Summary
The effect of non-steroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid (commonly known as aspirin), salicylic acid, piroxicam and indomethacin on the growth of rat glioma cells (RG 2)in vitro and aspirinin vivo was studied. Thein vitro studies reveal that aspirin and salicylic acid strongly inhibit growth of rat glioma (RG 2) cells in concentrations used in medicine for treatment of rheumatic diseases. On the other hand, indomethacin and piroxicam had no effect, indicating that the inhibitory effect on tumor growth is not due to the inhibition of prostaglandin synthesis. The synthesis of ATP was markedly reduced (34% of control) in the presence of drugs, whereas protein synthesis measured as3H-leucine incorporation was slightly more inhibited (73% of control) than cell growth. Aspirin administered to Fischer 344 rats inhibited growth of RG 2 cells inoculated into the caudate nucleusin vivo, both when administered the day before inoculation of tumor cells and when tumors had formed, i.e. 5 days post inoculation.
Similar content being viewed by others
References
Kernohan JW, Mabon RF, Svien HJ, Adson AW: A simplified classification of the gliomas. Proc Staff Meet Mayo Clin 24: 71–75, 1949
Salford LG, Brun A, Nirfalk S: Ten-year survival among patients with supratentorial astrocytomas grade III and IV. J Neurosurg 69: 506–509, 1988
Hial V, Horakova Z, Shaff RE, Beaven MA: Alteration of growth by aspirin and indomethacin: Studies with two transplantable tumors in mouse. Eur J Pharmacol 37: 367–376, 1976
Lynch NR, Castes M, Astoin M: Mechanism of inhibition of tumor growth by aspirin and indomethacin. Br J Cancer 38: 503–512, 1978
Kort WJ, Hulsman OM, van Schalkwijk V, Weljma IM: Reductive effect of aspirin treatment on primary tumor growth and metastasis of implanted fibrosarcoma in rats. JNCI 76: 711–717, 1986
Farrel CL, Megyesi J, Del Maestro RF: Effect of ibuprofen on tumor growth in the C6 spheroid implantation glioma model. J Neurosurg 68(6): 925–930, 1988
Thun MJ, Namboodiri MM, Calle EE, Flanders WD, Heath CW Jr: Aspirin use and risk of fatal cancer. Cancer Res 53: 1322–1327, 1993
Tønnessen TI, Aas AT, Sandvig K, Olsnes S: Effect of antiinflammatory analgesic drugs on the regulation of cytosolic pH by anion antiport. J Pharmacol Exp Ther 248: 1197–1206, 1989
Kariuri AR, Dobrowsky E, Tannock IF: Selective cellular acidification and toxicity of weak organic acids in an acidic microenvironment. Br J Cancer 68: 1080–1087, 1993
Newell KJ, Tannock IF: Reduction of intracellular pH as a possible mechanism for killing cells in acidic regions of solid tumors: Effect of carbonylcyanide-3-chlorphenyIhydralazone. Cancer Res 49: 4477–4482, 1989
Tannock IF, Rotin D: Acid pH in tumors and its potential for therapeutic exploitation. Cancer Res 49: 4373–4384, 1989
Johnson JD, Epel D: Intracellular pH and activation of sea urchin eggs after fertilization. Nature (London) 262: 661–664, 1976
Schulinder R, Rozengurt E: Na+/H+ antiport in Swiss 3T3 cells: Mitogenic stimulation leads to cytoplasmic alkalinisation. Proc Natl Acad Sci USA 79: 7778–7782, 1982
L'Allemain G, Paris S, Franchi A, Cragoe EJ Jr, Pouyssegur J: Blockade of the Na+/H+ antiport abolishes growth factor induced DNA synthesis in fibroblasts. Structure-activity relationships in the amiloride series. J Biol Chem 259: 4313–4319, 1984
Moolenaar WH, Tertoolen LG, De Laat SW: Phorbol ester and diacylglycerol mimic growth factors in raising cytoplasmic pH. Nature (London) 312: 371–374, 1984
L'Allemain G, Paris S, Pouyssegur J: Role of the Na+-dependent Cl−/HCO −3 exchange in regulation of intracellular pH in fibroblasts. J Biol Chem 260: 4877–4883, 1985
