Apoptotic and antiproliferative effects of amantadine and rimantadine in glioblastoma cells

Thitima Kasemsuk, Ruenruthai Kaeopu, Ruedeemars Yubolphan, Suttinee Phuagkhaopong, Pornpun Vivithanaporn

Abstract


Introduction: Glioblastoma (GBM) is a highly invasive tumor with a poor response to standard chemotherapeutic agents. Amantadine, an anti-influenza A with anti-Parkinson’s effect, inhibits cell proliferation and induces apoptosis in hepatocellular cancer cells. Rimantadine, a derivative of amantadine with comparable effect on influenza, also improves symptoms of Parkinson’s disease. Objectives: The present study aimed to investigate apoptotic and antiproliferative effects of amantadine and rimantadine in two GBM cell lines, A172 and U-87 MG. Materials and methods: Cell viability was measured by methyl-thiazolyl tetrazolium assays. Cell apoptosis, cell proliferation, and cell cycle analysis were determined by flow cytometry using Annexin V/7-aminoactinomycin D, carboxyfluorescein diacetate succinimidyl ester, and propidium iodide staining, respectively. Results: Rimantadine demonstrated greater cytotoxic effect than amantadine in both cell lines. Rimantadine at 500 μM increased the percentage of early and late apoptosis, while amantadine induced the late apoptosis only in U-87 MG cells. Amantadine and rimantadine at 250-500 μM suppressed cell proliferation only in U-87 MG cells. Furthermore, 500 μM of both drugs induced G0/G1 arrest in U-87 MG cells. Conclusion: Amantadine and rimantadine induce apoptosis and inhibit proliferation through G0/G1 arrest; however, rimantadine shows higher toxicity, suggesting the greater therapeutic potential of rimantadine for GBM.

Full Text:

119-124;PDF

References


Betakova T. M2 protein-a proton channel of influenza A virus. Curr Pharm Des 2007;13(31):3231-3235.

Blanpied TA, Clarke RJ, Johnson JW. Amantadine inhibits NMDA receptors by accelerating channel closure during channel block. J Neurosci 2005;25(13):3312-3322.

Mizoguchi K, Yokoo H, Yoshida M, Tanaka T, Tanaka M. Amantadine increases the extracellular dopamine levels in the striatum by re-uptake inhibition and by N-methyl-D-aspartate antagonism. Brain Res 1994;662(1-2):255-258.

Evidente VG, Adler CH, Caviness JN, Gwinn-Hardy K. A pilot study on the motor effects of rimantadine in Parkinson's disease. Clin Neuropharmacol 1999;22(1):30-32.

Singer C, Papapetropoulos S, Gonzalez MA, Roberts EL, Lieberman A. Rimantadine in Parkinson's disease patients experiencing peripheral adverse effects from amantadine: report of a case series. Mov Disord 2005;20(7):873-877.

Dolin R, Reichman RC, Madore HP, Maynard R, Linton PN, Webber-Jones J. A controlled trial of amantadine and rimantadine in the prophylaxis of influenza A infection. N Engl J Med 1982;307(10):580-584.

Hayden FG, Gwaltney JM, Jr., Van de Castle RL, Adams KF, Giordani B. Comparative toxicity of amantadine hydrochloride and rimantadine hydrochloride in healthy adults. Antimicrob Agents Chemother 1981;19(2):226-233.

Keyser LA, Karl M, Nafziger AN, Bertino JS, Jr. Comparison of central nervous system adverse effects of amantadine and rimantadine used as sequential prophylaxis of influenza A in elderly nursing home patients. Arch Intern Med 2000;160(10):1485-1488.

Kaefer V, Semedo JG, Silva Kahl VF, Von Borowsky RG, Gianesini J, Ledur Kist TB, et al. DNA damage in brain cells and behavioral deficits in mice after treatment with high doses of amantadine. J Appl Toxicol 2010;30(8):745-753.

Bogler O, Weller M. Apoptosis in gliomas, and its role in their current and future treatment. Front Biosci 2002;7:e339-353.

Evan GI, Vousden KH. Proliferation, cell cycle and apoptosis in cancer. Nature 2001;411(6835):342.

Lan Z, Chong Z, Liu C, Feng D, Fang D, Zang W, et al. Amantadine inhibits cellular proliferation and induces the apoptosis of hepatocellular cancer cells in vitro. Int J Mol Med 2015;36(3):904-910.

Piromkraipak P, Parakaw T, Phuagkhaopong S, Srihirun S, Chongthammakun S, Chaithirayanon K, et al. Cysteinyl leukotriene receptor antagonists induce apoptosis and inhibit proliferation of human glioblastoma cells by downregulating B-cell lymphoma 2 and inducing cell cycle arrest. Can J Physiol Pharmacol 2018;96(8):798-806.

