Molecular Mechanisms to Identify Anticancer Activity of Tomentin in A549 Lung Adeno Carcinoma Cells: Role of p53/Caspase-Mediated Pathways

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DOI: 10.21522/TIJPH.2013.SE.24.03.Art012

Authors : Vishnu Priya Veeraraghavan, Selvaraj Jayaraman, Jerine I

Abstract:

Cancer, a multifaceted disease with increasing prevalence, remains a significant global health concern. Lung cancer, in particular, presents a formidable challenge due to its high mortality rates. Tomentin, a phytochemical extracted from Sphaeralcea angustifolia, has garnered interest for its potential anti-cancer properties. This study employs both in vitro and in silico methods to elucidate tomentin's efficacy against lung cancer, focusing on the A549 cell line, a model for lung adenocarcinoma. The study begins by exploring the cytotoxic effects of tomentin on A549 cells through viability assays, apoptosis induction, and molecular pathway modulation. Results indicate dose-dependent inhibition of cell proliferation and activation of apoptotic pathways by tomentin treatment. Further analysis reveals tomentin's ability to scavenge DPPH radicals and inhibit protein denaturation, suggesting potent antioxidant and anti-inflammatory properties. Moreover, mRNA expression analysis demonstrates tomentin's regulatory effects on key genes involved in inflammation and apoptosis. Molecular docking studies reveal strong binding affinity between tomentin and critical proteins implicated in cancer progression, including MCL1, p53, Bcl-2, and Caspases.

References:

