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image of Molecular and Biochemical Evidence of Edaravone's Impact on Dasatinib-induced AGS Cell Senescence: A Promising Strategy for Gastric Cancer Therapy

Abstract

Introduction

Internal or external stress can induce cellular senescence, which reduces cell division. These metabolically active cells contribute to medication resistance. We examined the potential for edaravone (Eda) to cause apoptosis in dasatinib (Das)-induced senescent gastric adenocarcinoma cells (AGS). Our goal was to develop a new stomach cancer treatment.

Methods

All Eda doses evaluated were nontoxic to cells. Das decreased AGS cell survival in a dose-dependent manner. The study found that Das (5-10 μM) and Eda (100 μM) caused cell senescence in AGS cells. This was shown by increased β-galactosidase enzyme activity and reactive oxygen species levels and decreased telomerase enzyme activity. These are the biggest signs of aging.

Results

This combination therapy also upregulated the expression of cell-senescence genes p53, p16, p21, and p38. This resulted in increased expression of inflammation genes such as TNF-α, IL-1β, and IL-6.

Conclusion

The scratch assay showed that this combination medication down-regulated the cell migration-regulating matrix metalloproteinase-2 (MMP2) gene. Both Das and Eda decreased AGS cell proliferation, suggesting treatment with Eda may prevent metastasis.

