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Current Medicinal Chemistry

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ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

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Research Article

Identifying Luteolin as a Potential Drug for Treating Lung Adenocarcinoma with COVID-19 Affection based on Integration Analysis of Pharmacology and Transcriptome

Author(s): Ping Peng, Na Li, Ni Zhang, Xiangning Fu, Shu Peng, Yujie Zhao and Bo Ai*

Volume 31, Issue 33, 2024

Published on: 12 September, 2023

Page: [5432 - 5447] Pages: 16

DOI: 10.2174/0929867331666230908090326

Price: $65

Abstract

Background: Lung adenocarcinoma (LUAD) is a major type of lung cancer worldwide, and under the pandemic coronavirus disease 2019 (COVID-19), its cancer burden is enlarged. This study aimed to explore potential drug targets and potential drugs for developing effective treatments for patients with both lung cancer and COVID-19.

Methods: The interaction network of molecule compounds-target genes was constructed based on Traditional Chinese Medicines (TCMs) and gene expression data from public databases. The potential effectiveness of drugs was analyzed by molecular docking and molecular dynamics simulation. Western blot, transfection assay, Immunohistochemistry (IHC) staining, and flow cytometry were performed to investigate the function of HSP90AA1 in LUAD cells.

Result: Eight target genes (GSK3B, HMOX1, HSP90AA1, ICAM1, MAPK1, PLAU, RELA and TNFSF15.) were identified, and two of them (HSP90AA1 and RELA) were significantly associated with LUAD prognosis. Luteolin was discovered to bind with HSP90AA1. Moreover, in vitro cell experiments demonstrated that HSP90AA1 had higher expression in A549 cells, promoted cell viability and suppressed apoptosis in A549 cells and H1299 cells.

Conclusion: HSP90AA1 was a target gene for further designing effective drugs for LUAD patients. Luteolin was a potential drug for treating patients with both LUAD and COVID-19.

