The pyrazole derivative of usnic acid inhibits the proliferation of pancreatic cancer cells in vitro and in vivo.
Cancer
Cell death
Endoplasmic reticulum stress
Lichens
Usnic acid
Vacuolization
Journal
Cancer cell international
ISSN: 1475-2867
Titre abrégé: Cancer Cell Int
Pays: England
ID NLM: 101139795
Informations de publication
Date de publication:
24 Sep 2023
24 Sep 2023
Historique:
received:
11
05
2023
accepted:
03
09
2023
medline:
25
9
2023
pubmed:
25
9
2023
entrez:
24
9
2023
Statut:
epublish
Résumé
Pancreatic cancer is one of the leading causes of cancer death in Western societies. Its late diagnosis and resistance to chemotherapies result in a high mortality rate; thus, the development of more effective therapies for the treatment of pancreatic cancer is strongly warranted. Usnic acid (UA) is a secondary metabolite of lichens that shows modest antiproliferative activity toward cancer cells. Recently, we reported the synthesis of a UA pyrazole derivative, named 5, which was more active than the parent compound toward cervical cancer cells. Here, its anticancer potential has been evaluated in detail in other cancer cells, particularly pancreatic cancer cells. The impact of UA and derivative 5 on cell viability, morphology, cell cycle, and death was assessed using the MTT test, electron microscopy, flow cytometry, and immunoblotting, respectively. The calcium ions level was detected fluorometrically. In vivo, the anticancer activity of 5 was evaluated in a murine xenograft model. Derivative 5 inhibited the viability of different cancer cells. Noncancerous cells were less sensitive. It induced the release of calcium ions from the endoplasmic reticulum (ER) and ER stress, which was manifested by cell vacuolization. It was accompanied by G0/G1 cell cycle arrest and cell death of pancreatic cancer cells. When applied to nude mice with xenografted pancreatic cancer cells, 5 inhibited tumor growth, with no signs of kidney or liver toxicity. UA derivative 5 is superior to UA inhibiting the growth and proliferation of pancreatic cancer cells. ER stress exaggeration is a mechanism underlying the activity of derivative 5.
Sections du résumé
BACKGROUND
BACKGROUND
Pancreatic cancer is one of the leading causes of cancer death in Western societies. Its late diagnosis and resistance to chemotherapies result in a high mortality rate; thus, the development of more effective therapies for the treatment of pancreatic cancer is strongly warranted. Usnic acid (UA) is a secondary metabolite of lichens that shows modest antiproliferative activity toward cancer cells. Recently, we reported the synthesis of a UA pyrazole derivative, named 5, which was more active than the parent compound toward cervical cancer cells. Here, its anticancer potential has been evaluated in detail in other cancer cells, particularly pancreatic cancer cells.
METHODS
METHODS
The impact of UA and derivative 5 on cell viability, morphology, cell cycle, and death was assessed using the MTT test, electron microscopy, flow cytometry, and immunoblotting, respectively. The calcium ions level was detected fluorometrically. In vivo, the anticancer activity of 5 was evaluated in a murine xenograft model.
RESULTS
RESULTS
Derivative 5 inhibited the viability of different cancer cells. Noncancerous cells were less sensitive. It induced the release of calcium ions from the endoplasmic reticulum (ER) and ER stress, which was manifested by cell vacuolization. It was accompanied by G0/G1 cell cycle arrest and cell death of pancreatic cancer cells. When applied to nude mice with xenografted pancreatic cancer cells, 5 inhibited tumor growth, with no signs of kidney or liver toxicity.
CONCLUSIONS
CONCLUSIONS
UA derivative 5 is superior to UA inhibiting the growth and proliferation of pancreatic cancer cells. ER stress exaggeration is a mechanism underlying the activity of derivative 5.
Identifiants
pubmed: 37743482
doi: 10.1186/s12935-023-03054-x
pii: 10.1186/s12935-023-03054-x
pmc: PMC10518105
doi:
Types de publication
Journal Article
Langues
eng
Pagination
210Subventions
Organisme : Narodowe Centrum Nauki
ID : 2017/26/M/NZ7/00668
Informations de copyright
© 2023. BioMed Central Ltd., part of Springer Nature.