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2025-02-24
2025-06-23

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References

  1. Kong M. Chen H. Zhang R. Sheng H. Li L. Overall survival advantage of omentum preservation over omentectomy for advanced gastric cancer: A systematic review and meta-analysis. World J. Surg. 2022 46 8 1952 1961 10.1007/s00268‑022‑06562‑5 35462593
    [Google Scholar]
  2. Krenzien F. Nevermann N. Krombholz A. Benzing C. Haber P. Fehrenbach U. Lurje G. Pelzer U. Pratschke J. Schmelzle M. Schöning W. Treatment of intrahepatic cholangiocarcinoma-a multidisciplinary approach. Cancers 2022 14 2 362 10.3390/cancers14020362 35053523
    [Google Scholar]
  3. Wagner A.D. Syn N.L. Moehler M. Grothe W. Yong W.P. Tai B.C. Ho J. Unverzagt S. Chemotherapy for advanced gastric cancer. Cochrane Database Syst. Rev. 2017 8 8 CD004064 28850174
    [Google Scholar]
  4. Kalmuk J. Rinder D. Heltzel C. Lockhart A.C. An overview of the preclinical discovery and development of trastuzumab deruxtecan: A novel gastric cancer therapeutic. Expert Opin. Drug Discov. 2022 17 5 427 436 10.1080/17460441.2022.2050692 35426752
    [Google Scholar]
  5. Wu P.C. Wang Q. Grobman L. Chu E. Wu D.Y. Accelerated cellular senescence in solid tumor therapy. Exp. Oncol. 2012 34 3 298 305 23070015
    [Google Scholar]
  6. Kregel K.C. Zhang H.J. An integrated view of oxidative stress in aging: Basic mechanisms, functional effects, and pathological considerations. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2007 292 1 R18 R36 10.1152/ajpregu.00327.2006 16917020
    [Google Scholar]
  7. Lin J. Epel E. Stress and telomere shortening: Insights from cellular mechanisms. Ageing Res. Rev. 2022 73 101507 10.1016/j.arr.2021.101507 34736994
    [Google Scholar]
  8. Liao Z. Yeo H.L. Wong S.W. Zhao Y. Cellular senescence: Mechanisms and therapeutic potential. Biomedicines 2021 9 12 1769 10.3390/biomedicines9121769 34944585
    [Google Scholar]
  9. Sanada F. Taniyama Y. Muratsu J. Otsu R. Shimizu H. Rakugi H. Morishita R. IGF binding protein-5 induces cell senescence. Front. Endocrinol. 2018 9 53 10.3389/fendo.2018.00053 29515523
    [Google Scholar]
  10. Mosieniak G. Sliwinska M.A. Alster O. Strzeszewska A. Sunderland P. Piechota M. Was H. Sikora E. Polyploidy formation in doxorubicin-treated cancer cells can favor escape from senescence. Neoplasia 2015 17 12 882 893 10.1016/j.neo.2015.11.008 26696370
    [Google Scholar]
  11. Watanabe S. Kawamoto S. Ohtani N. Hara E. Impact of senescence-associated secretory phenotype and its potential as a therapeutic target for senescence-associated diseases. Cancer Sci. 2017 108 4 563 569 10.1111/cas.13184 28165648
    [Google Scholar]
  12. Campisi J. Kim S. Lim C.S. Rubio M. Cellular senescence, cancer and aging: The telomere connection. Exp. Gerontol. 2001 36 10 1619 1637 10.1016/S0531‑5565(01)00160‑7 11672984
    [Google Scholar]
  13. Demaria M. O’Leary M.N. Chang J. Shao L. Liu S. Alimirah F. Koenig K. Le C. Mitin N. Deal A.M. Alston S. Academia E.C. Kilmarx S. Valdovinos A. Wang B. Bruin d.A. Kennedy B.K. Melov S. Zhou D. Sharpless N.E. Muss H. Campisi J. Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. Cancer Discov. 2017 7 2 165 176 10.1158/2159‑8290.CD‑16‑0241 27979832
    [Google Scholar]
  14. Shi M. Lou B. Ji J. Shi H. Zhou C. Yu Y. Liu B. Zhu Z. Zhang J. Synergistic antitumor effects of dasatinib and oxaliplatin in gastric cancer cells. Cancer Chemother. Pharmacol. 2013 72 1 35 44 10.1007/s00280‑013‑2166‑1 23712327
    [Google Scholar]
