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image of Atranorin Triggers Intrinsic and Extrinsic Apoptosis and Suppresses Migration in Human Melanoma Cells

Abstract

Introduction

Malignant melanoma is a highly aggressive skin malignancy characterised by metastatic properties and resistance to conventional therapies. This indicates a necessity to explore novel, efficacious treatment modalities. Atranorin, a secondary metabolite derived from lichen, has demonstrated a diverse range of bioactivities. However, the antineoplastic mechanisms of atranorin in melanoma remain underexplored.

Methods

Human melanoma cancer cell lines (A-375, G-361, and MDA-MB-435) and normal human melanocytes were treated with various concentrations of atranorin. Cell viability and proliferation were evaluated by MTT assay, apoptosis was assessed using Annexin V-FITC/PI flow cytometry, and cell cycle distribution was determined by PI staining and flow cytometry. Gene expression of apoptosis-related markers was quantified by qRT-PCR, and protein levels were analyzed by Western blot. Cell migration was evaluated by the wound healing assay.

Results

Atranorin demonstrated selective toxicity in human melanoma cancer cells, exhibiting minimal effect on normal human melanocytes. In a study on human malignant melanoma A-375 cells, it was found that atranorin, at an IC concentration of 12 μM, significantly increased the number of apoptotic cells by approximately 11-fold. Furthermore, the results of the study indicated that atranorin induced G1 phase arrest and inhibited migratory capacity by around 60%. Molecular profiling revealed the upregulation of the intrinsic ( and ) and extrinsic ( and ) apoptotic pathways, and the downregulation of the anti-apoptotic genes and . In line with these observations, protein analyses revealed increased levels of cleaved caspase-3, caspase-9, and PARP, thereby providing evidence for the activation of apoptotic cascades.

Discussion

In this study, the therapeutic effect of atranorin was comprehensively evaluated for the first time on A-375 melanoma cells, and it was highlighted as a natural compound with strong anti-cancer potential.

Conclusion

This study is the first to demonstrate the potent anti-melanoma effect of atranorin. This demonstrates the natural compounds' effects on cell proliferation, cell cycle progression, and the suppression of metastasis. These findings emphasize the potential of atranorin as a novel natural compound for use in adjunctive or targeted melanoma therapy, and highlight the need for further preclinical and clinical evaluation.

