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. 1989 Dec;86(23):9494–9498. doi: 10.1073/pnas.86.23.9494

Lithium chloride potentiates tumor necrosis factor-mediated cytotoxicity in vitro and in vivo.

R Beyaert 1, B Vanhaesebroeck 1, P Suffys 1, F Van Roy 1, W Fiers 1
PMCID: PMC298523  PMID: 2556714

Abstract

Tumor necrosis factor (TNF) is cytotoxic for several transformed cell lines in vitro. In the presence of LiCl, the murine fibrosarcoma cell lines L929 and WEHI 164 clone 13 became greater than 10 times more sensitive to TNF-mediated cytotoxicity. The human tumor cell lines BT20 and HeLa D98/AH2 were also responsive to the cytotoxicity-enhancing effect of LiCl. Other monovalent or divalent cations did not affect TNF-mediated cytotoxicity. The potentiating effect of LiCl on TNF cytotoxicity was largely independent of transcription, and LiCl could be added to the cells as early as 2 hr before or as late as 4 hr after TNF without loss of effectiveness. The mechanism by which LiCl increases the cytotoxic response seems to differ from the sensitizing effect of actinomycin D or interferon gamma, since the latter treatments overcame TNF resistance of several cell lines, whereas LiCl did not. Evidence is presented that LiCl acts, either directly or indirectly, via the TNF-activated phospholipase A2 pathway. In nude mice, a combination of TNF and LiCl led to hemorrhagic necrosis and growth inhibition of L929 tumors, whereas little effect was observed when TNF was administered alone. HeLa D98/AH2 tumors also were sensitive to the potentiating effect of LiCl in vivo. We conclude that LiCl enhances the effectiveness of TNF in vitro and in vivo, results that may have therapeutic implications.

