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image of Parthenolide Inhibits Tumor Cell Growth and Metastasis in Melanoma A2058 Cells

Abstract

Background

Skin melanoma is a potentially lethal cancer and ranks as the 17th most common cancer worldwide. Overcoming resistance to advanced-stage melanoma is a significant challenge in its treatment. Parthenolide (PAR) is recognized as a potent anticancer small molecule, yet its potential in treating melanoma is poorly investigated.

Objective

Our objective was to investigate the apoptotic and anti-metastatic properties of PAR against the A2058 melanoma cells .

Methods

This study employed various assays, such as cytotoxicity, apoptosis, cell cycle analysis, reactive oxygen species (ROS) production, mRNA expressions, western blotting, gelatin zymography, and scratch assay. The synergy between PAR and dacarbazine, a chemotherapy drug for treating skin cancer, was also assessed.

Results

Our study revealed that PAR significantly reduced the viability of A2058 cancer cells, demonstrating greater potency against cancer cells compared to normal L929 cells (IC: 20 µM vs. 27 µM after 24h). PAR increased ROS production, elevated mRNA expression of pro-apoptotic Bax and NME1 genes, and decreased expression of the MITF gene. PAR induced apoptosis and cell cycle arrest in A2058 cells, as evidenced by the increased proportion of cells in the late apoptotic phase and sub-G1 cell cycle arrest. MMP-2 and MMP-9 mRNA and protein expressions, gelatinase activity, and the migration of A2058 cells were also decreased by PAR, suggesting its potential to suppress cancer cell invasion.

Conclusion

These results, along with the synergic effect with dacarbazine, indicated that PAR may have the potential to be a therapeutic drug for melanoma by triggering apoptosis and suppressing invasion and migration.

