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image of The Mesoionic 1,3,4-thiadiazolium Derivative, MI-D, is a Potential Drug for Treating Glioblastoma by Impairing Mitochondrial Functions Linked to Energy Provision in Glioma Cells

Abstract

Background

Mesoionic compound MI-D possesses important biological activities, such as anti-inflammatory and antitumoral against melanoma and hepatocarcinoma. Glioblastoma is the most aggressive and common central nervous system tumor in adults. Currently, chemotherapies are not entirely effective, and the survival of patients diagnosed with glioblastoma is extremely short.

Objective

In this study, we aimed to evaluate the cytotoxicity of MI-D in noninvasive A172 glioblastoma cells and establish which changes in functions linked to energy provision are associated with this effect.

Methods

Cells A172 were cultured under glycolysis and phosphorylation oxidative conditions and evaluated: viability by the MTT method, oxygen consumption by high-resolution respirometry, levels of pyruvate, lactate, citrate, and ATP, and glutaminase and citrate synthase activities by spectrophotometric methods.

Results

Under glycolysis-dependent conditions, MI-D caused significant cytotoxic effects with impaired cell respiration, reducing the maximal capacity of the electron transport chain. However, A172 cells were more susceptible to MI-D effects under oxidative phosphorylation-dependent conditions. At the IC inhibition of basal and maximal respiration of A172 cells was observed, without stimulation of the glycolytic pathway or Krebs cycle, along with inhibition of the activity of glutaminase enzyme, resulting in a 30% ATP deficit. Additionally, independent of metabolic conditions, MI-D treatment induced cell death in A172 cells by apoptosis machinery/processes.

Conclusion

The impairment of mitochondrial respiration by MI-D under the condition sustained by oxidative phosphorylation may enhance the cytotoxic effect on A172 glioma cells, although the mechanism of cell death relies on apoptosis.