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2026-01-15
2026-02-27

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References

  1. Chen J.Y. Fernandez K. Fadadu R.P. Reddy R. Kim M.O. Tan J. Wei M.L. Skin cancer diagnosis by lesion, physician, and examination type. JAMA Dermatol. 2025 161 2 135 146 10.1001/jamadermatol.2024.4382 39535756
    [Google Scholar]
  2. Ray A. Sarkar S. Schwenker F. Sarkar R. Decoding skin cancer classification: Perspectives, insights, and advances through researchers’ lens. Sci. Rep. 2024 14 1 30542 10.1038/s41598‑024‑81961‑3 39695157
    [Google Scholar]
  3. Ugurel S. Gutzmer R. Melanom. J. Dtsch. Dermatol. Ges. 2023 21 4 343 348 10.1111/ddg.15053_g 36999586
    [Google Scholar]
  4. Chaurasiya M. Kumar G. Paul S. Verma S.S. Rawal R.K. Natural product-loaded lipid-based nanocarriers for skin cancer treatment: An overview. Life Sci. 2024 357 123043 10.1016/j.lfs.2024.123043 39233200
    [Google Scholar]
  5. Hanahan D. Hallmarks of cancer: New dimensions. Cancer Discov. 2022 12 1 31 46 10.1158/2159‑8290.CD‑21‑1059 35022204
    [Google Scholar]
  6. Gupta J. Abed H.S. Uthirapathy S. Kyada A. Rab S.O. Shit D. Janney B. Nathiya D. Kadhim A.J. Mustafa Y.F. Beyond TRAIL resistance: Novel strategies for potentiating TRAIL-induced apoptosis in cancer. Exp. Cell Res. 2025 450 1 114619 10.1016/j.yexcr.2025.114619 40451526
    [Google Scholar]
  7. Sayegh N.E. Kreidieh F. Zaatari G. Fakhruddin N. Oral malignant melanoma with colon metastasis mimicking melanosis coli: Case report. Hum. Pathol. Rep. 2025 41 300784 10.1016/j.hpr.2025.300784
    [Google Scholar]
  8. Chan A. Berman H. Zaid S.K. Ghai S. Kulkarni S. Freitas V. Streamlining diagnosis of melanoma metastasis to the breast: A case report emphasizing distinctive MRI features as crucial diagnostic tool. Radiol. Case Rep. 2025 20 8 3898 3902 10.1016/j.radcr.2025.04.081 40492160
    [Google Scholar]
  9. Rosenberg A. DeBusk L. Shah M. Burshtein J. Zakria D. Rigel D. Updated techniques for melanoma diagnosis. Dermatol. Clin. 2025 43 3 433 442 10.1016/j.det.2025.03.010 40581423
    [Google Scholar]
  10. Dohm A.E. Nakashima J.Y. Kalagotla H. Jiang S.X. Tang J.D. Bhandari M. Kim Y. Graham J.A. Khushalani N.I. Forsyth P.A. Etame A.B. Liu J.K. Tran N.D. Vogelbaum M.A. Wuthrick E.J. Yu H.H.M. Oliver D.E. Ahmed K.A. Stereotactic radiosurgery and anti-PD-1 + CTLA-4 therapy, anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors, BRAF inhibitors, or conventional chemotherapy for the management of melanoma brain metastases. Eur. J. Cancer 2023 192 113287 10.1016/j.ejca.2023.113287 37657227
    [Google Scholar]
  11. Wang Y. Chen S. Ma T. Long Q. Chen L. Xu K. Cao Y. Promotion of apoptosis in melanoma cells by taxifolin through the PI3K/AKT signaling pathway: Screening of natural products using WGCNA and CMAP platforms. Int. Immunopharmacol. 2024 138 112517 10.1016/j.intimp.2024.112517 38924866
    [Google Scholar]
  12. Lee J. Kim K.A. Yu E. Oh S.W. Kwon K. Kim G. Lee B.S. Ryoo R. Kim K.H. Lee J. Roridin E and satratoxin H, macrocyclic trichothecene mycotoxins, induce endoplasmic reticulum stress-dependent apoptosis through ribosome interaction in B16 mouse melanoma cells. Bioorg. Chem. 2025 164 108842 10.1016/j.bioorg.2025.108842 40811904
    [Google Scholar]
  13. Han R. Balsiger T. Dobrzyński M. Dürr L. Hell T. Smieško M. Solis P.N. Hamburger M. Pertz O. Teufel R. Garo E. Coumarins and betulinic acid analogues from Mammea americana and their inhibitory activities on oncogenic MAPK/ERK and PI3K/AKT pathways in human melanoma cells. Phytochemistry 2025 238 114580 10.1016/j.phytochem.2025.114580 40516889
    [Google Scholar]
