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Anticarcinogenic properties of malic acid on glioblastoma cell line through necrotic cell death mechanism

Year 2021, Volume: 9 Issue: 1, 22 - 29, 30.06.2021
https://doi.org/10.51354/mjen.848282

Abstract

This study aimed to investigate the anticarcinogenic and genotoxic damage potentials of malic acid on human fibroblast cells (HDFa) and glioblastoma (U87-MG) cell lines. MTT cell viability and LDH release assays were performed to understand cytotoxic features of malic acid on different cell lines. Also, Hoechst 33258 fluorescent staining was used to monitor nuclear abnormalities including micronucleus, lobbed, and notched structures. Furthermore, cellular death mechanisms behind the malic acid application were investigated via the use of flow cytometry analysis. According to cell viability analysis, malic acid showed a greater effect on U87-MG compared to HDFa cell line in terms of cytotoxicity. Similarly, chromosomal integrity assay put forth a higher number of nuclear abnormalities in U87-MG cells when compared to HDFa cell lines, and aberrations were analyzed to amplify when malic acid concentration increased. Finally, flow cytometry analysis demonstrated higher necrotic cell death in U87-MG cells than HDFa cell line. On the other hand, apoptotic cell death was the main cytotoxic mechanism against malic acid exposure in the HDFa cell line. In light of these results, it can be concluded that in higher concentrations, malic acid has an anticarcinogenic effect on glioblastoma cells via the necrotic pathway, and it also shows apoptotic properties on the fibroblast cell line. When mutagenic properties are compared, it could be understood that malic acid had a greater impact on glioblastoma cells.