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[1]
Sung, H.; Ferlay, J.; Siegel, R.L.; 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), 209-249.
[http://dx.doi.org/10.3322/caac.21660] [PMID: 33538338]
[2]
Zappa, C.; Mousa, S.A. Non-small cell lung cancer: Current treatment and future advances. Transl. Lung Cancer Res., 2016, 5(3), 288-300.
[http://dx.doi.org/10.21037/tlcr.2016.06.07] [PMID: 27413711]
[3]
Cao, M.; Chen, W. Epidemiology of lung cancer in China. Thorac. Cancer, 2019, 10(1), 3-7.
[http://dx.doi.org/10.1111/1759-7714.12916] [PMID: 30485694]
[4]
Pan, J.; Yang, H.; Zhu, L.; Lou, Y.; Jin, B. Qingfei Jiedu decoction inhibits PD-L1 expression in lung adenocarcinoma based on network pharmacology analysis, molecular docking and experimental verification. Front. Pharmacol., 2022, 13, 897966.
[http://dx.doi.org/10.3389/fphar.2022.897966] [PMID: 36091822]
[5]
Geng, X.; Chi, W.; Lin, X.; Niu, Z.; Jiang, Q.; Sui, Y.; Jiang, J. Determining the mechanism of action of the Qishan formula against lung adenocarcinoma by integration of network pharmacology, molecular docking, and proteomics. Medicine (Baltimore), 2023, 102(13), e33384.
[http://dx.doi.org/10.1097/MD.0000000000033384] [PMID: 37000102]
[6]
Zhang, D.; Zhang, T.; Zhang, Y.; Li, Z.; Li, H.; Zhang, Y.; Liu, C.; Han, Z.; Li, J.; Zhu, J. Screening the components of Saussurea involucrata for novel targets for the treatment of NSCLC using network pharmacology. BMC Complement. Med. Ther, 2022, 22(1), 53.
[http://dx.doi.org/10.1186/s12906-021-03501-0] [PMID: 35227278]
[7]
Calabrò, L.; Peters, S.; Soria, J.C.; Di Giacomo, A.M.; Barlesi, F.; Covre, A.; Altomonte, M.; Vegni, V.; Gridelli, C.; Reck, M.; Rizvi, N.; Maio, M. Challenges in lung cancer therapy during the COVID-19 pandemic. Lancet Respir. Med., 2020, 8(6), 542-544.
[http://dx.doi.org/10.1016/S2213-2600(20)30170-3] [PMID: 32278368]
[8]
Van Haren, R.M.; Delman, A.M.; Turner, K.M.; Waits, B.; Hemingway, M.; Shah, S.A.; Starnes, S.L. Impact of the COVID-19 pandemic on lung cancer screening program and subsequent lung cancer. J. Am. Coll. Surg., 2021, 232(4), 600-605.
[http://dx.doi.org/10.1016/j.jamcollsurg.2020.12.002] [PMID: 33346080]
[9]
Luo, J.; Rizvi, H.; Preeshagul, I.R.; Egger, J.V.; Hoyos, D.; Bandlamudi, C.; McCarthy, C.G.; Falcon, C.J.; Schoenfeld, A.J.; Arbour, K.C.; Chaft, J.E.; Daly, R.M.; Drilon, A.; Eng, J.; Iqbal, A.; Lai, W.V.; Li, B.T.; Lito, P.; Namakydoust, A.; Ng, K.; Offin, M.; Paik, P.K.; Riely, G.J.; Rudin, C.M.; Yu, H.A.; Zauderer, M.G.; Donoghue, M.T.A.; Łuksza, M.; Greenbaum, B.D.; Kris, M.G.; Hellmann, M.D. COVID-19 in patients with lung cancer. Ann. Oncol., 2020, 31(10), 1386-1396.
[http://dx.doi.org/10.1016/j.annonc.2020.06.007] [PMID: 32561401]
[10]
Guckenberger, M.; Belka, C.; Bezjak, A.; Bradley, J.; Daly, M.E.; DeRuysscher, D.; Dziadziuszko, R.; Faivre-Finn, C.; Flentje, M.; Gore, E.; Higgins, K.A.; Iyengar, P.; Kavanagh, B.D.; Kumar, S.; Le Pechoux, C.; Lievens, Y.; Lindberg, K.; McDonald, F.; Ramella, S.; Rengan, R.; Ricardi, U.; Rimner, A.; Rodrigues, G.B.; Schild, S.E.; Senan, S.; Simone, C.B., II; Slotman, B.J.; Stuschke, M.; Videtic, G.; Widder, J.; Yom, S.S.; Palma, D. Practice recommendations for lung cancer radiotherapy during the COVID-19 pandemic: An ESTRO-ASTRO consensus statement. Radiother. Oncol., 2020, 146, 223-229.
[http://dx.doi.org/10.1016/j.radonc.2020.04.001] [PMID: 32342863]