Références
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49.
doi: 10.3322/caac.21660
pubmed: 33538338
Klein AP. Pancreatic cancer epidemiology: understanding the role of lifestyle and inherited risk factors. Nat Rev Gastroenterol Hepatol. 2021;18(7):493–502.
doi: 10.1038/s41575-021-00457-x
pubmed: 34002083
pmcid: 9265847
Wood LD, Hruban RH. Pathology and molecular genetics of pancreatic neoplasms. Cancer J. 2012;18(6):492–501.
doi: 10.1097/PPO.0b013e31827459b6
pubmed: 23187835
pmcid: 4013751
Ingolfsdottir K. Usnic acid. Phytochemistry. 2002;61(7):729–36.
doi: 10.1016/S0031-9422(02)00383-7
pubmed: 12453567
Araujo AA, de Melo MG, Rabelo TK, Nunes PS, Santos SL, Serafini MR, Santos MR, Quintans-Junior LJ, Gelain DP. Review of the biological properties and toxicity of usnic acid. Nat Prod Res. 2015;29(23):2167–80.
doi: 10.1080/14786419.2015.1007455
pubmed: 25707417
Luzina OA, Salakhutdinov NF. Biological activity of usnic acid and its derivatives: Part 2. Effects on higher organisms molecular and physicochemical aspects. Russ J Bioorg Chem. 2016;42:249–68.
doi: 10.1134/S1068162016030109
Galanty A, Pasko P, Podolak I. Enantioselective activity of usnic acid: a comprehensive review and future perspectives. Phytochem Rev. 2019;18:527–48.
doi: 10.1007/s11101-019-09605-3
Solarova Z, Liskova A, Samec M, Kubatka P, Busselberg D, Solar P. Anticancer potential of lichens’ secondary metabolites. Biomolecules. 2020;10(1):87.
doi: 10.3390/biom10010087
pubmed: 31948092
pmcid: 7022966
Qi W, Lu C, Huang H, Zhang W, Song S, Liu B. (+)-Usnic acid induces ROS-dependent apoptosis via inhibition of mitochondria respiratory chain complexes and Nrf2 expression in lung squamous cell carcinoma. Int J Mol Sci. 2020;21(3):876.
doi: 10.3390/ijms21030876
pubmed: 32013250
pmcid: 7037438
Backorova M, Backor M, Mikes J, Jendzelovsky R, Fedorocko 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.
doi: 10.1016/j.tiv.2010.09.004
pubmed: 20837130
Studzinska-Sroka E, Majchrzak-Celinska A, Zalewski P, Szwajgier D, Baranowska-Wojcik E, Kapron B, Plech T, Zarowski M, Cielecka-Piontek J. Lichen-derived compounds and extracts as biologically active substances with anticancer and neuroprotective properties. Pharmaceuticals (Basel). 2021;14(12):1293.
doi: 10.3390/ph14121293
pubmed: 34959693
Geng X, Zhang X, Zhou B, Zhang C, Tu J, Chen X, Wang J, Gao H, Qin G, Pan W. Usnic acid induces cycle arrest, apoptosis, and autophagy in gastric cancer cells in vitro and in vivo. Med Sci Monit. 2018;24:556–66.
doi: 10.12659/MSM.908568
pubmed: 29374767
pmcid: 5798279
Sanchez W, Maple JT, Burgart LJ, Kamath PS. Severe hepatotoxicity associated with use of a dietary supplement containing usnic acid. Mayo Clin Proc. 2006;81(4):541–4.
doi: 10.4065/81.4.541
pubmed: 16610575
Guo L, Shi Q, Fang JL, Mei N, Ali AA, Lewis SM, Leakey JEA, Frankos VH. Review of usnic acid and Usnea barbata toxicity. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2008;26(4):317–38.
doi: 10.1080/10590500802533392
pubmed: 19034791
pmcid: 5739313
Han D, Matsumaru K, Rettori D, Kaplowitz N. Usnic acid-induced necrosis of cultured mouse hepatocytes: inhibition of mitochondrial function and oxidative stress. Biochem Pharmacol. 2004;67(3):439–51.
doi: 10.1016/j.bcp.2003.09.032
pubmed: 15037196
da Silva Santos NP, Nascimento SC, Wanderley MS, Pontes-Filho NT, da Silva JF, de Castro CM, Pereira EC, da Silva NH, Honda NK, Santos-Magalhaes NS. Nanoencapsulation of usnic acid: an attempt to improve antitumour activity and reduce hepatotoxicity. Eur J Pharm Biopharm. 2006;64(2):154–60.