References

  • Pal SK, Mittal B. "Improving cancer care in India: Prospects and challenges", Asian Pacific J Cancer Prev 5, (2004), 226–228.
  • Caparica R, Júlio A, Araújo MEM, Baby AR, Fonte P, Costa JG, et al. "Anticancer Activity of Rutin and Its Combination with Ionic Liquids on Renal Cells", Biomolecules, 10, (2020), 233.
  • Pitucha M, Korga-Plewko A, Kozyra P, Iwan M, Kaczor AA. "2,4-Dichlorophenoxyacetic Thiosemicarbazides as a New Class of Compounds against Stomach Cancer Potentially Intercalating with DNA", Biomolecules, 10, (2020), 296.
  • Lambert J-C, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, et al. "Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease", Nat Genet, 45, (2013), 1452–1458.
  • Sato A, Sunayama J, Okada M, Watanabe E, Seino S, Shibuya K, et al. "Glioma-Initiating Cell Elimination by Metformin Activation of FOXO3 via AMPK. Stem Cells", Transl Med, 1, (2012), 811–824
  • Marinelli L, Fornasari E, Eusepi P, Ciulla M, Genovese S, Epifano F, et al. "Carvacrol prodrugs as novel antimicrobial agents", Eur J Med Chem, 178, (2019), 515–529.
  • Turkez H, Togar B, Polat E. "Olive leaf extract modulates permethrin induced genetic and oxidative damage in rats", Cytotechnology, 64, (2012), 459–464.
  • Turkez H, Geyikoglu F, Yousef MI. "Beneficial effect of astaxanthin on 2,3,7,8-tetrachlorodibenzo- p -dioxin-induced liver injury in rats", Toxicol Ind Health, 29, (2013), 591–599
  • Ploskonos M v., Syatkin S p., Neborak E v., Hilal A, Sungrapova K y., Sokuyev R i., et al. "Polyamine Analogues of Propanediamine Series Inhibit Prostate Tumor Cell Growth and Activate the Polyamine Catabolic Pathway", Anticancer Res, 40, (2020), 1437–1441.
  • Al Bawab A, Friberg SE, Bergamaschi MM, Santos ODH. "Some non-equilibrium phenomena in the malic acid/water/Polysorbate 81 system", Int J Pharm, 332, (2007), 140–146.
  • Fiume MZ. "Final Report on the Safety Assessment of Malic Acid and Sodium Malate", Int J Toxicol, 20, (2001), 47–55.
  • Tyka AK, Chwastowski M, Cison T, Palka T, Tyka A, Szygula Z, et al. "Effect of creatine malate supplementation on physical performance, body composition and selected hormone levels in spinters and long-distance runners", Acta Physiol Hung, 102, (2015), 114–122.
  • Manfredini R, De Giorgi A, Storari A, Fabbian F. "Pears and renal stones: Possible weapon for prevention? A comprehensive narrative review", Eur Rev Med Pharmacol Sci, 20, (2016), 414-25
  • Gõmez-Moreno G, Aguilar-Salvatierra A, Guardia J, Uribe-Marioni A, Cabrera-Ayala M, Delgado-Ruiz RA, et al. "The efficacy of a topical sialogogue spray containing 1% malic acid in patients with antidepressant-induced dry mouth: A double-blind, randomized clinical trial", Depress Anxiety, 30, (2013), 137–142.
  • Ljubimova JY, Fujita M, Khazenzon NM, Lee B-S, Wachsmann-Hogiu S, Farkas DL, et al. "Nanoconjugate based on polymalic acid for tumor targeting", Chem Biol Interact, 171, (2008), 195–203.
  • Ljubimova JY, Fujita M, Ljubimov A V., Torchilin VP, Black KL, Holler E. "Poly(malic acid) nanoconjugates containing various antibodies and oligonucleotides for multitargeting drug delivery", Nanomedicine, 3, (2008), 247–265.
  • Tang S-C, Yang J-H. Dual "Effects of Alpha-Hydroxy Acids on the Skin", Molecules, 23, (2018), 863.
  • Hsiao Y-P, Lai W-W, Wu S-B, Tsai C-H, Tang S-C, Chung J-G, et al. "Triggering Apoptotic Death of Human Epidermal Keratinocytes by Malic Acid: Involvement of Endoplasmic Reticulum Stress- and Mitochondria-Dependent Signaling Pathways", Toxins (Basel), 7, (2015), 81–96.
  • Fujita M, Lee B-S, Khazenzon NM, Penichet ML, Wawrowsky KA, Patil R, et al. "Brain tumor tandem targeting using a combination of monoclonal antibodies attached to biopoly(β-l-malic acid)", J Control Release, 122, (2007), 356–363.
