: L-lactate transport in Ehrlich ascites tumor cells. Biochem J 154: 405–414, 1976

    Google Scholar 

  28. Song CW, Lyons JC, Makepeace CM, Griffin RJ, Cragoe EJ: Effects of HMA, an analog of amiloride, on the thermosensitivity of tumors in vivo. Int J Radiat Oncol Biol Phys 30: 133–139, 1994

    Google Scholar 

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Authors and Affiliations

  1. Department of Radiology, University of Michigan, Ann Arbor, USA

    Oded Ben-Yoseph

  2. Department of Therapeutic Radiology, University of Minnesota, Minneapolis, USA

    John C. Lyons, Chang W. Song & Brian D. Ross

Authors
  1. Oded Ben-Yoseph
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  2. John C. Lyons
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  3. Chang W. Song
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  4. Brian D. Ross
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Ben-Yoseph, O., Lyons, J.C., Song, C.W. et al. Mechanism of action of lonidamine in the 9L brain tumor model involves inhibition of lactate efflux and intracellular acidification. J Neurooncol 36, 149–157 (1998). https://doi.org/10.1023/A:1005819604858

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