[11]
Varet, H.; Brillet-Guéguen, L.; Coppée, J.Y.; Dillies, M.A. SARTools: A DESeq2- and EdgeR-based R pipeline for comprehensive differential analysis of RNA-Seq data. PLoS One, 2016, 11(6), e0157022.
[http://dx.doi.org/10.1371/journal.pone.0157022] [PMID: 27280887]
[12]
Su, G.; Morris, J. H.; Demchak, B.; Bader, G. D. Biological network exploration with Cytoscape 3. Curr Protoc Bioinformatics, 2014, 47, 11-24.
[13]
Yu, G.; Wang, L.G.; Han, Y.; He, Q.Y. clusterProfiler: An R package for comparing biological themes among gene clusters. OMICS, 2012, 16(5), 284-287.
[http://dx.doi.org/10.1089/omi.2011.0118] [PMID: 22455463]
[14]
Yoshihara, K.; Shahmoradgoli, M.; Martínez, E.; Vegesna, R.; Kim, H.; Torres-Garcia, W.; Treviño, V.; Shen, H.; Laird, P.W.; Levine, D.A.; Carter, S.L.; Getz, G.; Stemke-Hale, K.; Mills, G.B.; Verhaak, R.G.W. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat. Commun., 2013, 4(1), 2612.
[http://dx.doi.org/10.1038/ncomms3612] [PMID: 24113773]
[15]
Becht, E.; Giraldo, N.A.; Lacroix, L.; Buttard, B.; Elarouci, N.; Petitprez, F.; Selves, J.; Laurent-Puig, P.; Sautès-Fridman, C.; Fridman, W.H.; de Reyniès, A. Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression. Genome Biol., 2016, 17(1), 218.
[http://dx.doi.org/10.1186/s13059-016-1070-5] [PMID: 27765066]
[16]
Barbie, D.A.; Tamayo, P.; Boehm, J.S.; Kim, S.Y.; Moody, S.E.; Dunn, I.F.; Schinzel, A.C.; Sandy, P.; Meylan, E.; Scholl, C.; Fröhling, S.; Chan, E.M.; Sos, M.L.; Michel, K.; Mermel, C.; Silver, S.J.; Weir, B.A.; Reiling, J.H.; Sheng, Q.; Gupta, P.B.; Wadlow, R.C.; Le, H.; Hoersch, S.; Wittner, B.S.; Ramaswamy, S.; Livingston, D.M.; Sabatini, D.M.; Meyerson, M.; Thomas, R.K.; Lander, E.S.; Mesirov, J.P.; Root, D.E.; Gilliland, D.G.; Jacks, T.; Hahn, W.C. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature, 2009, 462(7269), 108-112.
[http://dx.doi.org/10.1038/nature08460] [PMID: 19847166]
[17]
Chen, B.; Khodadoust, M.S.; Liu, C.L.; Newman, A.M.; Alizadeh, A.A. Profiling tumor infiltrating immune cells with CIBERSORT. Methods Mol. Biol., 2018, 1711, 243-259.
[http://dx.doi.org/10.1007/978-1-4939-7493-1_12] [PMID: 29344893]
[18]
Huang Z.; Liu J.; Zhang C.; & Yang X.;Lipofectamine 2000™ at transfection dose promotes EphA2 transcription in an HDAC4-dependent manner to reduce its cytotoxicity. Heliyon,2022, 8(12):e12118.
[19]
Wang, J.; Wang, W.; Kollman, P.A.; Case, D.A. Antechamber: An accessory software package for molecular mechanical calculations. J. Am. Chem. Soc., 2001, 222, U403.
[20]
Wang, J.; Wolf, R.M.; Caldwell, J.W.; Kollman, P.A.; Case, D.A. Development and testing of a general amber force field. J. Comput. Chem., 2004, 25(9), 1157-1174.
[http://dx.doi.org/10.1002/jcc.20035] [PMID: 15116359]
[21]
Maier, J.A.; Martinez, C.; Kasavajhala, K.; Wickstrom, L.; Hauser, K.E.; Simmerling, C. ff14SB: Improving the accuracy of protein side chain and backbone parameters from ff99SB. J. Chem. Theory Comput., 2015, 11(8), 3696-3713.
[http://dx.doi.org/10.1021/acs.jctc.5b00255] [PMID: 26574453]
[22]
Mark, P.; Nilsson, L. Structure and dynamics of the TIP3P, SPC, and SPC/E water models at 298 K. J. Phys. Chem. A, 2001, 105(43), 9954-9960.
[http://dx.doi.org/10.1021/jp003020w]
[23]
Sousa da Silva, A.W.; Vranken, W.F. ACPYPE - AnteChamber PYthon Parser interfacE. BMC Res. Notes, 2012, 5(1), 367.