  • Fujita M, Khazenzon NM, Ljubimov A V., Lee B-S, Virtanen I, Holler E, et al. "Inhibition of laminin-8 in vivo using a novel poly(malic acid)-based carrier reduces glioma angiogenesis", Angiogenesis, 9, (2006), 183–191
  • Galstyan A, Markman JL, Shatalova ES, Chiechi A, Korman AJ, Patil R, et al. "Blood–brain barrier permeable nano immunoconjugates induce local immune responses for glioma therapy", Nat Commun, 10, (2019), 3850.
  • Emsen B, Aslan A, Turkez H, Joughi A, Kaya A. "The anti-cancer efficacies of diffractaic, lobaric, and usnic acid: In vitro inhibition of glioma", J Cancer Res Ther, 14, (2018), 941.
  • Türkez H, Arslan ME, Özdemir Ö, Chikha O. "Ameliorative effect of boric acid against nicotine-induced cytotoxicity on cultured human primary alveolar epithelial cells", BORON, 1, (2016), 104–109.
  • Türkez H, Arslan ME, Sönmez E, Açikyildiz M, Tatar A, Geyikoğlu F. "Synthesis, characterization and cytotoxicity of boron nitride nanoparticles: emphasis on toxicogenomics", Cytotechnology, 71, (2019), 351–361.
  • Turkez H, Arslan ME, Ozdemir O. "Genotoxicity testing: progress and prospects for the next decade", Expert Opin Drug Metab Toxicol, 13, (2017), 1–10.
  • Marinelli L, Fornasari E, Di Stefano A, Turkez H, Arslan ME, Eusepi P, et al. "(R)-α-Lipoyl-Gly-L-Pro-L-Glu dimethyl ester as dual acting agent for the treatment of Alzheimer’s disease", Neuropeptides, 66, (2017), 52–58.
  • Iyyappan J, Bharathiraja B, Baskar G, Kamalanaban E. "Process optimization and kinetic analysis of malic acid production from crude glycerol using Aspergillus niger", Bioresour Technol, 281, (2019), 18–25.
  • Dai Z, Zhou H, Zhang S, Gu H, Yang Q, Zhang W, et al. "Current advance in biological production of malic acid using wild type and metabolic engineered strains", Bioresour Technol, 258, (2018), 345–353.
  • Chiriac A, Brzezinski P. "Topical malic acid in combination with citric acid: an option to treat recalcitrant warts", Dermatol Ther, 28, (2015), 336–338.
  • Ouchi T, Fujino A, Tanaka K, Banba T. "Synthesis and antitumor activity of conjugates of poly(α-malic acid) and 5-fluorouracils bound via ester, amide or carbamoyl bonds", J Control Release, 12, (1990), 143–153.
  • Ouchi T, Kobayashi H, Hirai K, Ohya Y. "Design of Poly(α-malic acid)—Antitumor Drug—Saccharide Conjugate Exhibiting Cell-Specific Antitumor Activity", Pol Del Sys, 520, (1993), 382–94.
  • Al-Ani FY, Al-Lami SK. "Absence of mutagenic activity of acidity regulators in the Ames Salmonella/microsome test", Mutat Res Toxicol, 206, (1988), 467–470.
  • Kuroda M, Yoshida D, Mizusaki S. "Mutagenicity of pyrolyzates of natural substances toward Salmonella typhimurium TA97", Agric Biol Chem, 49, (1985), 1893–1895.
  • Ishidate M, Sofuni T, Yoshikawa K, Hayashi M, Nohmi T, Sawada M, et al. "Primary mutagenicity screening of food additives currently used in Japan", Food Chem Toxicol, 22, (1984), 623–636.
  • Guo H, Chen H, Hong C, Jiang D, Zheng B. "Exogenous malic acid alleviates cadmium toxicity in Miscanthus sacchariflorus through enhancing photosynthetic capacity and restraining ROS accumulation", Ecotoxicol Environ Saf, 141, (2017), 119–128.
  • Domingo JL, Gómez M, Llobet JM, Corbella J. "Citric, malic and succinic acids as possible alternatives to deferoxamine in aluminum toxicity", J Toxicol Clin Toxicol, 26, (1988), 67–79.
  • Majida A.J. al-Qayim and Sawsan Mashi. "Renal effects of propolis and malic acid in Aluminium Exposed Male Rats", Appl Sci Reports, 1, (2014).
  • Al-qayim MAJ, Saadoon D. "Assessment of the Ameliorative Role of Proplis and Malic Acid in Intestinal and Liver Functions of Aluminum", Int J Sci Nat, (2013).
Year 2021, Volume: 9 Issue: 1, 22 - 29, 30.06.2021
https://doi.org/10.51354/mjen.848282