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2024-10-16
2024-11-26

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References

  1. Khosravi S. Tam K.J. Ardekani G.S. Martinka M. McElwee K.J. Ong C.J. eIF4E is an adverse prognostic marker of melanoma patient survival by increasing melanoma cell invasion. J. Invest. Dermatol. 2015 135 5 1358 1367 10.1038/jid.2014.552 25562667
    [Google Scholar]
  2. Patel M. Eckburg A. Gantiwala S. Hart Z. Dein J. Lam K. Puri N. Resistance to molecularly targeted therapies in melanoma. Cancers (Basel) 2021 13 5 1115 10.3390/cancers13051115 33807778
    [Google Scholar]
  3. Lesiak K. Koprowska K. Zalesna I. Nejc D. Düchler M. Czyz M. Parthenolide, a sesquiterpene lactone from the medical herb feverfew, shows anticancer activity against human melanoma cells in vitro . Melanoma Res. 2010 20 1 21 34 10.1097/CMR.0b013e328333bbe4 19949351
    [Google Scholar]
  4. Gray-Schopfer V. Wellbrock C. Marais R. Melanoma biology and new targeted therapy. Nature 2007 445 7130 851 857 10.1038/nature05661 17314971
    [Google Scholar]
  5. Torre L.A. Bray F. Siegel R.L. Ferlay J. Lortet-Tieulent J. Jemal A. Global cancer statistics, 2012. CA Cancer J. Clin. 2015 65 2 87 108 10.3322/caac.21262 25651787
    [Google Scholar]
  6. Montor W.R. Salas A.R.O.S.E. Melo F.H.M. Receptor tyrosine kinases and downstream pathways as druggable targets for cancer treatment: The current arsenal of inhibitors. Mol. Cancer 2018 17 1 55 10.1186/s12943‑018‑0792‑2 29455659
    [Google Scholar]
  7. Schrank Z. Chhabra G. Lin L. Iderzorig T. Osude C. Khan N. Kuckovic A. Singh S. Miller R. Puri N. Current molecular-targeted therapies in NSCLC and their mechanism of resistance. Cancers (Basel) 2018 10 7 224 10.3390/cancers10070224 29973561
    [Google Scholar]
  8. Sharifi-Rad J. Ozleyen A. Boyunegmez Tumer T. Oluwaseun Adetunji C. El Omari N. Balahbib A. Taheri Y. Bouyahya A. Martorell M. Martins N. Cho W.C. Natural products and synthetic analogs as a source of antitumor drugs. Biomolecules 2019 9 11 679 10.3390/biom9110679 31683894
    [Google Scholar]
  9. Huang M. Lu J.J. Ding J. Natural products in cancer therapy: Past, present and future. Nat. Prod. Bioprospect. 2021 11 1 5 13 10.1007/s13659‑020‑00293‑7 33389713
    [Google Scholar]
  10. Zhu S. Sun P. Bennett S. Charlesworth O. Tan R. Peng X. Gu Q. Kujan O. Xu J. The therapeutic effect and mechanism of parthenolide in skeletal disease, cancers, and cytokine storm. Front. Pharmacol. 2023 14 1111218 10.3389/fphar.2023.1111218 37033622
    [Google Scholar]
  11. Guzman M.L. Rossi R.M. Neelakantan S. Li X. Corbett C.A. Hassane D.C. Becker M.W. Bennett J.M. Sullivan E. Lachowicz J.L. Vaughan A. Sweeney C.J. Matthews W. Carroll M. Liesveld J.L. Crooks P.A. Jordan C.T. An orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells. Blood 2007 110 13 4427 4435 10.1182/blood‑2007‑05‑090621 17804695
    [Google Scholar]
  12. Sun Y. St Clair D.K. Xu Y. Crooks P.A. St Clair W.H. A NADPH oxidase-dependent redox signaling pathway mediates the selective radiosensitization effect of parthenolide in prostate cancer cells. Cancer Res. 2010 70 7 2880 2890 10.1158/0008‑5472.CAN‑09‑4572 20233868
    [Google Scholar]
  13. Xu Y. Fang F. Miriyala S. Crooks P.A. Oberley T.D. Chaiswing L. Noel T. Holley A.K. Zhao Y. Kiningham K.K. Clair D.K.S. Clair W.H.S. KEAP1 is a redox sensitive target that arbitrates the opposing radiosensitive effects of parthenolide in normal and cancer cells. Cancer Res. 2013 73 14 4406 4417 10.1158/0008‑5472.CAN‑12‑4297 23674500
    [Google Scholar]
  14. Guzman M.L. Rossi R.M. Karnischky L. Li X. Peterson D.R. Howard D.S. Jordan C.T. The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. Blood 2005 105 11 4163 4169 10.1182/blood‑2004‑10‑4135 15687234
    [Google Scholar]
  15. Zhang Z. Qiao Y. Sun Q. Peng L. Sun L. A novel SLC25A1 inhibitor, parthenolide, suppresses the growth and stemness of liver cancer stem cells with metabolic vulnerability. Cell Death Discov. 2023 9 1 350 10.1038/s41420‑023‑01640‑6 37741815