  14. Piskorz W.M. Krętowski R. Cechowska-Pasko M. Marizomib (Salinosporamide A) promotes apoptosis in A375 and G361 melanoma cancer cells. Mar. Drugs 2024 22 7 315 10.3390/md22070315 39057424
    [Google Scholar]
  15. Chen J. Huang C. Liu F. Xu Z. Li L. Huang Z. Zhang H. Methylwogonin exerts anticancer effects in A375 human malignant melanoma cells through apoptosis induction, DNA damage, cell invasion inhibition and downregulation of the mTOR/PI3K/Akt signalling pathway. Arch. Med. Sci. 2019 15 4 1056 1064 10.5114/aoms.2018.73711 31360200
    [Google Scholar]
  16. Atanasov A.G. Zotchev S.B. Dirsch V.M. Orhan I.E. Banach M. Rollinger J.M. Barreca D. Weckwerth W. Bauer R. Bayer E.A. Majeed M. Bishayee A. Bochkov V. Bonn G.K. Braidy N. Bucar F. Cifuentes A. D’Onofrio G. Bodkin M. Diederich M. Dinkova-Kostova A.T. Efferth T. El Bairi K. Arkells N. Fan T.P. Fiebich B.L. Freissmuth M. Georgiev M.I. Gibbons S. Godfrey K.M. Gruber C.W. Heer J. Huber L.A. Ibanez E. Kijjoa A. Kiss A.K. Lu A. Macias F.A. Miller M.J.S. Mocan A. Müller R. Nicoletti F. Perry G. Pittalà V. Rastrelli L. Ristow M. Russo G.L. Silva A.S. Schuster D. Sheridan H. Skalicka-Woźniak K. Skaltsounis L. Sobarzo-Sánchez E. Bredt D.S. Stuppner H. Sureda A. Tzvetkov N.T. Vacca R.A. Aggarwal B.B. Battino M. Giampieri F. Wink M. Wolfender J.L. Xiao J. Yeung A.W.K. Lizard G. Popp M.A. Heinrich M. Berindan-Neagoe I. Stadler M. Daglia M. Verpoorte R. Supuran C.T. Natural products in drug discovery: Advances and opportunities. Nat. Rev. Drug Discov. 2021 20 3 200 216 10.1038/s41573‑020‑00114‑z 33510482
    [Google Scholar]
  17. Islam M.R. Islam F. Nafady M.H. Akter M. Mitra S. Das R. Urmee H. Shohag S. Akter A. Chidambaram K. Alhumaydhi F.A. Emran T.B. Cavalu S. Natural small molecules in breast cancer treatment: Understandings from a therapeutic viewpoint. Molecules 2022 27 7 2165 10.3390/molecules27072165 35408561
    [Google Scholar]
  18. 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]
  19. Dar T.U.H. Dar S.A. Islam S.U. Mangral Z.A. Dar R. Singh B.P. Verma P. Haque S. Lichens as a repository of bioactive compounds: An open window for green therapy against diverse cancers. Semin. Cancer Biol. 2022 86 Pt 2 1120 1137 10.1016/j.semcancer.2021.05.028 34052413
    [Google Scholar]
  20. Yılmaz M. Türk A.Ö. Tay T. Kıvanç M. The antimicrobial activity of extracts of the lichen Cladonia foliacea and its (-)-usnic acid, atranorin, and fumarprotocetraric acid constituents. Z. Naturforsch. C J. Biosci. 2004 59 3-4 249 254 10.1515/znc‑2004‑3‑423 15241936
    [Google Scholar]
  21. Kosanić M. Ranković B. Stanojković T. Rančić A. Manojlović N. Cladonia lichens and their major metabolites as possible natural antioxidant, antimicrobial and anticancer agents. Lebensm. Wiss. Technol. 2014 59 1 518 525 10.1016/j.lwt.2014.04.047
    [Google Scholar]
  22. Vu T.H. Le Lamer A.C. Lalli C. Boustie J. Samson M. Lohézic-Le Dévéhat F. Le Seyec J. Depsides: Lichen metabolites active against hepatitis C virus. PLoS One 2015 10 3 e0120405 10.1371/journal.pone.0120405 25793970
    [Google Scholar]
  23. Kosanić M. Ranković B. Stanojković T. Vasiljević P. Kočović A. Manojlović A. Anđić M. Bradić J. Jakovljević V. Manojlović N. Phytochemical composition, biological activity and anti-inflammatory potential of acetone extract from the lichen Platismatia glauca (L.) W.L. Culb. & C.F. Culb. Nat. Prod. Res. 2025 39 5 1111 1121 10.1080/14786419.2023.2294479 38099357
    [Google Scholar]
  24. Gaikwad S.B. Mapari S.V. Sutar R.R. Syed M. Khare R. Behera B.C. In vitro and in silico studies of lichen compounds atranorin and salazinic acid as potential antioxidant, antibacterial and anticancer agents. Chem. Biodivers. 2023 20 12 e202301229 10.1002/cbdv.202301229 37888876