  15. Wang X. Xue Q. Wu L. Wang B. Liang H. Retracted: Dasatinib promotes TRAIL -mediated apoptosis by upregulating CHOP -dependent death receptor 5 in gastric cancer. FEBS Open Bio. 2018 8 5 732 742 10.1002/2211‑5463.12404 29744288
    [Google Scholar]
  16. Choi K.M. Cho E. Bang G. Lee S.J. Kim B. Kim J.H. Park S.G. Han E.H. Chung Y.H. Kim J.Y. Kim E. Kim J.Y. Activity-based protein profiling reveals potential dasatinib targets in gastric cancer. Int. J. Mol. Sci. 2020 21 23 9276 10.3390/ijms21239276 33291786
    [Google Scholar]
  17. Song Y. Sun X. Bai W.L. Ji W.Y. Antitumor effects of Dasatinib on laryngeal squamous cell carcinoma in vivo and in vitro. Eur. Arch. Otorhinolaryngol. 2013 270 4 1397 1404 10.1007/s00405‑013‑2394‑3 23404469
    [Google Scholar]
  18. Hegedüs L. Szücs K.D. Kudla M. Heidenreich J. Jendrossek V. Peña-Llopis S. Garay T. Czirok A. Aigner C. Plönes T. Vega-Rubin-de-Celis S. Hegedüs B. Nintedanib and dasatinib treatments induce protective autophagy as a potential resistance mechanism in mpm cells. Front. Cell Dev. Biol. 2022 10 852812 10.3389/fcell.2022.852812 35392170
    [Google Scholar]
  19. Witzel S. Maier A. Steinbach R. Grosskreutz J. Koch J.C. Sarikidi A. Petri S. Günther R. Wolf J. Hermann A. Prudlo J. Cordts I. Lingor P. Löscher W.N. Kohl Z. Hagenacker T. Ruckes C. Koch B. Spittel S. Günther K. Michels S. Dorst J. Meyer T. Ludolph A.C. Safety and effectiveness of long-term intravenous administration of edaravone for treatment of patients with amyotrophic lateral sclerosis. JAMA Neurol. 2022 79 2 121 130 10.1001/jamaneurol.2021.4893 35006266
    [Google Scholar]
  20. Luo L. Song Z. Li X. Huiwang Zeng Y. Qinwang Meiqi He J. Efficacy and safety of edaravone in treatment of amyotrophic lateral sclerosis—a systematic review and meta-analysis. Neurol. Sci. 2019 40 2 235 241 10.1007/s10072‑018‑3653‑2 30483992
    [Google Scholar]
  21. Yang Y. Yi J. Pan M. Hu B. Duan H. Edaravone alleviated propofol-induced neurotoxicity in developing hippocampus by mbdnf/trkb/pi3k pathway. Drug Des. Devel. Ther. 2021 15 1409 1422 10.2147/DDDT.S294557 33833500
    [Google Scholar]
  22. Zhao X. Zhang E. Ren X. Bai X. Wang D. Bai L. Luo D. Guo Z. Wang Q. Yang J. Edaravone alleviates cell apoptosis and mitochondrial injury in ischemia–reperfusion-induced kidney injury via the JAK/STAT pathway. Biol. Res. 2020 53 1 28 10.1186/s40659‑020‑00297‑0 32620154
    [Google Scholar]
  23. Rahimifard M. Baeeri M. Bahadar H. Moini-Nodeh S. Khalid M. Haghi-Aminjan H. Mohammadian H. Abdollahi M. Therapeutic effects of gallic acid in regulating senescence and diabetes; an in vitro study. Molecules 2020 25 24 5875 10.3390/molecules25245875 33322612
    [Google Scholar]
  24. Mahdizade E. Baeeri M. Hodjat M. Rahimifard M. Navaei-Nigjeh M. Haghi-Aminjan H. Moeini-Nodeh S. Hassani S. Dehghan G. Hosseinpour-Feizi M.A. Abdollahi M. Impact of acrylamide on cellular senescence response and cell cycle distribution via an in-vitro study. Iran. J. Pharm. Res. 2021 20 4 165 177 35194437
    [Google Scholar]
  25. Nobakht-Haghighi N. Rahimifard M. Baeeri M. Rezvanfar M.A. Nodeh M.S. Haghi-Aminjan H. Hamurtekin E. Abdollahi M. Regulation of aging and oxidative stress pathways in aged pancreatic islets using alpha-lipoic acid. Mol. Cell. Biochem. 2018 449 1-2 267 276 10.1007/s11010‑018‑3363‑3 29696608
    [Google Scholar]
  26. Baeeri M. Mohammadi-Nejad S. Rahimifard M. Navaei-Nigjeh M. Moeini-Nodeh S. Khorasani R. Abdollahi M. Molecular and biochemical evidence on the protective role of ellagic acid and silybin against oxidative stress-induced cellular aging. Mol. Cell. Biochem. 2018 441 1-2 21 33 10.1007/s11010‑017‑3172‑0 28887692