    [Google Scholar]
  16. Karimian Ensaf P. Goodarzi M.T. Homayouni Tabrizi M. Neamati A. Hosseinyzadeh S.S. A novel nanoformulation of parthenolide coated with polydopamine shows selective cytotoxicity and induces apoptosis in gastric cancer cells. Naunyn Schmiedebergs Arch. Pharmacol. 2024 397 6 4435 4445 10.1007/s00210‑023‑02907‑6 38108837
    [Google Scholar]
  17. Gehren A.S. de Souza W.F. Sousa-Squiavinato A.C.M. Ramos D.A.A. Pires B.R.B. Abdelhay E.S.F.W. Morgado-Diaz J.A. Parthenolide inhibits proliferation and invasion, promotes apoptosis, and reverts the cell–cell adhesion loss through downregulation of NF‐κB pathway TNF‐α‐activated in colorectal cancer cells. Cell Biol. Int. 2023 47 9 1638 1649 10.1002/cbin.12060 37337926
    [Google Scholar]
  18. An T. Yin H. Lu Y. Liu F. The emerging potential of parthenolide nanoformulations in tumor therapy. Drug Des. Devel. Ther. 2022 16 1255 1272 10.2147/DDDT.S355059 35517982
    [Google Scholar]
  19. Tahiliani M. Koh K.P. Shen Y. Pastor W.A. Bandukwala H. Brudno Y. Agarwal S. Iyer L.M. Liu D.R. Aravind L. Rao A. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 2009 324 5929 930 935 10.1126/science.1170116 19372391
    [Google Scholar]
  20. Saadane A. Masters S. DiDonato J. Li J. Berger M. Parthenolide inhibits IkappaB kinase, NF-kappaB activation, and inflammatory response in cystic fibrosis cells and mice. Am. J. Respir. Cell Mol. Biol. 2007 36 6 728 736 10.1165/rcmb.2006‑0323OC 17272824
    [Google Scholar]
  21. Zhang S. Lin Z.N. Yang C.F. Shi X. Ong C.N. Shen H.M. Suppressed NF- B and sustained JNK activation contribute to the sensitization effect of parthenolide to TNF- -induced apoptosis in human cancer cells. Carcinogenesis 2004 25 11 2191 2199 10.1093/carcin/bgh234 15256485
    [Google Scholar]
  22. Nakshatri H. Rice S.E. Bhat-Nakshatri P. Antitumor agent parthenolide reverses resistance of breast cancer cells to tumor necrosis factor-related apoptosis-inducing ligand through sustained activation of c-Jun N-terminal kinase. Oncogene 2004 23 44 7330 7344 10.1038/sj.onc.1207995 15286701
    [Google Scholar]
  23. Sobota R. Szwed M. Kasza A. Bugno M. Kordula T. Parthenolide inhibits activation of signal transducers and activators of transcription (STATs) induced by cytokines of the IL-6 family. Biochem. Biophys. Res. Commun. 2000 267 1 329 333 10.1006/bbrc.1999.1948 10623619
    [Google Scholar]
  24. Carlisi D. D’Anneo A. Angileri L. Lauricella M. Emanuele S. Santulli A. Vento R. Tesoriere G. Parthenolide sensitizes hepatocellular carcinoma cells to trail by inducing the expression of death receptors through inhibition of STAT3 activation. J. Cell. Physiol. 2011 226 6 1632 1641 10.1002/jcp.22494 21413021
    [Google Scholar]
  25. Ghorbanzadeh Neghab M. Jalili-Nik M. Soltani A. Afshari A.R. Hassanian S.M. Rafatpanah H. Rezaee S.A. Sadeghnia H.R. Ataei Azimi S. Mashkani B. Rigosertib is more potent than wortmannin and rapamycin against adult T-cell leukemia-lymphoma. Biofactors 2023 49 6 1174 1188 10.1002/biof.1985 37345860
    [Google Scholar]
  26. Tajvar Nasab N. Jalili-Nik M. Afshari A.R. Rezaei Farimani A. Soukhtanloo M. Urolithin B inhibits proliferation and migration and promotes apoptosis and necrosis by inducing G2/M arrest and targeting MMP‐2/‐9 expression in osteosarcoma cells. J. Biochem. Mol. Toxicol. 2023 37 12 e23486 10.1002/jbt.23486 37555500
    [Google Scholar]
  27. Neves J. Jorge J. Alves R. Gonçalves A.C. Sarmento-Ribeiro A.B. Cytotoxic effects of parthenolide on lymphoid malignancies’ cell lines. Porto Biomed. J. 2017 2 5 183 10.1016/j.pbj.2017.07.020 32258632
    [Google Scholar]
  28. Al-Fatlawi A.A. Al-Fatlawi A.A. Irshad M. Rahisuddin Ahmad A. Effect of parthenolide on growth and apoptosis regulatory genes of human cancer cell lines. Pharm. Biol. 2015 53 1 104 109 10.3109/13880209.2014.911919 25289524