    [Google Scholar]
  25. Jeon Y.J. Kim S. Kim J.H. Youn U.J. Suh S.S. The comprehensive roles of ATRANORIN, A secondary metabolite from the antarctic lichen Stereocaulon caespitosum, in HCC tumorigenesis. Molecules 2019 24 7 1414 10.3390/molecules24071414 30974882
    [Google Scholar]
  26. Cardile V. Graziano A.C.E. Avola R. Piovano M. Russo A. Potential anticancer activity of lichen secondary metabolite physodic acid. Chem. Biol. Interact. 2017 263 36 45 10.1016/j.cbi.2016.12.007 28012710
    [Google Scholar]
  27. Basnet B.B. Liu H. Liu L. Suleimen Y.M. Diversity of anticancer and antimicrobial compounds from lichens and lichen-derived fungi: A systematic review (1985-2017). Curr. Org. Chem. 2019 22 25 2487 2500 10.2174/1385272822666181109110813
    [Google Scholar]
  28. Zhou R. Yang Y. Park S.Y. Nguyen T.T. Seo Y.W. Lee K.H. Lee J.H. Kim K.K. Hur J.S. Kim H. The lichen secondary metabolite atranorin suppresses lung cancer cell motility and tumorigenesis. Sci. Rep. 2017 7 1 8136 10.1038/s41598‑017‑08225‑1 28811522
    [Google Scholar]
  29. Harikrishnan A. Veena V. Lakshmi B. Shanmugavalli R. Theres S. Prashantha C.N. Shah T. Oshin K. Togam R. Nandi S. Atranorin, an antimicrobial metabolite from lichen Parmotrema rampoddense exhibited in vitro anti-breast cancer activity through interaction with Akt activity. J. Biomol. Struct. Dyn. 2021 39 4 1248 1258 10.1080/07391102.2020.1734482 32096436
    [Google Scholar]
  30. Bačkorová M. Bačkor M. Mikeš J. Jendželovský R. Fedoročko P. Variable responses of different human cancer cells to the lichen compounds parietin, atranorin, usnic acid and gyrophoric acid. Toxicol. In Vitro 2011 25 1 37 44 10.1016/j.tiv.2010.09.004 20837130
    [Google Scholar]
  31. Paluszczak J. Kleszcz R. Studzińska-Sroka E. Krajka-Kuźniak V. Lichen-derived caperatic acid and physodic acid inhibit Wnt signaling in colorectal cancer cells. Mol. Cell. Biochem. 2018 441 1-2 109 124 10.1007/s11010‑017‑3178‑7 28887754
    [Google Scholar]
  32. Ensoy M. Cansaran-Duman D. Targeting ferroptosis with small molecule atranorin (ATR) as a novel therapeutic strategy and providing new insight into the treatment of breast cancer. Pharmaceuticals 2024 17 10 1380 10.3390/ph17101380 39459017
    [Google Scholar]
  33. Galanty A. Koczurkiewicz P. Wnuk D. Paw M. Karnas E. Podolak I. Węgrzyn M. Borusiewicz M. Madeja Z. Czyż J. Michalik M. Usnic acid and atranorin exert selective cytostatic and anti-invasive effects on human prostate and melanoma cancer cells. Toxicol. In Vitro 2017 40 161 169 10.1016/j.tiv.2017.01.008 28095330
    [Google Scholar]
  34. Shaaban S. Althikrallah H.A. Negm A. Abo Elmaaty A. Al-Karmalawy A.A. Repurposed organoselenium tethered amidic acids as apoptosis inducers in melanoma cancer via P53, BAX, caspases-3, 6, 8, 9, BCL-2, MMP2, and MMP9 modulations. RSC Advances 2024 14 26 18576 18587 10.1039/D4RA02944E 38860260
    [Google Scholar]
  35. Behera B.P. Mishra S.R. Mahapatra K.K. Patil S. Efferth T. Bhutia S.K. SIRT1-activating butein inhibits arecoline-induced mitochondrial dysfunction through PGC1α and MTP18 in oral cancer. Phytomedicine 2024 129 155511 10.1016/j.phymed.2024.155511 38723523
    [Google Scholar]
  36. Yangın S. Cansaran-Duman D. Eskiler G.G. Aras S. The molecular mechanisms of vulpinic acid induced programmed cell death in melanoma. Mol. Biol. Rep. 2022 49 9 8273 8280 10.1007/s11033‑022‑07619‑3 35960408
    [Google Scholar]
  37. Jama H.A. Ensoy M. Yılmazer A. Cansaran-Duman D. Delineating the potential therapeutic effects of lobaric acid as a novel strategy in the treatment of melanoma. Curr. Med. Chem. 2025 32 14 2792 2808 10.2174/0109298673322435240913095954 39838682
    [Google Scholar]
