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Usnic Acid Exerts Antiproliferative and Apoptotic Effects by Suppressing NF-B p50 in DU145 Cells

Year 2023, , 251 - 257, 21.12.2023
https://doi.org/10.26650/EurJBiol.2023.1274707

Abstract

Objective: Nuclear factor kappa B (NF-κB) is one pathway that controls the expression of genes involved in many cancer events such as proliferation, apoptosis, metastasis, and invasion. Usnic acid is a molecule with many biological effects such as being anticholinergic, gastroprotective, anti-inflammatory, anti-cancerous, and especially antioxidant. This study aims to mechanistically examine the apoptotic behaviors of usnic acid in DU145 prostate cancer cells and the molecules it acts on in the NF-κB pathway.

Materials and Methods: This study investigates the apoptotic changes in DU145 cells after usnic acid administration through JC-1 staining and caspase-3 activity measurements. In addition, it tests the effects of usnic acid on subunit p50 and p65 protein and gene expressions in the NF-κB pathway through the respective Western blot and qPCR measurements.

Results: The IC50 values of usnic acid at 24 and 48 h in DU145 cells were calculated as 167.06±12.35 μM and 42.15±3.76 μM, respectively. In addition, JC-1 staining showed usnic acid-treated DU145 cells to trigger apoptosis by increasing the membrane permeability of their mitochondria. NF-κB p50 protein expression was also found to be suppressed after usnic acid administration.

Conclusion: The results of this study show usnic acid administration to suppress proliferation and to induce mitochondrial apoptosis by suppressing the NF-κB pathway in DU145 cells. This effect of usnic acid indicates it to be combinable with chemotherapeutic agents and evaluable as an alternative in cancer treatment.

References

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  • Odabasoglu F, Cakir A, Suleyman H, et al. Gastroprotective and antioxidant effects of usnic acid on indomethacin-induced gastric ulcer in rats. J Ethnopharmacol. 2006; 103(1):59-65. google scholar
  • Kohlhardt-Floehr C, Boehm F, Troppens S, Lademann J, Truscott TG. Prooxidant and antioxidant behaviour of usnic acid from lichens under UVB-light irradiation-Studies on human cells. J Photochem Photobiol B. 2010;101(1):97-102. google scholar
  • Han D, Matsumaru K, Rettori D, Kaplowitz N. Usnic acid-induced necrosis of cultured mouse hepatocytes: Inhibition of mitochondrial function and oxidative stress. Biochem Pharma-col. 2004;67(3):439-451. google scholar
  • Pramyothin P, Janthasoot W, Pongnimitprasert N, Phrukudom S, Ruangrungsi N. Hepatotoxic effect of (+) usnic acid from Usnea siamensis Wainio in rats, isolated rat hepatocytes and isolated rat liver mitochondria. J Ethnopharmacol. 2004;90(2-3): 381-387. google scholar
  • Sonko BJ, Schmitt TC, Guo L, et al. Assessment of usnic acid toxicity in rat primary hepatocytes using 13C isotopomer dis-tribution analysis of lactate, glutamate and glucose. Food Chem Toxicol. 2011;49(11):2968-2974. google scholar
  • Sahu SC, Amankwa-Sakyi M, O’Donnell Jr MW, Sprando RL. Effects of usnic acid exposure on human hepatoblastoma HepG2 cells in culture. J Appl Toxicol. 2012;32(9):722-730. google scholar
  • Mariappan N, Elks CM, Sriramula S, et al. NF-kB-induced oxida-tive stress contributes to mitochondrial and cardiac dysfunction in type II diabetes. Cardiovasc Res. 2010;85(3):473-483. google scholar
  • Elks CM, Mariappan N, Haque M, Guggilam A, Majid DS, Fran-cis J. Chronic NF-kB blockade reduces cytosolic and mitochon-drial oxidative stress and attenuates renal injury and hypertension in SHR. Am J Physiol Renal Physiol. 2009;296(2):298-305. google scholar
  • Takai M, Uehara Y, Beisler JA. Usnic acid derivatives as potential antineoplastic agents. JMed Chem. 1979; 22(11):1380-1384. google scholar
  • Cardarelli M, Serino G, Campanella L, et al. Antimitotic effects of usnic acid on different biological systems. Cell Mol Life Sci. 1997;53:667-672. google scholar
  • Backorova M, Jendzelovsky R, Kello M, Backor M, Mikes J, Fedorocko P. Lichen secondary metabolites are responsible for induction of apoptosis in HT-29 and A2780 human cancer cell lines. Toxicol In Vitro. 2012;26(3): 462-468. google scholar
  • Dincsoy AB, Duman DC. Changes in apoptosis-related gene ex-pression profiles in cancer cell lines exposed to usnic acid lichen secondary metabolite. Turk J Biol. 2017;41(3): 484-493. google scholar
  • Jin JQ, Li CQ, He LC. Down-regulatory effect of usnic acid on nu-clear factor-KB-dependent tumor necrosis factor-a and inducible nitric oxide synthase expression in lipopolysaccharide-stimulated macrophages RAW 264.7. Phytother Res. 2008; 22(12):1605-1609. google scholar
Year 2023, , 251 - 257, 21.12.2023
https://doi.org/10.26650/EurJBiol.2023.1274707