Abstract

References

  • Pal SK, Mittal B. "Improving cancer care in India: Prospects and challenges", Asian Pacific J Cancer Prev 5, (2004), 226–228.
  • Caparica R, Júlio A, Araújo MEM, Baby AR, Fonte P, Costa JG, et al. "Anticancer Activity of Rutin and Its Combination with Ionic Liquids on Renal Cells", Biomolecules, 10, (2020), 233.
  • Pitucha M, Korga-Plewko A, Kozyra P, Iwan M, Kaczor AA. "2,4-Dichlorophenoxyacetic Thiosemicarbazides as a New Class of Compounds against Stomach Cancer Potentially Intercalating with DNA", Biomolecules, 10, (2020), 296.
  • Lambert J-C, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, et al. "Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease", Nat Genet, 45, (2013), 1452–1458.
  • Sato A, Sunayama J, Okada M, Watanabe E, Seino S, Shibuya K, et al. "Glioma-Initiating Cell Elimination by Metformin Activation of FOXO3 via AMPK. Stem Cells", Transl Med, 1, (2012), 811–824
  • Marinelli L, Fornasari E, Eusepi P, Ciulla M, Genovese S, Epifano F, et al. "Carvacrol prodrugs as novel antimicrobial agents", Eur J Med Chem, 178, (2019), 515–529.
  • Turkez H, Togar B, Polat E. "Olive leaf extract modulates permethrin induced genetic and oxidative damage in rats", Cytotechnology, 64, (2012), 459–464.
  • Turkez H, Geyikoglu F, Yousef MI. "Beneficial effect of astaxanthin on 2,3,7,8-tetrachlorodibenzo- p -dioxin-induced liver injury in rats", Toxicol Ind Health, 29, (2013), 591–599
  • Ploskonos M v., Syatkin S p., Neborak E v., Hilal A, Sungrapova K y., Sokuyev R i., et al. "Polyamine Analogues of Propanediamine Series Inhibit Prostate Tumor Cell Growth and Activate the Polyamine Catabolic Pathway", Anticancer Res, 40, (2020), 1437–1441.
  • Al Bawab A, Friberg SE, Bergamaschi MM, Santos ODH. "Some non-equilibrium phenomena in the malic acid/water/Polysorbate 81 system", Int J Pharm, 332, (2007), 140–146.
  • Fiume MZ. "Final Report on the Safety Assessment of Malic Acid and Sodium Malate", Int J Toxicol, 20, (2001), 47–55.
  • Tyka AK, Chwastowski M, Cison T, Palka T, Tyka A, Szygula Z, et al. "Effect of creatine malate supplementation on physical performance, body composition and selected hormone levels in spinters and long-distance runners", Acta Physiol Hung, 102, (2015), 114–122.
  • Manfredini R, De Giorgi A, Storari A, Fabbian F. "Pears and renal stones: Possible weapon for prevention? A comprehensive narrative review", Eur Rev Med Pharmacol Sci, 20, (2016), 414-25
  • Gõmez-Moreno G, Aguilar-Salvatierra A, Guardia J, Uribe-Marioni A, Cabrera-Ayala M, Delgado-Ruiz RA, et al. "The efficacy of a topical sialogogue spray containing 1% malic acid in patients with antidepressant-induced dry mouth: A double-blind, randomized clinical trial", Depress Anxiety, 30, (2013), 137–142.
  • Ljubimova JY, Fujita M, Khazenzon NM, Lee B-S, Wachsmann-Hogiu S, Farkas DL, et al. "Nanoconjugate based on polymalic acid for tumor targeting", Chem Biol Interact, 171, (2008), 195–203.
  • Ljubimova JY, Fujita M, Ljubimov A V., Torchilin VP, Black KL, Holler E. "Poly(malic acid) nanoconjugates containing various antibodies and oligonucleotides for multitargeting drug delivery", Nanomedicine, 3, (2008), 247–265.
  • Tang S-C, Yang J-H. Dual "Effects of Alpha-Hydroxy Acids on the Skin", Molecules, 23, (2018), 863.
  • Hsiao Y-P, Lai W-W, Wu S-B, Tsai C-H, Tang S-C, Chung J-G, et al. "Triggering Apoptotic Death of Human Epidermal Keratinocytes by Malic Acid: Involvement of Endoplasmic Reticulum Stress- and Mitochondria-Dependent Signaling Pathways", Toxins (Basel), 7, (2015), 81–96.
  • Fujita M, Lee B-S, Khazenzon NM, Penichet ML, Wawrowsky KA, Patil R, et al. "Brain tumor tandem targeting using a combination of monoclonal antibodies attached to biopoly(β-l-malic acid)", J Control Release, 122, (2007), 356–363.
  • Fujita M, Khazenzon NM, Ljubimov A V., Lee B-S, Virtanen I, Holler E, et al. "Inhibition of laminin-8 in vivo using a novel poly(malic acid)-based carrier reduces glioma angiogenesis", Angiogenesis, 9, (2006), 183–191
  • Galstyan A, Markman JL, Shatalova ES, Chiechi A, Korman AJ, Patil R, et al. "Blood–brain barrier permeable nano immunoconjugates induce local immune responses for glioma therapy", Nat Commun, 10, (2019), 3850.
  • Emsen B, Aslan A, Turkez H, Joughi A, Kaya A. "The anti-cancer efficacies of diffractaic, lobaric, and usnic acid: In vitro inhibition of glioma", J Cancer Res Ther, 14, (2018), 941.
  • Türkez H, Arslan ME, Özdemir Ö, Chikha O. "Ameliorative effect of boric acid against nicotine-induced cytotoxicity on cultured human primary alveolar epithelial cells", BORON, 1, (2016), 104–109.
  • Türkez H, Arslan ME, Sönmez E, Açikyildiz M, Tatar A, Geyikoğlu F. "Synthesis, characterization and cytotoxicity of boron nitride nanoparticles: emphasis on toxicogenomics", Cytotechnology, 71, (2019), 351–361.
  • Turkez H, Arslan ME, Ozdemir O. "Genotoxicity testing: progress and prospects for the next decade", Expert Opin Drug Metab Toxicol, 13, (2017), 1–10.
  • Marinelli L, Fornasari E, Di Stefano A, Turkez H, Arslan ME, Eusepi P, et al. "(R)-α-Lipoyl-Gly-L-Pro-L-Glu dimethyl ester as dual acting agent for the treatment of Alzheimer’s disease", Neuropeptides, 66, (2017), 52–58.
  • Iyyappan J, Bharathiraja B, Baskar G, Kamalanaban E. "Process optimization and kinetic analysis of malic acid production from crude glycerol using Aspergillus niger", Bioresour Technol, 281, (2019), 18–25.
  • Dai Z, Zhou H, Zhang S, Gu H, Yang Q, Zhang W, et al. "Current advance in biological production of malic acid using wild type and metabolic engineered strains", Bioresour Technol, 258, (2018), 345–353.
  • Chiriac A, Brzezinski P. "Topical malic acid in combination with citric acid: an option to treat recalcitrant warts", Dermatol Ther, 28, (2015), 336–338.
  • Ouchi T, Fujino A, Tanaka K, Banba T. "Synthesis and antitumor activity of conjugates of poly(α-malic acid) and 5-fluorouracils bound via ester, amide or carbamoyl bonds", J Control Release, 12, (1990), 143–153.
  • Ouchi T, Kobayashi H, Hirai K, Ohya Y. "Design of Poly(α-malic acid)—Antitumor Drug—Saccharide Conjugate Exhibiting Cell-Specific Antitumor Activity", Pol Del Sys, 520, (1993), 382–94.
  • Al-Ani FY, Al-Lami SK. "Absence of mutagenic activity of acidity regulators in the Ames Salmonella/microsome test", Mutat Res Toxicol, 206, (1988), 467–470.
  • Kuroda M, Yoshida D, Mizusaki S. "Mutagenicity of pyrolyzates of natural substances toward Salmonella typhimurium TA97", Agric Biol Chem, 49, (1985), 1893–1895.
  • Ishidate M, Sofuni T, Yoshikawa K, Hayashi M, Nohmi T, Sawada M, et al. "Primary mutagenicity screening of food additives currently used in Japan", Food Chem Toxicol, 22, (1984), 623–636.
  • Guo H, Chen H, Hong C, Jiang D, Zheng B. "Exogenous malic acid alleviates cadmium toxicity in Miscanthus sacchariflorus through enhancing photosynthetic capacity and restraining ROS accumulation", Ecotoxicol Environ Saf, 141, (2017), 119–128.
  • Domingo JL, Gómez M, Llobet JM, Corbella J. "Citric, malic and succinic acids as possible alternatives to deferoxamine in aluminum toxicity", J Toxicol Clin Toxicol, 26, (1988), 67–79.
  • Majida A.J. al-Qayim and Sawsan Mashi. "Renal effects of propolis and malic acid in Aluminium Exposed Male Rats", Appl Sci Reports, 1, (2014).
  • Al-qayim MAJ, Saadoon D. "Assessment of the Ameliorative Role of Proplis and Malic Acid in Intestinal and Liver Functions of Aluminum", Int J Sci Nat, (2013).
There are 38 citations in total.