Wechsler W, Kleihues P, Matsumoto S, Zulch KT, Ivankovic S, Preussman R, Druckrey H: Pathology of experimental neurogenic tumors chemically induced during prenatal and postnatal life. Ann NY Acad Sci 159: 360–408, 1969
Mies G, Paschen W, Csiba L, Krajewski S, Wechsler W, Hossman KA: Comparison of regional tissue pH measured with the umbilliferonemethod and14C-DMO technique in rat brain. J Cereb Blood Flow Metab (Suppl) 5: 247–248, 1985
Aas AT, Brun A, Pero RW, Salford LG: Chlorpromazine in combination with nitrosourea inhibits experimental glioma growth. Br J Neurosurg 8: 187–192, 1994
Insel PA: Analgesic-antipyretics and antiinflammatory agents; drugs employed in the treatment of rheumatoid arthritis and gout. In: Gilman AG, Rall TW, Nies AS, Taylor P (eds) The Pharmacological Basis of Therapeutics. Pergamon Press, New York 638–681, 1990
Tönnessen TI, Ludt J, Sandvig K, Olsnes S: Bicarbonate/chloride antiport in Vero cells: I. Evidence for both sodiumlinked and sodium-independent exchange. J Cell Physiol 132: 183–191, 1987
Olsnes S, Ludt J, Tönnessen TI, Sandvig K: Bicarbonate/chloride antiport in Vero cells: Mechanisms for bicarbonatedependent regulation of intracellular pH. J Cell Physiol 132: 192–202, 1987
Vane JR: Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature New Biology 231: 232–235, 1971
Rosoff PM, Stein LF, Cantley LC: Phorbol esters induce differentiation in a pre-B-lymphocyte cell line by enhancing Na+/H+ exchange. J Biol Chem 259: 7056–7060, 1984
Ober SS, Pardee AB: Intracellular pH is increased after transforming of Chinese hamster embryo fibroblasts. Proc Natl Acad Sci USA 84: 2766–2770, 1987
Rotin D, Steele-Norwood D, Grinstein S, Tannock I: Requirement of the Na+/H+ exchanger for tumor growth. Cancer Res 49: 205–211, 1989
Vaughan-Jones RD: Regulation of chloride in quiescent sheep heart Purkinje fibres studied using intracellular chloride and pH-sensitive microelectrodes. J Physiol 295: 111137, 1979
Roos A, Boron WF: Intracellular pH. Physiol Rev 61: 296–434, 1981
Jentsch TJ, Janicke I, Sorgenfrei D, Keller SK, Wiederholt M: The regulation of intracellular pH in monkey kidney epithelial cells (BSC-1). Roles of Na+/H+ antiport, Na+-HCO3-(NaHCO3 −) symport and Cl−/HCO3 − exchange. J Biol Chem 261: 12120–12127, 1986
Cassel D, Whitely B, Zhaung T, Glaser L: Mitogenic-inde-pendent activation of the Na+/H+ exchange in human epidermoid carcinoma A431 cells: Regulation by medium osmolarity. J Cell Physiol 122: 178–186, 1985
Bierman AJ, Cragoe EJ Jr, de Laat SW, Moolenaar WH: Bicarbonate determines cytoplasmic pH and suppresses mitogen-induced alkalinization in fibroblastic cells. J Biol Chem 263: 15253–15256, 1988
Ganz MB, Boyarsky G, Sterzel RB, Boron WF: Arginine vasopressin enhances pHi regulation in the presence of HCO3 } by stimulating the three acid-base transport systems. Nature 337: 648–651, 1989
Reinertsen KV, Tönnessen TI, Jacobsen J, Sandvig K, Olsnes S: Role of chloride/bicarbonate antiport in the control of cytosolic pH. J Biol Chem 263: 11117–11125, 1988
Rottenberg DA, Ginos JZ, Kearfott KJ, Junck L, Bignern DD:In vivo measurement of regional brain tissue pH using positron emission tomography. Ann Neurol 15(suppl): S98–102, 1984
Oberhaensli RD, Bore PJ, Rampling RP, Hilton-Jones D, Hands LJ, Radda GK: Biochemical investigation of human tumorsin vivo with phosphorus-31 magnetic resonance spectroscopy. The Lancet, July 5th, pp 8–11, 1986
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Aas, A.T., Tønnessen, T.I., Brun, A. et al. Growth inhibition of rat glioma cellsin vitro andin vivo by aspirin. J Neuro-Oncol 24, 171–180 (1995). https://doi.org/10.1007/BF01078487
Issue Date:
DOI: https://doi.org/10.1007/BF01078487