Abstract

References

  • Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: Cancer J Clin. 2021;71(3):209-249. google scholar
  • Gandaglia G, Leni R, Bray F, et al. Epidemiology and prevention of prostate cancer. Eur Urol Oncol. 2021;4(6):877-892. google scholar
  • Rawla P. Epidemiology of prostate cancer. World J Oncol. 2019;10(2):63-89. google scholar
  • Hurwitz M. Chemotherapy in prostate cancer. Curr Oncol Rep. 2015;17:1-10. google scholar
  • Erstad DJ, Cusack JC. Targeting the NF-kB pathway in cancer therapy. Surg Oncol Clin. 2013;22(4):705-746. google scholar
  • Rinkenbaugh AL, Baldwin AS. The NF-kB pathway and cancer stem cells. Cells. 2016;5(2):16. doi: 10.3390/cells5020016. google scholar
  • Ingolfsdottir K. Usnic acid. Phytochem.2002;61(7):729-736. google scholar
  • Araujo AA, de Melo MG, Rabelo TK, et al. Review of the bi-ological properties and toxicity of usnic acid. Nat Prod Res. 2015;29(23):2167-2180. google scholar
  • Cakmak KC, Gulcin I. Anticholinergic and antioxidant activ-ities of usnic acid-an activity-structure insight. Toxicol Rep. 2019;6:1273-1280. google scholar
  • Hoa NT, Van Bay M, Mechler A, Vo QV. Is usnic acid a promising radical scavenger? ACS Omega. 2020;5(28):17715-17720. google scholar
  • Maulidiyah M, Rachman F, Mulkiyan OMZ, et al. Antioxidant activity of usnic acid compound from methanol extract of Lichen usnea sp. J Oleo Sci. 2023;72(2):179-188. google scholar
  • Erdoğan Ö, Paşa S, Demirbolat GM, Çevik Ö. Green biosynthesis, characterization, and cytotoxic effect of magnetic iron nanopar-ticles using Brassica oleracea var capitata sub var rubra (red cabbage) aqueous peel extract. Turk J Chem. 2021; 45(4):1086-1096. google scholar
  • Sivandzade F, Bhalerao A, Cucullo L. Analysis of the mito-chondrial membrane potential using the cationic JC-1 dye as a sensitive fluorescent probe. Bio-protoc. 2019;9(1):e3128. doi: 10.21769/BioProtoc.3128. google scholar
  • Erdogan O, Cevik O. Myricetin can control metastasis and invasion by suppressing ATF2-related signaling pathway in Rapamycin-resistant HepG2 hepatocellular cancer cells. J Res Pharm. 2023;27(2):557-565. google scholar
  • Pasa S, Erdogan O, Cevik O. Design, synthesis and investiga-tion of procaine based new Pd complexes as DNA methyltrans-ferase inhibitor on gastric cancer cells. Inorg Chem Commun. 2021;132:108846. https://doi.org/10.1016/j.inoche.2021.108846. google scholar
  • Inoue Ji, Gohda J, Akiyama T, Semba K. NF-B activation in devel-opment and progression of cancer. Cancer Sci. 2007;98(3):268-274. google scholar
  • Sun SC. The non-canonical NF-B pathway in immunity and in-flammation. Nat Rev Immunol. 2017;17(9):545-558. google scholar
  • Naugler WE, Karin M. NF-B and cancer—identifying targets and mechanisms. Curr Opin Genet Dev. 2008;18(1):19-26. google scholar
  • Yamamoto Y, Gaynor RB. Therapeutic potential of inhibition of the NF-kB pathway in the treatment of inflammation and cancer. J Clin Invest. 2001;107(2):135-142. google scholar
  • Ramadass V, Vaiyapuri T, Tergaonkar V. Small molecule NF-kB pathway inhibitors in clinic. Int J Mol Sci. 2020;21(14):5164. doi: 10.3390/ijms21145164 google scholar
  • Cevik O, Acidereli H, Turut FA, Yildirim S, Acilan C. Cabazitaxel exhibits more favorable molecular changes compared to other taxanes in androgen-independent prostate cancer cells. J Biochem Mol Toxicol. 2020;34(9):e22542. doi: 10.1002/jbt.22542. google scholar