doi: 10.1016/j.ejpb.2006.05.018
pubmed: 16899355
Gunawan GA, Gimla M, Gardiner MG, Herman-Antosiewicz A, Reekie TA. Divergent reactivity of usnic acid and evaluation of its derivatives for antiproliferative activity against cancer cells. Bioorg Med Chem. 2023;79: 117157.
doi: 10.1016/j.bmc.2023.117157
pubmed: 36652792
Pyrczak-Felczykowska A, Narlawar R, Pawlik A, Guzow-Krzeminska B, Artymiuk D, Hac A, Rys K, Rendina LM, Reekie TA, Herman-Antosiewicz A. Synthesis of usnic acid derivatives and evaluation of their antiproliferative activity against cancer cells. J Nat Prod. 2019;82(7):1768–78.
doi: 10.1021/acs.jnatprod.8b00980
pubmed: 31282672
Pyrczak-Felczykowska A, Reekie TA, Jakalski M, Hac A, Malinowska M, Pawlik A, Rys K, Guzow-Krzeminska B, Herman-Antosiewicz A. The isoxazole derivative of usnic acid induces an ER stress response in breast cancer cells that leads to paraptosis-like cell death. Int J Mol Sci. 2022;23(3):1802.
doi: 10.3390/ijms23031802
pubmed: 35163724
pmcid: 8837022
Oyadomari S, Araki E, Mori M. Endoplasmic reticulum stress-mediated apoptosis in pancreatic beta-cells. Apoptosis. 2002;7(4):335–45.
doi: 10.1023/A:1016175429877
pubmed: 12101393
Mollinedo F, Gajate C. Direct endoplasmic reticulum targeting by the selective alkylphospholipid analog and antitumor ether lipid edelfosine as a therapeutic approach in pancreatic cancer. Cancers (Basel). 2021;13(16):4173.
doi: 10.3390/cancers13164173
pubmed: 34439330
Botrus G, Miller RM, Uson Junior PLS, Kannan G, Han H, Von Hoff DD. Increasing stress to induce apoptosis in pancreatic cancer via the Unfolded Protein Response (UPR). Int J Mol Sci. 2022;24(1):577.
doi: 10.3390/ijms24010577
pubmed: 36614019
pmcid: 9820188
Einarsdottir E, Groeneweg J, Bjornsdottir GG, Harethardottir G, Omarsdottir S, Ingolfsdottir K, Ogmundsdottir HM. Cellular mechanisms of the anticancer effects of the lichen compound usnic acid. Planta Med. 2010;76(10):969–74.
doi: 10.1055/s-0029-1240851
pubmed: 20143294
Bessadottir M, Egilsson M, Einarsdottir E, Magnusdottir IH, Ogmundsdottir MH, Omarsdottir S, Ogmundsdottir HM. Proton-shuttling lichen compound usnic acid affects mitochondrial and lysosomal function in cancer cells. PLoS ONE. 2012;7(12): e51296.
doi: 10.1371/journal.pone.0051296
pubmed: 23227259
pmcid: 3515546
Mallavadhani UV, Vanga NR, Balabhaskara R, Jain N. Synthesis and antiproliferative activity of novel (+)-usnic acid analogues. J Asian Nat Prod Res. 2020;22(3):562–77.
doi: 10.1080/10286020.2019.1603220
Marciniak SJ, Ron D. Endoplasmic reticulum stress signaling in disease. Physiol Rev. 2006;86(4):1133–49.
doi: 10.1152/physrev.00015.2006
pubmed: 17015486
Schroder M, Kaufman RJ. ER stress and the unfolded protein response. Mutat Res. 2005;569(1–2):29–63.
doi: 10.1016/j.mrfmmm.2004.06.056
pubmed: 15603751
Corazzari M, Gagliardi M, Fimia GM, Piacentini M. Endoplasmic reticulum stress, unfolded protein response, and cancer cell fate. Front Oncol. 2017;7:78.
doi: 10.3389/fonc.2017.00078
pubmed: 28491820
pmcid: 5405076
Fonseca SG, Gromada J, Urano F. Endoplasmic reticulum stress and pancreatic beta-cell death. Trends Endocrinol Metab. 2011;22(7):266–74.
pubmed: 21458293
pmcid: 3130122
Robinson CM, Talty A, Logue SE, Mnich K, Gorman AM, Samali A. An emerging role for the unfolded protein response in pancreatic cancer. Cancers (Basel). 2021;13(2):261.
doi: 10.3390/cancers13020261
pubmed: 33445669