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Selected References

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  1. Avissar S., Schreiber G., Danon A., Belmaker R. H. Lithium inhibits adrenergic and cholinergic increases in GTP binding in rat cortex. Nature. 1988 Feb 4;331(6155):440–442. doi: 10.1038/331440a0. [DOI] [PubMed] [Google Scholar]
  2. Balkwill F. R., Lee A., Aldam G., Moodie E., Thomas J. A., Tavernier J., Fiers W. Human tumor xenografts treated with recombinant human tumor necrosis factor alone or in combination with interferons. Cancer Res. 1986 Aug;46(8):3990–3993. [PubMed] [Google Scholar]
  3. Benos D. J. Amiloride: a molecular probe of sodium transport in tissues and cells. Am J Physiol. 1982 Mar;242(3):C131–C145. doi: 10.1152/ajpcell.1982.242.3.C131. [DOI] [PubMed] [Google Scholar]
  4. Bray J., Turner A. R., Dusel F. Lithium and the mitogenic response of human lymphocytes. Clin Immunol Immunopathol. 1981 May;19(2):284–288. doi: 10.1016/0090-1229(81)90070-2. [DOI] [PubMed] [Google Scholar]
  5. Carswell E. A., Old L. J., Kassel R. L., Green S., Fiore N., Williamson B. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A. 1975 Sep;72(9):3666–3670. doi: 10.1073/pnas.72.9.3666. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Devos R., Opsomer C., Scahill S. J., Van der Heyden J., Fiers W. Purification of recombinant glycosylated human gamma interferon expressed in transformed Chinese hamster ovary cells. J Interferon Res. 1984 Fall;4(4):461–468. doi: 10.1089/jir.1984.4.461. [DOI] [PubMed] [Google Scholar]
  7. Downes C. P., Stone M. A. Lithium-induced reduction in intracellular inositol supply in cholinergically stimulated parotid gland. Biochem J. 1986 Feb 15;234(1):199–204. doi: 10.1042/bj2340199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Fiers W., Beyaert R., Brouckaert P., Everaerdt B., Haegeman G., Suffys P., Tavernier J., Vandenabeele P., Vanhaesebroeck B., Van Ostade X. Gene cloning and structure--function relationship of cytokines such as TNF and interleukins. Immunol Lett. 1987 Dec;16(3-4):219–226. doi: 10.1016/0165-2478(87)90150-7. [DOI] [PubMed] [Google Scholar]
  9. Fransen L., Müller R., Marmenout A., Tavernier J., Van der Heyden J., Kawashima E., Chollet A., Tizard R., Van Heuverswyn H., Van Vliet A. Molecular cloning of mouse tumour necrosis factor cDNA and its eukaryotic expression. Nucleic Acids Res. 1985 Jun 25;13(12):4417–4429. doi: 10.1093/nar/13.12.4417. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Fransen L., Van der Heyden J., Ruysschaert R., Fiers W. Recombinant tumor necrosis factor: its effect and its synergism with interferon-gamma on a variety of normal and transformed human cell lines. Eur J Cancer Clin Oncol. 1986 Apr;22(4):419–426. doi: 10.1016/0277-5379(86)90107-0. [DOI] [PubMed] [Google Scholar]
  11. Fuggetta M. P., Alvino E., Romani L., Grohmann U., Potenza C., Giuliani A. Increase of natural killer activity of mouse lymphocytes following in vitro and in vivo treatment with lithium. Immunopharmacol Immunotoxicol. 1988;10(1):79–91. doi: 10.3109/08923978809014403. [DOI] [PubMed] [Google Scholar]
  12. Hart D. A., Groenewoud Y., Chamberland S. Characterization of lithium-induced enzyme release from human polymorphonuclear leukocytes. Biochem Cell Biol. 1986 Sep;64(9):880–885. doi: 10.1139/o86-117. [DOI] [PubMed] [Google Scholar]
  13. Imamura K., Sherman M. L., Spriggs D., Kufe D. Effect of tumor necrosis factor on GTP binding and GTPase activity in HL-60 and L929 cells. J Biol Chem. 1988 Jul 25;263(21):10247–10253. [PubMed] [Google Scholar]
  14. Ives H. E., Yee V. J., Warnock D. G. Mixed type inhibition of the renal Na+/H+ antiporter by Li+ and amiloride. Evidence for a modifier site. J Biol Chem. 1983 Aug 25;258(16):9710–9716. [PubMed] [Google Scholar]
  15. Lapetina E. G., Billah M. M., Cuatrecasas P. The initial action of thrombin on platelets. Conversion of phosphatidylinositol to phosphatidic acid preceding the production of arachidonic acid. J Biol Chem. 1981 May 25;256(10):5037–5040. [PubMed] [Google Scholar]
  16. Majerus P. W., Connolly T. M., Bansal V. S., Inhorn R. C., Ross T. S., Lips D. L. Inositol phosphates: synthesis and degradation. J Biol Chem. 1988 Mar 5;263(7):3051–3054. [PubMed] [Google Scholar]
  17. Naccarato W. F., Ray R. E., Wells W. W. Biosynthesis of myo-inositol in rat mammary gland. Isolation and properties of the enzymes. Arch Biochem Biophys. 1974 Sep;164(1):194–201. doi: 10.1016/0003-9861(74)90022-8. [DOI] [PubMed] [Google Scholar]
  18. Neale M. L., Fiera R. A., Matthews N. Involvement of phospholipase A2 activation in tumour cell killing by tumour necrosis factor. Immunology. 1988 May;64(1):81–85. [PMC free article] [PubMed] [Google Scholar]
  19. Paris S., Pouysségur J. Further evidence for a phospholipase C-coupled G protein in hamster fibroblasts. Induction of inositol phosphate formation by fluoroaluminate and vanadate and inhibition by pertussis toxin. J Biol Chem. 1987 Feb 15;262(5):1970–1976. [PubMed] [Google Scholar]
  20. Perez H. D., Kaplan H. B., Goldstein I. M., Shenkman L., Borkowsky W. Reversal of an abnormality of polymorphonuclear leukocyte chemotaxis with lithium. Clin Immunol Immunopathol. 1980 Jul;16(3):308–315. doi: 10.1016/0090-1229(80)90136-1. [DOI] [PubMed] [Google Scholar]
  21. Richman C. M., Kinnealey A., Hoffman P. C. Granulopoietic effects of lithium on human bone marrow in vitro. Exp Hematol. 1981 Apr;9(4):449–455. [PubMed] [Google Scholar]
  22. Russell W. C., Newman C., Williamson D. H. A simple cytochemical technique for demonstration of DNA in cells infected with mycoplasmas and viruses. Nature. 1975 Feb 6;253(5491):461–462. doi: 10.1038/253461a0. [DOI] [PubMed] [Google Scholar]
  23. Scahill S. J., Devos R., Van der Heyden J., Fiers W. Expression and characterization of the product of a human immune interferon cDNA gene in Chinese hamster ovary cells. Proc Natl Acad Sci U S A. 1983 Aug;80(15):4654–4658. doi: 10.1073/pnas.80.15.4654. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Suffys P., Beyaert R., Van Roy F., Fiers W. Involvement of a serine protease in tumour-necrosis-factor-mediated cytotoxicity. Eur J Biochem. 1988 Dec 1;178(1):257–265. doi: 10.1111/j.1432-1033.1988.tb14451.x. [DOI] [PubMed] [Google Scholar]
  25. Suffys P., Beyaert R., Van Roy F., Fiers W. Reduced tumour necrosis factor-induced cytotoxicity by inhibitors of the arachidonic acid metabolism. Biochem Biophys Res Commun. 1987 Dec 16;149(2):735–743. doi: 10.1016/0006-291x(87)90429-3. [DOI] [PubMed] [Google Scholar]
  26. Suffys P., Beyaert R., Van Roy F., Fiers W. TNF in combination with interferon-gamma is cytotoxic to normal, untransformed mouse and rat embryo fibroblast-like cells. Anticancer Res. 1989 Jan-Feb;9(1):167–171. [PubMed] [Google Scholar]
  27. Volonté C. Lithium stimulates the binding of GTP to the membranes of PC12 cells cultured with nerve growth factor. Neurosci Lett. 1988 Apr 22;87(1-2):127–132. doi: 10.1016/0304-3940(88)90157-7. [DOI] [PubMed] [Google Scholar]
  28. Williamson B. D., Carswell E. A., Rubin B. Y., Prendergast J. S., Old L. J. Human tumor necrosis factor produced by human B-cell lines: synergistic cytotoxic interaction with human interferon. Proc Natl Acad Sci U S A. 1983 Sep;80(17):5397–5401. doi: 10.1073/pnas.80.17.5397. [DOI] [PMC free article] [PubMed] [Google Scholar]

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