    [Google Scholar]
  29. Lin M. Bi H. Yan Y. Huang W. Zhang G. Zhang G. Tang S. Liu Y. Zhang L. Ma J. Zhang J. Parthenolide suppresses non-small cell lung cancer GLC-82 cells growth via B-Raf/MAPK/Erk pathway. Oncotarget 2017 8 14 23436 23447 10.18632/oncotarget.15584 28423582
    [Google Scholar]
  30. George V.C. Kumar D.R. Kumar R.A. Relative in vitro potentials of parthenolide to induce apoptosis and cell cycle arrest in skin cancer cells. Curr. Drug Discov. Technol. 2016 13 1 34 40 10.2174/1570163813666160224124029 26906908
    [Google Scholar]
  31. Jorge J. Neves J. Alves R. Geraldes C. Gonçalves A.C. Sarmento-Ribeiro A.B. Parthenolide induces ROS-mediated apoptosis in lymphoid malignancies. Int. J. Mol. Sci. 2023 24 11 9167 10.3390/ijms24119167 37298119
    [Google Scholar]
  32. Duan D. Zhang J. Yao J. Liu Y. Fang J. Targeting thioredoxin reductase by parthenolide contributes to inducing apoptosis of HeLa cells. J. Biol. Chem. 2016 291 19 10021 10031 10.1074/jbc.M115.700591 27002142
    [Google Scholar]
  33. Grichnik J.M. Burch J.A. Schulteis R.D. Shan S. Liu J. Darrow T.L. Vervaert C.E. Seigler H.F. Melanoma, a tumor based on a mutant stem cell? J. Invest. Dermatol. 2006 126 1 142 153 10.1038/sj.jid.5700017 16417230
    [Google Scholar]
  34. Hehner S.P. Heinrich M. Bork P.M. Vogt M. Ratter F. Lehmann V. Schulze-Osthoff K. Dröge W. Schmitz M.L. Sesquiterpene lactones specifically inhibit activation of NF-kappa B by preventing the degradation of I kappa B-alpha and I kappa B-beta. J. Biol. Chem. 1998 273 3 1288 1297 10.1074/jbc.273.3.1288 9430659
    [Google Scholar]
  35. babaei G. Aliarab A. Abroon S. Rasmi Y. Aziz S.G.G. Application of sesquiterpene lactone: A new promising way for cancer therapy based on anticancer activity. Biomed. Pharmacother. 2018 106 239 246 10.1016/j.biopha.2018.06.131 29966966
    [Google Scholar]
  36. Anderson K.N. Bejcek B.E. Parthenolide induces apoptosis in glioblastomas without affecting NF-kappaB. J. Pharmacol. Sci. 2008 106 2 318 320 10.1254/jphs.SC0060164 18277052
    [Google Scholar]
  37. Zhang S. Ong C.N. Shen H.M. Critical roles of intracellular thiols and calcium in parthenolide-induced apoptosis in human colorectal cancer cells. Cancer Lett. 2004 208 2 143 153 10.1016/j.canlet.2003.11.028 15142672
    [Google Scholar]
  38. Che S.T. Bie L. Li X. Qi H. Yu P. Zuo L. Parthenolide inhibits the proliferation and induces the apoptosis of human uveal melanoma cells. Int. J. Ophthalmol. 2019 12 10 1531 1538 10.18240/ijo.2019.10.03 31637187
    [Google Scholar]
  39. Nakagawa Y. Iinuma M. Matsuura N. Yi K. Naoi M. Nakayama T. Nozawa Y. Akao Y. A potent apoptosis-inducing activity of a sesquiterpene lactone, arucanolide, in HL60 cells: A crucial role of apoptosis-inducing factor. J. Pharmacol. Sci. 2005 97 2 242 252 10.1254/jphs.FP0040456 15699578
    [Google Scholar]
  40. Kim S.L. Kieu T.T.T. Jeon B.J. Kim S.H. Kim I.H. Lee S.O. Lee S.T. Kim S.W. Synergistic effect of parthenolide in combination with 5-fluorouracil in SW480 cells. Intest. Res. 2012 10 4 357 364 10.5217/ir.2012.10.4.357 34731562
    [Google Scholar]
  41. Cheng G. Xie L. Parthenolide induces apoptosis and cell cycle arrest of human 5637 bladder cancer cells in vitro . Molecules 2011 16 8 6758 6768 10.3390/molecules16086758 21829151
    [Google Scholar]
  42. Kim I.H. Kim S.W. Kim S.H. Lee S.O. Lee S.T. Kim D.G. Lee M.J. Park W.H. Parthenolide-induced apoptosis of hepatic stellate cells and anti-fibrotic effects in an in vivo rat model. Exp. Mol. Med. 2012 44 7 448 456 10.3858/emm.2012.44.7.051 22581380
    [Google Scholar]
  43. Kim S.L. Liu Y.C. Park Y.R. Seo S.Y. Kim S.H. Kim I.H. Lee S.O. Lee S.T. Kim D.G. Kim S.W. Parthenolide enhances sensitivity of colorectal cancer cells to TRAIL by inducing death receptor 5 and promotes TRAIL-induced apoptosis. Int. J. Oncol. 2015 46 3 1121 1130 10.3892/ijo.2014.2795 25502339
    [Google Scholar]