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2024-10-21
2024-12-04

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References

  1. Paiva R.O. Kneipp L.F. dos Reis C.M. Echevarria A. Mesoionic compounds with antifungal activity against Fusarium verticillioides. BMC Microbiol. 2015 15 1 11 10.1186/s12866‑015‑0340‑9 25649493
    [Google Scholar]
  2. Zhang J. Song R. Wu S. Cai D. Wu Z. Liu Z. Hu D. Song B. Discovery of Pyrido[1,2- a ]pyrimidinone Mesoionic Compounds Incorporating a Dithioacetal Moiety as Novel Potential Insecticidal Agents. J. Agric. Food Chem. 2021 69 50 15136 15144 10.1021/acs.jafc.1c05823 34878774
    [Google Scholar]
  3. Brandt A.P. Gozzi G.J. Pires A.R.A. Martinez G.R. dos Santos Canuto A.V. Echevarria A. Di Pietro A. Cadena S.M.S.C. Impairment of oxidative phosphorylation increases the toxicity of SYD-1 on hepatocarcinoma cells (HepG2). Chem. Biol. Interact. 2016 256 154 160 10.1016/j.cbi.2016.07.007 27417255
    [Google Scholar]
  4. Senff-Ribeiro A. Echevarria A. Silva E.F. Franco C.R.C. Veiga S.S. Oliveira M.B.M. Cytotoxic effect of a new 1,3,4-thiadiazolium mesoionic compound (MI-D) on cell lines of human melanoma. Br. J. Cancer 2004 91 2 297 304 10.1038/sj.bjc.6601946 15199390
    [Google Scholar]
  5. Corrêa-Ferreira M.L. do Rocio Andrade Pires A. Barbosa I.R. Echevarria A. Pedrassoli G.H. Winnischofer S.M.B. Noleto G.R. Cadena S.M.S.C. The mesoionic compound MI-D changes energy metabolism and induces apoptosis in T98G glioma cells. Mol. Cell. Biochem. 2022 477 8 2033 2045 10.1007/s11010‑022‑04423‑2 35420333
    [Google Scholar]
  6. Newton C.G. Ramsden C.A. Meso-ionic heterocycles (1976–1980). Tetrahedron 1982 38 20 2965 3011 10.1016/0040‑4020(82)80186‑5
    [Google Scholar]
  7. Ferlay J. Ervik M. Lam F. Colombet M. Mery L. Piñeros M. Znaor A. Soerjomataram I.B.F. Global cancer observatory: Cancer today. 2024 Available from: https://gco.iarc.fr/today
  8. Cancer Stat Facts S.E.E.R. Brain and other nervous system cancer 2023 Available from: https://seer.cancer.gov/statfacts/html/brain.html
  9. Obara-Michlewska M. Szeliga M. Targeting glutamine addiction in gliomas. Cancers. Cancers (Basel). 2020 12 2 310
    [Google Scholar]
  10. Le Rhun E. Preusser M. Roth P. Reardon D.A. van den Bent M. Wen P. Reifenberger G. Weller M. Molecular targeted therapy of glioblastoma. Cancer Treat. Rev. 2019 80 101896 10.1016/j.ctrv.2019.101896 31541850
    [Google Scholar]
  11. Zanders E.D. Svensson F. Bailey D.S. Therapy for glioblastoma: Is it working? Drug Discov. Today 2019 24 5 1193 1201 10.1016/j.drudis.2019.03.008 30878561
    [Google Scholar]
  12. Minniti G. Muni R. Lanzetta G. Marchetti P. Enrici R.M. Chemotherapy for glioblastoma: current treatment and future perspectives for cytotoxic and targeted agents. Anticancer Res. 2009 29 12 5171 5184 20044633
    [Google Scholar]
  13. Colquhoun A. Cell biology-metabolic crosstalk in glioma. Int. J. Biochem. Cell Biol. 2017 89 171 181 10.1016/j.biocel.2017.05.022 28549626
    [Google Scholar]
  14. Cadena S.M.S.C. Carnieri E.G.S. Echevarria A. de Oliveira M.B.M. Effect of MI‐D, a new mesoionic compound, on energy‐linked functions of rat liver mitochondria. FEBS Lett. 1998 440 1-2 46 50 10.1016/S0014‑5793(98)01427‑6 9862422
    [Google Scholar]
  15. Senff-Ribeiro A. Echevarria A. Silva E.F. Veiga S.S. Oliveira M.B.M. Antimelanoma activity of 1,3,4-thiadiazolium mesoionics: A structure–activity relationship study. Anticancer Drugs 2004 15 3 269 275 10.1097/00001813‑200403000‑00012 15014361
    [Google Scholar]
  16. Gozzi G.J. Pires A.R.A. Valdameri G. Rocha M.E.M. Martinez G.R. Noleto G.R. Acco A. Alves de Souza C.E. Echevarria A. Moretto dos Reis C. Di Pietro A. Suter Correia Cadena S.M. Selective cytotoxicity of 1,3,4-thiadiazolium mesoionic derivatives on hepatocarcinoma cells (HepG2). PLoS One 2015 10 6 e0130046 10.1371/journal.pone.0130046 26083249
    [Google Scholar]