Spector R. Transport of amantadine and rimantadine through the blood-brain barrier. J Pharmacol Exp Ther 1988;244(2):516-519.

Kornhuber J, Quack G, Danysz W, Jellinger K, Danielczyk W, Gsell W, et al. Therapeutic brain concentration of the NMDA receptor antagonist amantadine. Neuropharmacology 1995;34(7):713-721.

Stensjoen AL, Solheim O, Kvistad KA, Haberg AK, Salvesen O, Berntsen EM. Growth dynamics of untreated glioblastomas in vivo. Neuro Oncol 2015;17(10):1402-1411.

Clark C, Woodson MM, Nagasawa HT. Inhibition of lymphocyte proliferation by amantadine and its isomer, 2-aminoadamantane; impact on Lyt-2+ T cells while sparing L3T4+ T cells. Immunopharmacology 1991;21(1):41-50.

MacLachlan TK, Sang N, Giordano A. Cyclins, cyclin-dependent kinases and cdk inhibitors: implications in cell cycle control and cancer. Crit Rev Eukaryot Gene Expr 1995;5(2).

Transm JN. Amantadine and memantine are NMDA receptor antagonists with neuroprotective properties. J Neural Transm 1994;43:91-104.

Caumont AS, Octave JN, Hermans E. Amantadine and memantine induce the expression of the glial cell line-derived neurotrophic factor in C6 glioma cells. Neurosci Lett 2006;394(3):196-201.

Ossola B, Schendzielorz N, Chen SH, Bird GS, Tuominen RK, Mannisto PT, et al. Amantadine protects dopamine neurons by a dual action: reducing activation of microglia and inducing expression of GDNF in astroglia [corrected]. Neuropharmacology 2011;61(4):574-582.

Kim JH, Lee HW, Hwang J, Kim J, Lee MJ, Han HS, et al. Microglia-inhibiting activity of Parkinson's disease drug amantadine. Neurobiol Aging 2012;33(9):2145-2159.

Drayton SJ, Davies K, Steinberg M, Leroi I, Rosenblatt A, Lyketsos CG. Amantadine for executive dysfunction syndrome in patients with dementia. Psychosomatics 2004;45(3):205-209.

Giacino JT, Whyte J, Bagiella E, Kalmar K, Childs N, Khademi A, et al. Placebo-controlled trial of amantadine for severe traumatic brain injury. N Engl J Med 2012;366(9):819-826.

Stelmaschuk S, Will MC, Meyers T. Amantadine to Treat Cognitive Dysfunction in Moderate to Severe Traumatic Brain Injury. J Trauma Nurs 2015;22(4):194-203; quiz E191-192.

Ghalaenovi H, Fattahi A, Koohpayehzadeh J, Khodadost M, Fatahi N, Taheri M, et al. The effects of amantadine on traumatic brain injury outcome: a double-blind, randomized, controlled, clinical trial. Brain Inj 2018;32(8):1050-1055.

Zoidis G, Kolocouris N, Naesens L, De Clercq E. Design and synthesis of 1, 2-annulated adamantane piperidines with anti-influenza virus activity. Bioorg Med Chem 2009;17(4):1534-1541.

Manchand PS, Cerruti RL, Martin JA, Hill CH, Merrett JH, Keech E, et al. Synthesis and antiviral activity of metabolites of rimantadine. J Med Chem 1990;33(7):1992-1995.

Zoidis G, Kolocouris N, Foscolos GB, Kolocouris A, Fytas G, Karayannis P, et al. Are the 2-isomers of the drug rimantadine active anti-influenza A agents? Antivir Chem Chemother 2003;14(3):153-164.

Zoidis G, Fytas C, Papanastasiou I, Foscolos GB, Fytas G, Padalko E, et al. Heterocyclic rimantadine analogues with antiviral activity. Bioorg Med Chem 2006;14(10):3341-3348.

Garcia JC, Justo JF, Machado WV, Assali LV. Structural, electronic, and vibrational properties of amino-adamantane and rimantadine isomers. J Phys Chem A 2010;114(44):11977-11983.

Warnick JE, Jessup PJ, Overman LE, Eldefrawi ME, Nimit Y, Daly J, et al. Pumiliotoxin-C and synthetic analogues. A new class of nicotinic antagonists. Mol Pharmacol 1982;22(3):565-573.

Kelly JM, Quack G, Miles MM. In vitro and in vivo activities of aminoadamantane and aminoalkylcyclohexane derivatives against Trypanosoma brucei. Antimicrob Agents Chemother 2001;45(5):1360-1366.

Papanastasiou I, Tsotinis A, Kolocouris N, Prathalingam SR, Kelly JM. Design, synthesis, and trypanocidal activity of new aminoadamantane derivatives. J Med Chem 2008;51(5):1496-1500.


Refbacks

  • There are currently no refbacks.