Determination of Cytotoxic and Apoptotic Properties of Lobaric Acid, a Secondary Metabolite of Lichen and Investigation of Its Theoretical Potential

Year 2024, , 192 - 200, 30.09.2024

Hamit Emre Kızıl , Güleray Ağar , Yavuz Ekincioğlu

https://doi.org/10.56430/japro.1518450

Abstract

In this study, we aimed to elucidate some of the mechanisms of cell death induced by lobaric acid in A549 (human lung cancer) cells. For this purpose, the effects of cytotoxic concentrations on p53 and caspase-3 gene expressions were investigated. A549 cells were treated with varying concentrations of lobaric acid (12.5, 25, 50, and 100 µg/ml) for 48 hours and then their viability was evaluated and p53 and caspase-3 mRNA expressions were determined at statistically cytotoxic concentrations of 12.5, 50, and 100 µg/ml. According to beta-actin, it was determined that the increase in lobaric acid concentration revealed an upward trend in p53 and caspase-3 mRNA expressions. Furthermore, quantum chemical parameters such as frontier molecular orbitals, band gap energy and ionization potential, electronic affinity, chemical softness, chemical potential, electrophilicity index and chemical hardness were analyzed. Furthermore, molecular docking was performed to identify the binding sites and the binding behavior of lobaric acid to some target proteins (P53, Caspase-3 and Bcl-2).

Keywords

Apoptosis, Cytotoxicity, Lobaric acid, Molecular docking

Ethical Statement

The authors declare that this study does not require ethical committee approval or any legal permission. This study includes data obtained from a doctoral dissertation completed in 2016 (YÖK ID: 426087), and in line with the decisions taken by Ulakbim TR Dizin, Ethics Committee Permission is required for studies to be published since 2020. Other data obtained are web-based, virtual data.

Thanks

Some of the data in this study were obtained from Dr. Hamit Emre KIZIL’s PhD thesis (YÖK ID: 426087) completed in 2016. We are pleased to extend our deepest gratitude to the entire laboratory team for their unwavering moral support throughout the course of this doctoral thesis.