    [Google Scholar]
  27. Baeeri M. Bahadar H. Rahimifard M. Navaei-Nigjeh M. Khorasani R. Rezvanfar M.A. Gholami M. Abdollahi M. α-Lipoic acid prevents senescence, cell cycle arrest, and inflammatory cues in fibroblasts by inhibiting oxidative stress. Pharmacol. Res. 2019 141 214 223 10.1016/j.phrs.2019.01.003 30611855
    [Google Scholar]
  28. Momtaz S. Baeeri M. Rahimifard M. Haghi-Aminjan H. Hassani S. Abdollahi M. Manipulation of molecular pathways and senescence hallmarks by natural compounds in fibroblast cells J. Cell. Biochem. 2019 120 4 6209 6222 10.1002/jcb.27909 30474871
    [Google Scholar]
  29. Hodjat M. Baeeri M. Rezvanfar M.A. Rahimifard M. Gholami M. Abdollahi M. On the mechanism of genotoxicity of ethephon on embryonic fibroblast cells. Toxicol. Mech. Methods 2017 27 3 173 180 10.1080/15376516.2016.1273425 27997273
    [Google Scholar]
  30. Sarkhail P. Navidpour L. Rahimifard M. Hosseini N.M. Souri E. Bioassay-guided fractionation and identification of wound healing active compound from Pistacia vera L. hull extract. J. Ethnopharmacol. 2020 248 112335 10.1016/j.jep.2019.112335 31654800
    [Google Scholar]
  31. Niaz K. Hassan F.I. Mabqool F. Khan F. Momtaz S. Baeeri M. Navaei-Nigjeh M. Rahimifard M. Abdollahi M. Effect of styrene exposure on plasma parameters, molecular mechanisms and gene expression in rat model islet cells. Environ. Toxicol. Pharmacol. 2017 54 62 73 10.1016/j.etap.2017.06.020 28688303
    [Google Scholar]
  32. Gupta S. Panda P.K. Luo W. Hashimoto R.F. Ahuja R. Network analysis reveals that the tumor suppressor lncRNA GAS5 acts as a double-edged sword in response to DNA damage in gastric cancer. Sci. Rep. 2022 12 1 18312 10.1038/s41598‑022‑21492‑x 36316351
    [Google Scholar]
  33. Shaban S. El-Husseny M.W.A. Abushouk A.I. Salem A.M.A. Mamdouh M. Abdel-Daim M.M. Effects of antioxidant supplements on the survival and differentiation of stem cells. Oxid. Med. Cell. Longev. 2017 2017 5032102 10.1155/2017/5032102
    [Google Scholar]
  34. Guan L. Crasta K.C. Maier A.B. Assessment of cell cycle regulators in human peripheral blood cells as markers of cellular senescence. Ageing Res. Rev. 2022 78 101634 10.1016/j.arr.2022.101634 35460888
    [Google Scholar]
  35. Kudlova N. Sanctis D.J.B. Hajduch M. Cellular senescence: Molecular targets, biomarkers, and senolytic drugs. Int. J. Mol. Sci. 2022 23 8 4168 10.3390/ijms23084168 35456986
    [Google Scholar]
  36. Fakhri S. Moradi Z.S. DeLiberto L.K. Bishayee A. Cellular senescence signaling in cancer: A novel therapeutic target to combat human malignancies. Biochem. Pharmacol. 2022 199 114989 10.1016/j.bcp.2022.114989 35288153
    [Google Scholar]
  37. Fan T. Du Y. Zhang M. Zhu A.R. Zhang J. Senolytics cocktail dasatinib and quercetin alleviate human umbilical vein endothelial cell senescence via the traf6-mapk-nf-κb axis in a ythdf2-dependent manner. gerontology 2022 68 8 920 934 10.1159/000522656 35468611
    [Google Scholar]
  38. Sierra-Ramirez A. López-Aceituno J.L. Costa-Machado L.F. Plaza A. Barradas M. Fernandez-Marcos P.J. Transient metabolic improvement in obese mice treated with navitoclax or dasatinib/quercetin. Aging 2020 12 12 11337 11348 10.18632/aging.103607 32584785
    [Google Scholar]
  39. Hickson L.J. Prata L.L.G.P. Bobart S.A. Evans T.K. Giorgadze N. Hashmi S.K. Herrmann S.M. Jensen M.D. Jia Q. Jordan K.L. Kellogg T.A. Khosla S. Koerber D.M. Lagnado A.B. Lawson D.K. LeBrasseur N.K. Lerman L.O. McDonald K.M. McKenzie T.J. Passos J.F. Pignolo R.J. Pirtskhalava T. Saadiq I.M. Schaefer K.K. Textor S.C. Victorelli S.G. Volkman T.L. Xue A. Wentworth M.A. Gerdes W.E.O. Zhu Y. Tchkonia T. Kirkland J.L. Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine 2019 47 446 456 10.1016/j.ebiom.2019.08.069 31542391