  17. Trombetta-Lima M. Winnischofer S.M.B. Demasi M.A.A. Filho R.A. Carreira A.C.O. Wei B. de Assis Ribas T. Konig M.S. Bowman-Colin C. Oba-Shinjo S.M. Marie S.K.N. Stetler-Stevenson W. Sogayar M.C. Isolation and characterization of novel RECK tumor suppressor gene splice variants. Oncotarget 2015 6 32 33120 33133 10.18632/oncotarget.5305 26431549
    [Google Scholar]
  18. Corrẽa T.C.S. Brohem C.A. Winnischofer S.M.B. da Silva Cardeal L.B. Sasahara R.M. Taboga S.R. Sogayar M.C. Maria-Engler S.S. Downregulation of the RECK ‐tumor and metastasis suppressor gene in glioma invasiveness. J. Cell. Biochem. 2006 99 1 156 167 10.1002/jcb.20917 16791855
    [Google Scholar]
  19. Grynberg N. Santos A.C. Echevarria A. Synthesis and in vivo antitumor activity of new heterocyclic derivatives of the 1,3,4-thiadiazolium-2-aminide class. Anticancer Drugs 1997 8 1 88 91 10.1097/00001813‑199701000‑00012 9147617
    [Google Scholar]
  20. Souza dos Santos A.C. Echevarria A. Electronic effects on 13 C NMR chemical shifts of substituted 1,3,4‐thiadiazolium salts. Magn. Reson. Chem. 2001 39 4 182 186 10.1002/mrc.812
    [Google Scholar]
  21. Reilly T.P. Bellevue F.H. III Woster P.M. Svensson C.K. Comparison of the in vitro cytotoxicity of hydroxylamine metabolites of sulfamethoxazole and dapsone. Biochem. Pharmacol. 1998 55 6 803 810 10.1016/S0006‑2952(97)00547‑9 9586952
    [Google Scholar]
  22. Sladowski D. Steer S.J. Clothier R.H. Balls M. An improved MIT assay. J. Immunol. Methods 1993 157 1-2 203 207 10.1016/0022‑1759(93)90088‑O 8423364
    [Google Scholar]
  23. Kumar P. Nagarajan A. Uchil P.D. Analysis of cell viability by the lactate dehydrogenase assay. Cold Spring Harb. Protoc. 2018 2018 6 pdb.prot095497 10.1101/pdb.prot095497 29858337
    [Google Scholar]
  24. Ruas J.S. Siqueira-Santos E.S. Amigo I. Rodrigues-Silva E. Kowaltowski A.J. Castilho R.F. Underestimation of the maximal capacity of the mitochondrial electron transport system in oligomycin-treated cells. PLoS One 2016 11 3 e0150967 10.1371/journal.pone.0150967 26950698
    [Google Scholar]
  25. Czok R Lamprecht W. Phosphoenolpyruvate and D-Glycerate-2-phosphate. Methods of enzymatic analysis. 1974 3 1446 1451
    [Google Scholar]
  26. Gutmann I. Wahlefeld A. L-(+)-Lactate Determination with Lactate Dehydrogenase and NAD. Methods in Enzymatic Analysis New York Academic Press 1974 1464 1468
    [Google Scholar]
  27. Board M. Humm S. Newsholme E.A. Maximum activities of key enzymes of glycolysis, glutaminolysis, pentose phosphate pathway and tricarboxylic acid cycle in normal, neoplastic and suppressed cells. Biochem. J. 1990 265 2 503 509 10.1042/bj2650503 2302181
    [Google Scholar]
  28. Curthoys N.P. Lowry O.H. The distribution of glutaminase isoenzymes in the various structures of the nephron in normal, acidotic, and alkalotic rat kidney. J. Biol. Chem. 1973 248 1 162 168 10.1016/S0021‑9258(19)44458‑X 4692829
    [Google Scholar]
  29. Kenny J. Bao Y. Hamm B. Taylor L. Toth A. Wagers B. Curthoys N.P. Bacterial expression, purification, and characterization of rat kidney-type mitochondrial glutaminase. Protein Expr. Purif. 2003 31 1 140 148 10.1016/S1046‑5928(03)00161‑X 12963351
    [Google Scholar]
  30. Marroquin L.D. Hynes J. Dykens J.A. Jamieson J.D. Will Y. Circumventing the Crabtree effect: Replacing media glucose with galactose increases susceptibility of HepG2 cells to mitochondrial toxicants. Toxicol. Sci. 2007 97 2 539 547 10.1093/toxsci/kfm052 17361016
    [Google Scholar]
  31. Aguer C. Gambarotta D. Mailloux R.J. Moffat C. Dent R. McPherson R. Harper M.E. Galactose enhances oxidative metabolism and reveals mitochondrial dysfunction in human primary muscle cells. PLoS One 2011 6 12 e28536 10.1371/journal.pone.0028536 22194845
    [Google Scholar]
  32. Gohil V.M. Sheth S.A. Nilsson R. Wojtovich A.P. Lee J.H. Perocchi F. Discovery and therapeutic potential of drugs that shift energy metabolism from mitochondrial respiration to glycolysis. Nat. Biotechnol. 2010 28 249 255 10.1038/nbt.1606 20160716
    [Google Scholar]