Details

Primary Language English
Subjects Engineering
Journal Section Research Article
Authors

Mehmet Enes Arslan 0000-0002-1600-2305

Publication Date June 30, 2021
Published in Issue Year 2021 Volume: 9 Issue: 1

Cite

APA Arslan, M. E. (2021). Anticarcinogenic properties of malic acid on glioblastoma cell line through necrotic cell death mechanism. MANAS Journal of Engineering, 9(1), 22-29. https://doi.org/10.51354/mjen.848282
AMA Arslan ME. Anticarcinogenic properties of malic acid on glioblastoma cell line through necrotic cell death mechanism. MJEN. June 2021;9(1):22-29. doi:10.51354/mjen.848282
Chicago Arslan, Mehmet Enes. “Anticarcinogenic Properties of Malic Acid on Glioblastoma Cell Line through Necrotic Cell Death Mechanism”. MANAS Journal of Engineering 9, no. 1 (June 2021): 22-29. https://doi.org/10.51354/mjen.848282.
EndNote Arslan ME (June 1, 2021) Anticarcinogenic properties of malic acid on glioblastoma cell line through necrotic cell death mechanism. MANAS Journal of Engineering 9 1 22–29.
IEEE M. E. Arslan, “Anticarcinogenic properties of malic acid on glioblastoma cell line through necrotic cell death mechanism”, MJEN, vol. 9, no. 1, pp. 22–29, 2021, doi: 10.51354/mjen.848282.
ISNAD Arslan, Mehmet Enes. “Anticarcinogenic Properties of Malic Acid on Glioblastoma Cell Line through Necrotic Cell Death Mechanism”. MANAS Journal of Engineering 9/1 (June 2021), 22-29. https://doi.org/10.51354/mjen.848282.
JAMA Arslan ME. Anticarcinogenic properties of malic acid on glioblastoma cell line through necrotic cell death mechanism. MJEN. 2021;9:22–29.
MLA Arslan, Mehmet Enes. “Anticarcinogenic Properties of Malic Acid on Glioblastoma Cell Line through Necrotic Cell Death Mechanism”. MANAS Journal of Engineering, vol. 9, no. 1, 2021, pp. 22-29, doi:10.51354/mjen.848282.
Vancouver Arslan ME. Anticarcinogenic properties of malic acid on glioblastoma cell line through necrotic cell death mechanism. MJEN. 2021;9(1):22-9.

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