    [Google Scholar]
  40. Rahimifard M. Baeeri M. Mousavi T. Azarnezhad A. Haghi-Aminjan H. Abdollahi M. Combination therapy of cisplatin and resveratrol to induce cellular aging in gastric cancer cells: Focusing on oxidative stress, and cell cycle arrest. Front. Pharmacol. 2023 13 1068863 10.3389/fphar.2022.1068863 36686661
    [Google Scholar]
  41. Ewald J.A. Desotelle J.A. Wilding G. Jarrard D.F. Therapy-induced senescence in cancer. J. Natl. Cancer Inst. 2010 102 20 1536 1546 10.1093/jnci/djq364 20858887
    [Google Scholar]
  42. Engeland K. Cell cycle regulation: P53-p21-RB signaling. Cell Death Differ. 2022 29 5 946 960 10.1038/s41418‑022‑00988‑z 35361964
    [Google Scholar]
  43. Cheung C.T. Kaul S.C. Wadhwa R. Molecular bridging of aging and cancer. Ann. N. Y. Acad. Sci. 2010 1197 1 129 133 10.1111/j.1749‑6632.2009.05392.x 20536841
    [Google Scholar]
  44. Chen J. The cell-cycle arrest and apoptotic functions of p53 in tumor initiation and progression. Cold Spring Harb. Perspect. Med. 2016 6 3 a026104 10.1101/cshperspect.a026104 26931810
    [Google Scholar]
  45. Tonnessen-Murray C.A. Lozano G. Jackson J.G. The regulation of cellular functions by the p53 protein: Cellular senescence. Cold Spring Harb. Perspect. Med. 2017 7 2 a026112 10.1101/cshperspect.a026112 27881444
    [Google Scholar]
  46. Mijit M. Caracciolo V. Melillo A. Amicarelli F. Giordano A. Role of p53 in the regulation of cellular senescence. Biomolecules 2020 10 3 420 10.3390/biom10030420 32182711
    [Google Scholar]
  47. Kumari R. Jat P. Mechanisms of cellular senescence: Cell cycle arrest and senescence associated secretory phenotype. Front. Cell Dev. Biol. 2021 9 645593 10.3389/fcell.2021.645593 33855023
    [Google Scholar]
  48. Passos J.F. Nelson G. Wang C. Richter T. Simillion C. Proctor C.J. Miwa S. Olijslagers S. Hallinan J. Wipat A. Saretzki G. Rudolph K.L. Kirkwood T.B.L. Zglinicki v.T. Feedback between p21 and reactive oxygen production is necessary for cell senescence. Mol. Syst. Biol. 2010 6 1 347 10.1038/msb.2010.5 20160708
    [Google Scholar]
  49. Kim H.S. Kim Y. Lim M.J. Park Y.G. Park S.I. Sohn J. The p38-activated ER stress-ATF6α axis mediates cellular senescence. FASEB J. 2019 33 2 2422 2434 10.1096/fj.201800836R 30260700
    [Google Scholar]
  50. Rahman I. Marwick J. Kirkham P. Redox modulation of chromatin remodeling: Impact on histone acetylation and deacetylation, NF-κB and pro-inflammatory gene expression. Biochem. Pharmacol. 2004 68 6 1255 1267 10.1016/j.bcp.2004.05.042 15313424
    [Google Scholar]
  51. Akhter N. Wilson A. Thomas R. Al-Rashed F. Kochumon S. Al-Roub A. Arefanian H. Al-Madhoun A. Al- Mulla F. Ahmad R. Sindhu S. ROS/TNF-α crosstalk triggers the expression of il-8 and mcp-1 in human monocytic thp-1 cells via the NF-κB and ERK1/2 mediated signaling. Int. J. Mol. Sci. 2021 22 19 10519 10.3390/ijms221910519 34638857
    [Google Scholar]
  52. Zhao H. Wang Y. Liu Y. Yin K. Wang D. Li B. Yu H. Xing M. ROS-induced hepatotoxicity under cypermethrin: Involvement of the crosstalk between nrf2/keap1 and nf-κb/iκb-α pathways regulated by proteasome. Environ. Sci. Technol. 2021 55 9 6171 6183 10.1021/acs.est.1c00515 33843202
    [Google Scholar]
  53. Chattopadhyay M. Kodela R. Santiago G. Le T.T.C. Nath N. Kashfi K. NOSH-aspirin (NBS-1120) inhibits pancreatic cancer cell growth in a xenograft mouse model: Modulation of FoxM1, p53, NF-κB, iNOS, caspase-3 and ROS. Biochem. Pharmacol. 2020 176 113857 10.1016/j.bcp.2020.113857 32061771