References

• Andania, M. M., Ismed, F., Taher, M., Ichwan, S. J. A., Bakhtiar, A., & Arbain, D. (2019). Cytotoxic activities of extracts and isolated compounds of some potential sumatran medicinal plants against MCF-7 and HSC-3 cell lines. Journal of Mathematical & Fundamental Sciences, 51(3), 225-242. https://doi.org/10.5614/j.math.fund.sci.2019.51.3.2
• Aprile, G., Catalano, I., Migliozzi, A., & Mingo, A. (2011). Monitoring epiphytic lichen biodiversity to detect environmental quality and air pollution: The case study of Roccamonfina Park (Campania Region-Italy). In A. Moldoveanu (Ed.), Air pollution-new developments (pp. 227-245). IntechOpen. https://doi.org/10.5772/17907
• Aydın, S. (2012). Elazığ yöresinde yetişen dut, kızılcık, kiraz ve ceviz meyvelerinin antioksidan kapasiteleri ve bazı deney modellerinde oluşturulan oksidatif stres üzerine etkilerinin incelenmesi (Doctoral dissertation, Fırat University). (In Turkish)
• Biovia, D. S. (2019). Discovery Studio Modeling Environment, Release 2017. Dassault Systèmes.
• Bucar, F., Schneider, I., Ögmundsdóttir, H., & Ingólfsdóttir, K. (2004). Anti-proliferative lichen compounds with inhibitory activity on 12 (S)-HETE production in human platelets. Phytomedicine, 11(7-8), 602-606. https://doi.org/10.1016/j.phymed.2004.03.004
• Çakabay, B. (2012). Meme kanserinde GASC1 ekspresyonu (Specialty in medicine thesis, Ankara University). (In Turkish)
• Çapık, Ö. (2014). Usnik asitin kültürü yapılmış huvec ve üç farklı kanser hücre hattı (A549, HeLa ve AGS) üzerine sitotoksik, antiproliferatif ve apoptotik etkisinin belirlenmesi (Master’s thesis, Atatürk University). (In Turkish)
• Cárdenas, C., Rabi, N., Ayers, P. W., Morell, C., Jaramillo, P., & Fuentealba, P. (2009). Chemical reactivity descriptors for ambiphilic reagents: Dual descriptor, local hypersoftness, and electrostatic potential. The Journal of Physical Chemistry A, 113(30), 8660-8667. https://doi.org/10.1021/jp902792n
• Ekincioğlu, Y. (2023). Theoretical investigation of (E)-1-(2, 4-dichlorophenyl)-3-[4-(morpholin-4-yl) phenyl] prop-2-en-1-one molecule as a possible potential COVID-19 drug candidate: Molecular docking and DFT calculations. Russian Journal of Physical Chemistry A, 97(13), 3057-3067. https://doi.org/10.1134/S0036024423130241
• Emsen, B. (2015). Liken sekonder metabolitlerinin deneysel beyin tümör modeli üzerine potansiyel etkilerinin ın vitro yöntemlerle araştırılması (Doctoral dissertation, Karamanoğlu Mehmetbey University). (In Turkish)
• Emsen, B., Aslan, A., Turkez, H., Taghizadehghaleh, J. A., & Kaya, A. (2018). The anti-cancer efficacies of diffractaic, lobaric, and usnic acid: In vitro: Inhibition of glioma. Journal of Cancer Research and Therapeutics, 14(5), 941-951. https://doi.org/10.4103/0973-1482.177218
• Fahim, A. M., & Farag, A. M. (2020). Synthesis, antimicrobial evaluation, molecular docking and theoretical calculations of novel pyrazolo [1, 5-a] pyrimidine derivatives. Journal of Molecular Structure, 1199, 127025. https://doi.org/10.1016/j.molstruc.2019.127025
• Frisch, M., Trucks, G., Schlegel, H. B., Scuseria, G. E., Robb, M. A., Cheeseman, J. R., Scalmani, G., Barone, V., Mennucci, B., & Petersson, G., & et al. (2009). Gaussian 09, Revision B. 01. Gaussian Inc.
• González-González, S., Franco-Pérez, M., Jardínez, C., Cariño-Moreno, J. J., Ramírez-Sotelo, M. G., & Zamudio-Medina, A. (2023). Synthesis, characterization, and quantum chemistry local chemical reactivity description of new phosphorylated derivatives of piperazine. Phosphorus, Sulfur, and Silicon and the Related Elements, 198(8), 693-703. https://doi.org/10.1080/10426507.2023.2193404
• Hong, J.-M., Suh, S.-S., Kim, T. K., Kim, J. E., Han, S. J., Youn, U. J., Yim, J. H., & Kim, I.-C. (2018). Anti-cancer activity of lobaric acid and lobarstin extracted from the antarctic lichen Stereocaulon alpnum. Molecules, 23(3), 658. https://doi.org/10.3390/molecules23030658
• Ingólfsdóttir, K., Chung, G. A., Skúlason, V. G., Gissurarson, S. R., & Vilhelmsdóttir, M. (1998). Antimycobacterial activity of lichen metabolites in vitro. European Journal of Pharmaceutical Sciences, 6(2), 141-144. https://doi.org/10.1016/S0928-0987(97)00078-X