  44. Jalili-Nik M. Sabri H. Zamiri E. Soukhtanloo M. Roshan M.K. Hosseini A. Mollazadeh H. Vahedi M.M. Afshari A.R. Mousavi S.H. Cytotoxic effects of Ferula latisecta on human glioma U87 cells. Drug Res. (Stuttg.) 2019 69 12 665 670 10.1055/a‑0986‑6543 31499542
    [Google Scholar]
  45. Pereira A.M.M. Strasberg-Rieber M. Rieber M. Invasion-associated MMP-2 and MMP-9 are up-regulated intracellularly in concert with apoptosis linked to melanoma cell detachment. Clin. Exp. Metastasis 2005 22 4 285 295 10.1007/s10585‑005‑8672‑8 16170665
    [Google Scholar]
  46. Cory G. Scratch-Wound Assay. Methods Mol. Biol. 2011 769 25 30 10.1007/978‑1‑61779‑207‑6_2 21748666
    [Google Scholar]
  47. Czyz M. Lesiak-Mieczkowska K. Koprowska K. Szulawska-Mroczek A. Wozniak M. Cell context‐dependent activities of parthenolide in primary and metastatic melanoma cells. Br. J. Pharmacol. 2010 160 5 1144 1157 10.1111/j.1476‑5381.2010.00749.x 20590608
    [Google Scholar]
  48. Liu Y.C. Kim S.L. Park Y.R. Lee S.T. Kim S.W. Parthenolide promotes apoptotic cell death and inhibits the migration and invasion of SW620 cells. Intest. Res. 2017 15 2 174 181 10.5217/ir.2017.15.2.174 28522946
    [Google Scholar]
  49. Steeg P.S. Bevilacqua G. Kopper L. Thorgeirsson U.P. Talmadge J.E. Liotta L.A. Sobel M.E. Evidence for a novel gene associated with low tumor metastatic potential. J. Natl. Cancer Inst. 1988 80 3 200 204 10.1093/jnci/80.3.200 3346912
    [Google Scholar]
  50. Marino N. Nakayama J. Collins J.W. Steeg P.S. Insights into the biology and prevention of tumor metastasis provided by the Nm23 metastasis suppressor gene. Cancer Metastasis Rev. 2012 31 3-4 593 603 10.1007/s10555‑012‑9374‑8 22706779
    [Google Scholar]
  51. Leone A. Flatow U. King C.R. Sandeen M.A. Margulies I.M.K. Liotta L.A. Steeg P.S. Reduced tumor incidence, metastatic potential, and cytokine responsiveness of nm3-transfected melanoma cells. Cell 1991 65 1 25 35 10.1016/0092‑8674(91)90404‑M 2013093
    [Google Scholar]
  52. Carreira S. Goodall J. Denat L. Rodriguez M. Nuciforo P. Hoek K.S. Testori A. Larue L. Goding C.R. Mitf regulation of Dia1 controls melanoma proliferation and invasiveness. Genes Dev. 2006 20 24 3426 3439 10.1101/gad.406406 17182868
    [Google Scholar]
  53. Hoek K.S. Schlegel N.C. Brafford P. Sucker A. Ugurel S. Kumar R. Weber B.L. Nathanson K.L. Phillips D.J. Herlyn M. Schadendorf D. Dummer R. Metastatic potential of melanomas defined by specific gene expression profiles with no BRAF signature. Pigment Cell Res. 2006 19 4 290 302 10.1111/j.1600‑0749.2006.00322.x 16827748
    [Google Scholar]
  54. Koprowska K. Hartman M.L. Sztiller-Sikorska M. Czyz M.E. Parthenolide enhances dacarbazine activity against melanoma cells. Anticancer Drugs 2013 24 8 835 845 10.1097/CAD.0b013e3283635a04 23797801
    [Google Scholar]
  55. Wen J. You K.R. Lee S.Y. Song C.H. Kim D.G. Oxidative stress-mediated apoptosis. The anticancer effect of the sesquiterpene lactone parthenolide. J. Biol. Chem. 2002 277 41 38954 38964 10.1074/jbc.M203842200 12151389
    [Google Scholar]
  56. Kim H.Y. Lee H. Kim S.H. Jin H. Bae J. Choi H.K. Discovery of potential biomarkers in human melanoma cells with different metastatic potential by metabolic and lipidomic profiling. Sci. Rep. 2017 7 1 8864 10.1038/s41598‑017‑08433‑9 28821754
    [Google Scholar]
/content/journals/cmc/10.2174/0109298673334309240924081449
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Parthenolide Inhibits Tumor Cell Growth and Metastasis in Melanoma A2058 Cells
Bentham Science Publishers ; https://doi.org/10.2174/0109298673334309240924081449
/content/journals/cmc/10.2174/0109298673334309240924081449
/content/journals/cmc/10.2174/0109298673334309240924081449
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  • Article Type:     Research Article
Keywords: apoptosis ; p53 ; melanoma ; Parthenolide ; migration ; cell cycle arrest

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