  • Odabasoglu F, Cakir A, Suleyman H, et al. Gastroprotective and antioxidant effects of usnic acid on indomethacin-induced gastric ulcer in rats. J Ethnopharmacol. 2006; 103(1):59-65. google scholar
  • Kohlhardt-Floehr C, Boehm F, Troppens S, Lademann J, Truscott TG. Prooxidant and antioxidant behaviour of usnic acid from lichens under UVB-light irradiation-Studies on human cells. J Photochem Photobiol B. 2010;101(1):97-102. google scholar
  • Han D, Matsumaru K, Rettori D, Kaplowitz N. Usnic acid-induced necrosis of cultured mouse hepatocytes: Inhibition of mitochondrial function and oxidative stress. Biochem Pharma-col. 2004;67(3):439-451. google scholar
  • Pramyothin P, Janthasoot W, Pongnimitprasert N, Phrukudom S, Ruangrungsi N. Hepatotoxic effect of (+) usnic acid from Usnea siamensis Wainio in rats, isolated rat hepatocytes and isolated rat liver mitochondria. J Ethnopharmacol. 2004;90(2-3): 381-387. google scholar
  • Sonko BJ, Schmitt TC, Guo L, et al. Assessment of usnic acid toxicity in rat primary hepatocytes using 13C isotopomer dis-tribution analysis of lactate, glutamate and glucose. Food Chem Toxicol. 2011;49(11):2968-2974. google scholar
  • Sahu SC, Amankwa-Sakyi M, O’Donnell Jr MW, Sprando RL. Effects of usnic acid exposure on human hepatoblastoma HepG2 cells in culture. J Appl Toxicol. 2012;32(9):722-730. google scholar
  • Mariappan N, Elks CM, Sriramula S, et al. NF-kB-induced oxida-tive stress contributes to mitochondrial and cardiac dysfunction in type II diabetes. Cardiovasc Res. 2010;85(3):473-483. google scholar
  • Elks CM, Mariappan N, Haque M, Guggilam A, Majid DS, Fran-cis J. Chronic NF-kB blockade reduces cytosolic and mitochon-drial oxidative stress and attenuates renal injury and hypertension in SHR. Am J Physiol Renal Physiol. 2009;296(2):298-305. google scholar
  • Takai M, Uehara Y, Beisler JA. Usnic acid derivatives as potential antineoplastic agents. JMed Chem. 1979; 22(11):1380-1384. google scholar
  • Cardarelli M, Serino G, Campanella L, et al. Antimitotic effects of usnic acid on different biological systems. Cell Mol Life Sci. 1997;53:667-672. google scholar
  • Backorova M, Jendzelovsky R, Kello M, Backor M, Mikes J, Fedorocko P. Lichen secondary metabolites are responsible for induction of apoptosis in HT-29 and A2780 human cancer cell lines. Toxicol In Vitro. 2012;26(3): 462-468. google scholar
  • Dincsoy AB, Duman DC. Changes in apoptosis-related gene ex-pression profiles in cancer cell lines exposed to usnic acid lichen secondary metabolite. Turk J Biol. 2017;41(3): 484-493. google scholar
  • Jin JQ, Li CQ, He LC. Down-regulatory effect of usnic acid on nu-clear factor-KB-dependent tumor necrosis factor-a and inducible nitric oxide synthase expression in lipopolysaccharide-stimulated macrophages RAW 264.7. Phytother Res. 2008; 22(12):1605-1609. google scholar
There are 34 citations in total.

Details

Primary Language English
Subjects Plant Cell and Molecular Biology, Animal Cell and Molecular Biology
Journal Section Themed Articles - Research Articles
Authors

Ömer Erdoğan 0000-0002-8327-7077

Burçin İrem Abas 0000-0002-1018-5577

Özge Çevik 0000-0002-9325-3757

Publication Date December 21, 2023
Submission Date March 31, 2023
Published in Issue Year 2023

Cite

AMA Erdoğan Ö, Abas Bİ, Çevik Ö. Usnic Acid Exerts Antiproliferative and Apoptotic Effects by Suppressing NF-B p50 in DU145 Cells. Eur J Biol. December 2023;82(2):251-257. doi:10.26650/EurJBiol.2023.1274707