    [Google Scholar]
  54. Bringold F. Serrano M. Tumor suppressors and oncogenes in cellular senescence. Exp. Gerontol. 2000 35 3 317 329 10.1016/S0531‑5565(00)00083‑8 10832053
    [Google Scholar]
  55. Ohta Y. Nomura E. Shang J. Feng T. Huang Y. Liu X. Shi X. Nakano Y. Hishikawa N. Sato K. Takemoto M. Yamashita T. Abe K. Enhanced oxidative stress and the treatment by edaravone in mice model of amyotrophic lateral sclerosis. J. Neurosci. Res. 2019 97 5 607 619 10.1002/jnr.24368 30565312
    [Google Scholar]
  56. Hashemi G. Adhami H-R. Rahimifard M. Baeeri M. Sarkhail P. Investigation of in vitro Wound Healing Activity of Polygonatum orientale Desf. Rhizome. Tehran, Iran Traditional and Integrative Medicine 2022 231 243
    [Google Scholar]
  57. Kirkland J.L. Tchkonia T. Senolytic drugs: From discovery to translation. J. Intern. Med. 2020 288 5 518 536 10.1111/joim.13141 32686219
    [Google Scholar]
  58. Paez-Ribes M. González-Gualda E. Doherty G.J. Muñoz-Espín D. Targeting senescent cells in translational medicine. EMBO Mol. Med. 2019 11 12 e10234 10.15252/emmm.201810234 31746100
    [Google Scholar]
  59. Wyld L. Bellantuono I. Tchkonia T. Morgan J. Turner O. Foss F. George J. Danson S. Kirkland J.L. Senescence and cancer: A review of clinical implications of senescence and senotherapies. Cancers 2020 12 8 2134 10.3390/cancers12082134 32752135
    [Google Scholar]
  60. Mongiardi M.P. Pellegrini M. Pallini R. Levi A. Falchetti M.L. Cancer response to therapy-induced senescence: A matter of dose and timing. Cancers 2021 13 3 484 10.3390/cancers13030484 33513872
    [Google Scholar]
  61. Vyas D. Laput G. Vyas A. Chemotherapy-enhanced inflammation may lead to the failure of therapy and metastasis. OncoTargets Ther. 2014 7 1015 1023 10.2147/OTT.S60114 24959088
    [Google Scholar]
  62. Aggarwal V. Tuli H. Varol A. Thakral F. Yerer M. Sak K. Varol M. Jain A. Khan M. Sethi G. Role of reactive oxygen species in cancer progression: Molecular mechanisms and recent advancements. Biomolecules 2019 9 11 735 10.3390/biom9110735 31766246
    [Google Scholar]
  63. Chu L. Qu Y. An Y. Hou L. Li J. Li W. Fan G. Song B.L. Li E. Zhang L. Qi W. Induction of senescence-associated secretory phenotype underlies the therapeutic efficacy of PRC2 inhibition in cancer. Cell Death Dis. 2022 13 2 155 10.1038/s41419‑022‑04601‑6 35169119
    [Google Scholar]
  64. Chien M.H. Lin C.W. Cheng C.W. Wen Y.C. Yang S.F. Matrix metalloproteinase-2 as a target for head and neck cancer therapy. Expert Opin. Ther. Targets 2013 17 2 203 216 10.1517/14728222.2013.740012 23252422
    [Google Scholar]
  65. Azizi G. Goudarzvand M. Afraei S. Sedaghat R. Mirshafiey A. Therapeutic effects of dasatinib in mouse model of multiple sclerosis. Immunopharmacol. Immunotoxicol. 2015 37 3 287 294 10.3109/08923973.2015.1028074 25975582
    [Google Scholar]
/content/journals/cmc/10.2174/0109298673338322250211111422
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Molecular and Biochemical Evidence of Edaravone's Impact on Dasatinib-induced AGS Cell Senescence: A Promising Strategy for Gastric Cancer Therapy
Bentham Science Publishers ; https://doi.org/10.2174/0109298673338322250211111422
/content/journals/cmc/10.2174/0109298673338322250211111422
/content/journals/cmc/10.2174/0109298673338322250211111422
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  • Article Type:     Research Article
Keywords: chemotherapy ; Antioxidant ; edaravone ; cell senescence ; gastric cancer ; dasatinib

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