• Kapuci, M., Ulker, Z., Gurkan, S., & Alpsoy, L. (2014). Determination of cytotoxic and genotoxic effects of naphthalene, 1-naphthol and 2-naphthol on human lymphocyte culture. Toxicology and Industrial Health, 30(1), 82-89. https://doi.org/10.1177/0748233712451772
• Koopmans, T. (1934). Über die zuordnung von wellenfunktionen und eigenwerten zu den einzelnen elektronen eines atoms. Physica, 1(1-6), 104-113. https://doi.org/10.1016/S0031-8914(34)90011-2 (In German)
• Lichtenstein, P., Holm, N. V., Verkasalo, P. K., Iliadou, A., Kaprio, J., Koskenvuo, M., Pukkala, E., Skytthe, A., & Hemminki, K. (2000). Environmental and heritable factors in the causation of cancer—analyses of cohorts of twins from Sweden, Denmark, and Finland. The New England Journal of Medicine, 343(2), 78-85. https://doi.org/10.1056/NEJM200007133430201
• Livak, K. J., & Schmittgen, T. D. (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. Methods, 25(4), 402-408. https://doi.org/10.1006/meth.2001.1262
• Morita, H., Tsuchiya, T., Kishibe, K., Noya, S., Shiro, M., & Hirasawa, Y. (2009). Antimitotic activity of lobaric acid and a new benzofuran, sakisacaulon A from Stereocaulon sasakii. Bioorganic & Medicinal Chemistry Letters, 19(13), 3679-3681. https://doi.org/10.1016/j.bmcl.2009.03.170
• Mushtaq, A., Asif, R., Humayun, W. A., & Naseer, M. M. (2024). Novel isatin–triazole based thiosemicarbazones as potential anticancer agents: Synthesis, DFT and molecular docking studies. RSC Advances, 14(20), 14051-14067. https://doi.org/10.1039/D4RA01937G
• Nash, T. H. (1996). Lichen biology. Cambridge University Press.
• O’Boyle, N. M., Banck, M., James, C. A., Morley, C., Vandermeersch, T., & Hutchison, G. R. (2011). Open Babel: An open chemical toolbox. Journal of Cheminformatics, 3, 1-14. https://doi.org/10.1186/1758-2946-3-33
• Ögmundsdóttir, H. M., Zoëga, G. M., Gissurarson, S. R., & Ingólfsdóttir, K. (1998). Natural products: Anti‐proliferative effects of lichen‐derived inhibitors of 5‐lipoxygenase on malignant cell‐lines and mitogen‐stimulated lymphocytes. Journal of Pharmacy and Pharmacology, 50(1), 107-115. https://doi.org/10.1111/j.2042-7158.1998.tb03312.x
• Ravaglia, L. M., Gonçalves, K., Oyama, N. M., Coelho, R. G., Spielmann, A. A., & Honda, N. K. (2014). In vitro radical-scavenging activity, toxicity against A. salina, and NMR profiles of extracts of lichens collected from Brazil and Antarctica. Química Nova, 37, 1015-1021. https://doi.org/10.5935/0100-4042.20140159
• Seo, C., Sohn, J. H., Ahn, J. S., Yim, J. H., Lee, H. K., & Oh, H. (2009). Protein tyrosine phosphatase 1B inhibitory effects of depsidone and pseudodepsidone metabolites from the Antarctic lichen Stereocaulon alpinum. Bioorganic & Medicinal Chemistry Letters, 19(10), 2801-2803. https://doi.org/10.1016/j.bmcl.2009.03.108
• Spribille, T., Resl, P., Stanton, D. E., & Tagirdzhanova, G. (2022). Evolutionary biology of lichen symbioses. New Phytologist, 234(5), 1566-1582. https://doi.org/10.1111/nph.18048
• Srivastava, R. (2021). Theoretical studies on the molecular properties, toxicity, and biological efficacy of 21 new chemical entities. ACS Omega, 6(38), 24891-24901. https://doi.org/10.1021/acsomega.1c03736
• Takayama, T., Miyanishi, K., Hayashi, T., Sato, Y., & Niitsu, Y. (2006). Colorectal cancer: Genetics of development and metastasis. Journal of Gastroenterology, 41, 185-192. https://doi.org/10.1007/s00535-006-1801-6
• Thadhani, V. M., Choudhary, M. I., Ali, S., Omar, I., Siddique, H., & Karunaratne, V. (2011). Antioxidant activity of some lichen metabolites. Natural Product Research, 25(19), 1827-1837. https://doi.org/10.1080/14786419.2010.529546
• Thadhani, V. M., Choudhary, M. I., Khan, S., & Karunaratne, V. (2012). Antimicrobial and toxicological activities of some depsides and depsidones. Journal of the National Science Foundation of Sri Lanka, 40(1), 43-48. https://doi.org/10.4038/jnsfsr.v40i1.4167
• Trott, O., & Olson, A. J. (2010). AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of Computational Chemistry, 31(2), 455-461. https://doi.org/10.1002/jcc.21334