  33. Bradford M.M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 1976 72 1-2 248 254 10.1016/0003‑2697(76)90527‑3 942051
    [Google Scholar]
  34. Comelli M. Pretis I. Buso A. Mavelli I. Mitochondrial energy metabolism and signalling in human glioblastoma cell lines with different PTEN gene status. J. Bioenerg. Biomembr. 2018 50 1 33 52 10.1007/s10863‑017‑9737‑5 29209894
    [Google Scholar]
  35. Nguyen T. Durán R.V. Glutamine metabolism in cancer therapy. Cancer Drug Resist. 2018 1 126 138
    [Google Scholar]
  36. Chlastakova I Liskova M Kudelova J Dubska L Kleparnik K Matalova E Dynamics of caspase-3 activation and inhibition in embryonic micromasses evaluated by a photon-counting chemiluminescence approach. in vitro Cell Dev Biol Anim. 2012 48 9 545 549
    [Google Scholar]
  37. Rodrigues-Silva E. Siqueira-Santos E.S. Ruas J.S. Ignarro R.S. Figueira T.R. Rogério F. Castilho R.F. Evaluation of mitochondrial respiratory function in highly glycolytic glioma cells reveals low ADP phosphorylation in relation to oxidative capacity. J. Neurooncol. 2017 133 3 519 529 10.1007/s11060‑017‑2482‑0 28540666
    [Google Scholar]
  38. Molina J.R. Sun Y. Protopopova M. Gera S. Bandi M. Bristow C. McAfoos T. Morlacchi P. Ackroyd J. Agip A.N.A. Al-Atrash G. Asara J. Bardenhagen J. Carrillo C.C. Carroll C. Chang E. Ciurea S. Cross J.B. Czako B. Deem A. Daver N. de Groot J.F. Dong J.W. Feng N. Gao G. Gay J. Do M.G. Greer J. Giuliani V. Han J. Han L. Henry V.K. Hirst J. Huang S. Jiang Y. Kang Z. Khor T. Konoplev S. Lin Y.H. Liu G. Lodi A. Lofton T. Ma H. Mahendra M. Matre P. Mullinax R. Peoples M. Petrocchi A. Rodriguez-Canale J. Serreli R. Shi T. Smith M. Tabe Y. Theroff J. Tiziani S. Xu Q. Zhang Q. Muller F. DePinho R.A. Toniatti C. Draetta G.F. Heffernan T.P. Konopleva M. Jones P. Di Francesco M.E. Marszalek J.R. An inhibitor of oxidative phosphorylation exploits cancer vulnerability. Nat. Med. 2018 24 7 1036 1046 10.1038/s41591‑018‑0052‑4 29892070
    [Google Scholar]
  39. Dott W. Mistry P. Wright J. Cain K. Herbert K.E. Modulation of mitochondrial bioenergetics in a skeletal muscle cell line model of mitochondrial toxicity. Redox Biol. 2014 2 224 233 10.1016/j.redox.2013.12.028 24494197
    [Google Scholar]
  40. Porporato P.E. Filigheddu N. Pedro J.M.B.S. Kroemer G. Galluzzi L. Mitochondrial metabolism and cancer. Cell Res. 2018 28 3 265 280 10.1038/cr.2017.155 29219147
    [Google Scholar]
  41. Wang X. Chen Y. Wang J. Liu Z. Zhao S. Antitumor activity of a sulfated polysaccharide from Enteromorpha intestinalis targeted against hepatoma through mitochondrial pathway. Tumour Biol. 2014 35 2 1641 1647 10.1007/s13277‑013‑1226‑9 24197975
    [Google Scholar]
  42. Pereira R.A. Pires A.R.A. Echevarria A. Sousa-Pereira D. Noleto G.R. Suter Correia Cadena S.M. The toxicity of 1,3,4-thiadiazolium mesoionic derivatives on hepatocarcinoma cells (HepG2) is associated with mitochondrial dysfunction. Chem. Biol. Interact. 2021 349 109675 10.1016/j.cbi.2021.109675 34563518
    [Google Scholar]
  43. Sheikh TN Patwardhan PP Cremers S Schwartz GK Targeted inhibition of glutaminase as a potential new approach for the treatment of NF1 associated soft tissue malignancies. Oncotarget. 2017 8 55 94054 94068 10.18632/oncotarget.21573
    [Google Scholar]
/content/journals/acamc/10.2174/0118715206329159241010052746
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The Mesoionic 1,3,4-thiadiazolium Derivative, MI-D, is a Potential Drug for Treating Glioblastoma by Impairing Mitochondrial Functions Linked to Energy Provision in Glioma Cells
Bentham Science Publishers ; https://doi.org/10.2174/0118715206329159241010052746
/content/journals/acamc/10.2174/0118715206329159241010052746
/content/journals/acamc/10.2174/0118715206329159241010052746
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  • Article Type:     Research Article
Keywords: MI-D ; Glioma ; respiratory chain ; glycolysis ; A172 cells ; 1,3,4-thiazolium mesoionic

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