  38. Li P. Pu S. Lin C. He L. Zhao H. Yang C. Guo Z. Xu S. Zhou Z. Curcumin selectively induces colon cancer cell apoptosis and S cell cycle arrest by regulates Rb/E2F/p53 pathway. J. Mol. Struct. 2022 1263 133180 10.1016/j.molstruc.2022.133180
    [Google Scholar]
  39. Hosseini F. Ahmadi A. Hassanzade H. Gharedaghi S. Rassouli F.B. Jamialahmadi K. Inhibition of melanoma cell migration and invasion by natural coumarin auraptene through regulating EMT markers and reducing MMP-2 and MMP-9 activity. Eur. J. Pharmacol. 2024 971 176517 10.1016/j.ejphar.2024.176517 38537805
    [Google Scholar]
  40. Karagöz Y. Öztürk Karagöz B. Lichens in pharmacological action: What happened in the last decade? Eurasian J. Med. 2023 54 1 Suppl. 1 S195 S208 10.5152/eurasianjmed.2022.22335 36655467
    [Google Scholar]
  41. Chen Q. Ma K. Liu X. Chen S.H. Li P. Yu Y. Leung A.K.L. Yu X. Truncated PARP1 mediates ADP-ribosylation of RNA polymerase III for apoptosis. Cell Discov. 2022 8 1 3 10.1038/s41421‑021‑00355‑1 35039483
    [Google Scholar]
  42. Cordaro F.G. De Presbiteris A.L. Camerlingo R. Mozzillo N. Pirozzi G. Cavalcanti E. Manca A. Palmieri G. Cossu A. Ciliberto G. Ascierto P.A. Travali S. Patriarca E.J. Caputo E. Phenotype characterization of human melanoma cells resistant to dabrafenib. Oncol. Rep. 2017 38 5 2741 2751 10.3892/or.2017.5963 29048639
    [Google Scholar]
  43. King A.J. Arnone M.R. Bleam M.R. Moss K.G. Yang J. Fedorowicz K.E. Smitheman K.N. Erhardt J.A. Hughes-Earle A. Kane-Carson L.S. Sinnamon R.H. Qi H. Rheault T.R. Uehling D.E. Laquerre S.G. Dabrafenib; preclinical characterization, increased efficacy when combined with trametinib, while BRAF/MEK tool combination reduced skin lesions. PLoS One 2013 8 7 e67583 10.1371/journal.pone.0067583 23844038
    [Google Scholar]
  44. Vasudevan S. Flashner-Abramson E. Alkhatib H. Roy Chowdhury S. Adejumobi I.A. Vilenski D. Stefansky S. Rubinstein A.M. Kravchenko-Balasha N. Overcoming resistance to BRAFV600E inhibition in melanoma by deciphering and targeting personalized protein network alterations. NPJ Precis. Oncol. 2021 5 1 50 10.1038/s41698‑021‑00190‑3 34112933
    [Google Scholar]
  45. Tovar-Parra D. Zammit-Mangion M. Comparative analysis of the effect of the BRAF inhibitor dabrafenib in 2D and 3D cell culture models of human metastatic melanoma cells. In Vivo 2024 38 4 1579 1593 10.21873/invivo.13608 38936891
    [Google Scholar]
  46. Zanrè V. Bellinato F. Cardile A. Passarini C. Di Bella S. Menegazzi M. BRAF-mutated melanoma cell lines develop distinct molecular signatures after prolonged exposure to AZ628 or dabrafenib: Potential benefits of the antiretroviral treatments cabotegravir or doravirine on BRAF-inhibitor-resistant cells. Int. J. Mol. Sci. 2024 25 22 11939 10.3390/ijms252211939 39596009
    [Google Scholar]
  47. Margue C. Philippidou D. Kozar I. Cesi G. Felten P. Kulms D. Letellier E. Haan C. Kreis S. Kinase inhibitor library screening identifies synergistic drug combinations effective in sensitive and resistant melanoma cells. J. Exp. Clin. Cancer Res. 2019 38 1 56 10.1186/s13046‑019‑1038‑x 30728057
    [Google Scholar]
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Atranorin Triggers Intrinsic and Extrinsic Apoptosis and Suppresses Migration in Human Melanoma Cells
Bentham Science Publishers ; https://doi.org/10.2174/0109298673415871251125105259
/content/journals/cmc/10.2174/0109298673415871251125105259
/content/journals/cmc/10.2174/0109298673415871251125105259
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  • Article Type:     Research Article
Keywords: Western blot ; apoptosis ; metastasis ; Atranorin ; cell cycle ; melanoma

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