[1] Roy, P. S., & Saikia, B. J., 2016, Cancer and cure: A critical analysis. Indian journal of cancer, 53(3), 441–442. https://doi.org/10.4103/0019-509X.200658
[2] Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. Cell, 144(5), 646–674. https://doi.org/10.1016/j.cell.2011.02.013
[3] Jayaraman, S., Natarajan, S. R., Ponnusamy, B., Veeraraghavan, V. P., & Jasmine, S., 2023, Unlocking the potential of beta sitosterol: Augmenting the suppression of oral cancer cells through extrinsic and intrinsic signalling mechanisms. The Saudi Dental Journal, 35(8), 1007-1013.
[4] Brody H., 2014, Lung cancer. Nature, 513(7517), S1. https://doi.org/10.1038/513S1.
[5] Bilello, K. S., Murin, S., & Matthay, R. A., 2002, Epidemiology, etiology, and prevention of lung cancer. Clinics in chest medicine, 23(1), 1-25.
[6] Hammerschmidt, S., & Wirtz, H., 2009, Lung cancer: current diagnosis and treatment. Deutsches Arzteblatt international, 106(49), 809–820. https://doi.org/10.3238/arztebl.2009.0809
[7] Rivera, M. P., Detterbeck, F., & Mehta, A. C., 2003, Diagnosis of lung cancer: the guidelines. Chest, 123(1), 129S-136S.
[8] Maghfoor, I., & Perry, M. C., 2005, Lung cancer. Annals of Saudi medicine, 25(1), 1–12. https://doi.org/10.5144/0256-4947.2005.1
[9] Bertrams, W., Hönzke, K., Obermayer, B., Tönnies, M., Bauer, T. T., Schneider, P., Neudecker, J., Rückert, J. C., Stiewe, T., Nist, A., Eggeling, S., Suttorp, N., Wolff, T., Hippenstiel, S., Schmeck, B., & Hocke, A. C., 2022, Transcriptomic comparison of primary human lung cells with lung tissue samples and the human A549 lung cell line highlights cell type specific responses during infections with influenza A virus. Scientific reports, 12(1), 20608. https://doi.org/10.1038/s41598-022-24792-4
[10] Jayaraman, S., Devarajan, N., Rajagopal, P., Babu, S., Ganesan, S. K., Veeraraghavan, V. P., Palanisamy, C. P., Cui, B., Periyasamy, V., & Chandrasekar, K., 2021, β-Sitosterol Circumvents Obesity Induced Inflammation and Insulin Resistance by down-Regulating IKKβ/NF-κB and JNK Signaling Pathway in Adipocytes of Type 2 Diabetic Rats. Molecules (Basel, Switzerland), 26(7), 2101. https://doi.org/10.3390/molecules26072101.
[11] Yeung, Y. T., Aziz, F., Guerrero-Castilla, A., & Arguelles, S., 2018, Signaling Pathways in Inflammation and Anti-inflammatory Therapies. Current pharmaceutical design, 24(14), 1449–1484. https://doi.org/10.2174/1381612824666180327165604.
[12] Huq, A. K. M. M., Roney, M., Imran, S., Khan, S. U., Uddin, M. N., Htar, T. T., Baig, A.
[13] Barrera, K., González-Cortazar, M., Reyes-Pérez, R., Pérez-García, D., Herrera-Ruiz, M., Arellano-García, J., Cruz-Sosa, F., & Nicasio-Torres, P., 2023, Production of Two Isomers of Sphaeralcic Acid in Hairy Roots from Sphaeralcea angustifolia. Plants (Basel, Switzerland), 12(5), 1090. https://doi.org/10.3390/plants12051090.
[14] Gatasheh, M. K., Natarajan, S. R., Krishnamoorthy, R., Alsulami, T. S., Rajagopal, P., Palanisamy, C. P.,  & Jayaraman, S., 2024, Molecular analysis to identify novel potential biomarkers as drug targets in colorectal cancer therapy: an integrated bioinformatics analysis. Molecular & Cellular Oncology, 11(1), 2326699.
[15] Hatano, T., Edamatsu, R., Hiramatsu, M., MORI, A., Fujita, Y., Yasuhara, T., ... & OKUDA, T.,1989, Effects of the interaction of tannins with co-existing substances. VI.: effects of tannins and related polyphenols on superoxide anion radical, and on 1, 1-Diphenyl-2-picrylhydrazyl radical. Chemical and pharmaceutical bulletin, 37(8), 2016-2021.
[16] Padmanabhan, P., & Jangle, S. N., 2012, Evaluation of in-vitro anti-inflammatory activity of herbal preparation, a combination of four medicinal plants. International journal of basic and applied medical sciences, 2(1), 109-116.
[17] Elias, G., & Rao, M. N., 1988, Inhibition of albumin denaturation and antiinflammatory activity of dehydrozingerone and its analogs. Indian journal of experimental biology, 26(7), 540–542.
[18] Perumal, S., Langeshwaran, K., Selvaraj, J., Ponnulakshmi, R., Shyamaladevi, B., & Balasubramanian, M. P., 2018, Effect of diosmin on apoptotic signaling molecules in N-nitrosodiethylamine-induced hepatocellular carcinoma in experimental rats. Molecular and Cellular Biochemistry, 449, 27-37.
[19] Lavanya, M., Krishnamoorthy, R., Alshuniaber, M. A., Manoharadas, S., Palanisamy, C. P., Veeraraghavan, V. P., & Padmini, R., 2023, Formulation, characterization and evaluation of gelatin-syringic acid/zinc oxide nanocomposite for its effective anticancer, antioxidant and anti-inflammatory activities. Journal of King Saud University-Science, 35(8), 102909. 
[20] Jayaraman, S., & Veeraraghavan, V. P., 2023, Nucleostemin and p-STAT3 as early diagnostic potential markers in oral squamous cell carcinoma. Acta Marisiensis-Seria Medica, 69(4), 241-243.
[21] Pei, J., Yan, Y., Jayaraman, S., Rajagopal, P., Natarajan, P. M., Umapathy, V. R., ... & Mironescu, M., 2024, A review on advancements in the application of starch-based nanomaterials in biomedicine: Precision drug delivery and cancer therapy. International Journal of Biological Macromolecules, 130746.
[22] Nishida, J., & Kawabata, J., 2006, DPPH radical scavenging reaction of hydroxy- and methoxychalcones. Bioscience, Biotechnology, and Biochemistry, 70(1), 193–202. https://doi.org/10.1271/bbb.70.193
[23] Ojiako, O. A., Chikezie, P. C., & Ogbuji, A. C., 2015, Radical scavenging potentials of single and combinatorial herbal formulations in vitro. Journal of Traditional and Complementary Medicine, 6(2), 153–159. https://doi.org/10.1016/j.jtcme.2014.11.037
[24] Szerlauth, A., Muráth, S., Viski, S., & Szilagyi, I., 2019, Radical scavenging activity of plant extracts from improved processing. Heliyon, 5(11), e02763. https://doi.org/10.1016/j.heliyon.2019.e02763.
[25] Zhang, Y., Kim, Y. H. B., Puolanne, E., & Ertbjerg, P., 2022, Role of freezing-induced myofibrillar protein denaturation in the generation of thaw loss: A review. Meat Science, 190, 108841. https://doi.org/10.1016/j.meatsci.2022.108841.
[26] Ruzza, P., Honisch, C., Hussain, R., & Siligardi, G., 2021, Free Radicals and ROS Induce Protein Denaturation by UV Photostability Assay. International Journal of Molecular Sciences, 22(12), 6512. https://doi.org/10.3390/ijms22126512.
[27] Johnson, F H., & Campbell, D. H., 1946, Pressure and protein denaturation. The Journal of Biological Chemistry, 163, 689–698.
[28] Chaoul, N., & Albanesi, M., 2021, Tumor Infiltrating T Cell Cytotoxicity Assay. Methods in Molecular Biology (Clifton, N.J.), 2325, 41–54. https://doi.org/10.1007/978-1-0716-1507-2_3.
[29] Olatunde, O. Z., Yong, J., & Lu, C., 2023, Chemical Constituents from the Roots of Jasminum sambac (L.) Ait. and their Cytotoxicity to the Cancer Cell Lines. Anti-cancer Agents in Medicinal Chemistry, 23(16), 1860–1865. https://doi.org/10.2174/1871520623666230504102455.
[30] Lee, H., Jeon, Y., Moon, H., Lee, E. H., Lee, T. H., & Kim, H., 2023, Synthesis of 1,4-Dialkoxynaphthalene-Based Imidazolium Salts and Their Cytotoxicity in Cancer Cell Lines. International Journal of Molecular Sciences, 24(3), 2713. https://doi.org/10.3390/ijms24032713.
[31] Sreevarun, M., Ajay, R., Suganya, G., Rakshagan, V., Bhanuchander, V., & Suma, K., 2023, Formulation, Configuration, and Physical Properties of Dental Composite Resin Containing a Novel 2π + 2π Photodimerized Crosslinker - Cinnamyl Methacrylate: An In Vitro Research. The Journal of Contemporary Dental Practice, 24(6), 364–371. https://doi.org/10.5005/jp-journals-10024-3480
[32] Alam, M. K., Alqhtani, N. R., Alnufaiy, B., Alqahtani, A. S., Elsahn, N. A., Russo, D., Di Blasio, M., Cicciù, M., & Minervini, G., 2024, A systematic review and meta-analysis of the impact of resveratrol on oral cancer: potential therapeutic implications. BMC Oral Health, 24(1), 412. https://doi.org/10.1186/s12903-024-04045-8.
[33] Yadalam, P. K., Arumuganainar, D., Ronsivalle, V., Di Blasio, M., Badnjevic, A., Marrapodi, M. M., Cervino, G., & Minervini, G., 2024, Prediction of interactomic hub genes in PBMC cells in type 2 diabetes mellitus, dyslipidemia, and periodontitis. BMC Oral Health, 24(1), 385. https://doi.org/10.1186/s12903-024-04041-y.
[34] Jayaraman, S., Natarajan, S.R., Veeraraghavan, V.P., Jasmine, S., 2023, Unveiling the anti-cancer mechanisms of calotropin: Insights into cell growth inhibition, cell cycle arrest, and metabolic regulation in human oral squamous carcinoma cells (HSC-3). Journal of Oral Biology and Craniofacial Research, 13:704-713. 10.1016/j.jobcr.2023.09.002.
[35] Zhang, W., Tian, W., Wang, Y., Jin, X., Guo, H., Wang, Y., Tang, Y., & Yao, X., 2022, Explore the mechanism and substance basis of Mahuang FuziXixin Decoction for the treatment of lung cancer based on network pharmacology and molecular docking. Computers in Biology and Medicine, 151(Pt A), 106293. https://doi.org/10.1016/j.compbiomed.2022.106293.
[36] Arjmand, B., Hamidpour, S. K., Alavi-Moghadam, S., Yavari, H., Shahbazbadr, A., Tavirani, M. R., ... & Larijani, B., 2022, Molecular docking as a therapeutic approach for targeting cancer stem cell metabolic processes. Frontiers in Pharmacology, 13, 768556.
[37] Sharma, K. K., Singh, B., Mujwar, S., & Bisen, P. S., 2020, Molecular docking based analysis to elucidate the DNA topoisomerase IIβ as the potential target for the ganoderic acid: A natural therapeutic agent in cancer therapy. Current Computer-Aided Drug Design, 16(2), 176-189.
[38] Rajendran, P., Sekar, R., Zahra, H. A., Jayaraman, S., Rajagopal, P., Abdallah, B. M., Ali, E. M., Abdelsalam, S. A., & Veeraraghavan, V., 2023, Salivaomics to decode non-coding RNAs in oral cancer. A narrative review. Non-coding RNA Research, 8(3), 376–384. https://doi.org/10.1016/j.ncrna.2023.05.001.
[39] Jayaraman, S., Natararaj, S., & Veeraraghavan, V. P., 2024, Hesperidin Inhibits Oral Cancer Cell Growth via Apoptosis and Inflammatory Signaling-Mediated Mechanisms: Evidence From In vitro and In Silico Analyses. Cureus, 16(2), e53458