[http://dx.doi.org/10.1186/1756-0500-5-367] [PMID: 22824207]
[24]
Salomon-Ferrer, R.; Case, D.A.; Walker, R.C. An overview of the Amber biomolecular simulation package. Wiley Interdiscip. Rev. Comput. Mol. Sci., 2013, 3(2), 198-210.
[http://dx.doi.org/10.1002/wcms.1121]
[25]
Sagui, C.; Darden, T.A. Molecular dynamics simulations of biomolecules: Long-range electrostatic effects. Annu. Rev. Biophys. Biomol. Struct., 1999, 28(1), 155-179.
[http://dx.doi.org/10.1146/annurev.biophys.28.1.155] [PMID: 10410799]
[26]
Wang, L.; Ma, Q.; Yao, R.; Liu, J. Current status and development of anti-PD-1/PD-L1 immunotherapy for lung cancer. Int. Immunopharmacol., 2020, 79, 106088.
[http://dx.doi.org/10.1016/j.intimp.2019.106088] [PMID: 31896512]
[27]
Hellmann, M.D.; Ciuleanu, T.E.; Pluzanski, A.; Lee, J.S.; Otterson, G.A.; Audigier-Valette, C.; Minenza, E.; Linardou, H.; Burgers, S.; Salman, P.; Borghaei, H.; Ramalingam, S.S.; Brahmer, J.; Reck, M.; O’Byrne, K.J.; Geese, W.J.; Green, G.; Chang, H.; Szustakowski, J.; Bhagavatheeswaran, P.; Healey, D.; Fu, Y.; Nathan, F.; Paz-Ares, L. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N. Engl. J. Med., 2018, 378(22), 2093-2104.
[http://dx.doi.org/10.1056/NEJMoa1801946] [PMID: 29658845]
[28]
Hellmann, M.D.; Paz-Ares, L.; Bernabe Caro, R.; Zurawski, B.; Kim, S.W.; Carcereny Costa, E.; Park, K.; Alexandru, A.; Lupinacci, L.; de la Mora Jimenez, E.; Sakai, H.; Albert, I.; Vergnenegre, A.; Peters, S.; Syrigos, K.; Barlesi, F.; Reck, M.; Borghaei, H.; Brahmer, J.R.; O’Byrne, K.J.; Geese, W.J.; Bhagavatheeswaran, P.; Rabindran, S.K.; Kasinathan, R.S.; Nathan, F.E.; Ramalingam, S.S. Nivolumab plus ipilimumab in advanced non–small-cell lung cancer. N. Engl. J. Med., 2019, 381(21), 2020-2031.
[http://dx.doi.org/10.1056/NEJMoa1910231] [PMID: 31562796]
[29]
Zhang, L.; Zhu, F.; Xie, L.; Wang, C.; Wang, J.; Chen, R.; Jia, P.; Guan, H.Q.; Peng, L.; Chen, Y.; Peng, P.; Zhang, P.; Chu, Q.; Shen, Q.; Wang, Y.; Xu, S.Y.; Zhao, J.P.; Zhou, M. Clinical characteristics of COVID-19-infected cancer patients: A retrospective case study in three hospitals within Wuhan, China. Ann. Oncol., 2020, 31(7), 894-901.
[http://dx.doi.org/10.1016/j.annonc.2020.03.296] [PMID: 32224151]
[30]
Liang, W.; Guan, W.; Chen, R.; Wang, W.; Li, J.; Xu, K.; Li, C.; Ai, Q.; Lu, W.; Liang, H.; Li, S.; He, J. Cancer patients in SARS-CoV-2 infection: A nationwide analysis in China. Lancet Oncol., 2020, 21(3), 335-337.
[http://dx.doi.org/10.1016/S1470-2045(20)30096-6] [PMID: 32066541]
[31]
Shah, A.C.; Badawy, S.M. Telemedicine in pediatrics: Systematic review of randomized controlled trials. JMIR Pediatr. Parent., 2021, 4(1), e22696.
[http://dx.doi.org/10.2196/22696] [PMID: 33556030]
[32]
Chen, L.H.; Liao, C.Y.; Lai, L.C.; Tsai, M.H.; Chuang, E.Y. Semaphorin 6A attenuates the migration capability of lung cancer cells via the NRF2/HMOX1 Axis. Sci. Rep., 2019, 9(1), 13302.
[http://dx.doi.org/10.1038/s41598-019-49874-8] [PMID: 31527696]
[33]
Dong, Z.; Yang, P.; Qiu, X.; Liang, S.; Guan, B.; Yang, H.; Li, F.; Sun, L.; Liu, H.; Zou, G.; Zhao, K. KCNQ1OT1 facilitates progression of non-small-cell lung carcinoma via modulating miRNA-27b-3p/HSP90AA1 axis. J. Cell. Physiol., 2019, 234(7), 11304-11314.
[http://dx.doi.org/10.1002/jcp.27788] [PMID: 30471108]
[34]
Kotteas, E.A.; Boulas, P.; Gkiozos, I.; Tsagkouli, S.; Tsoukalas, G.; Syrigos, K.N. The intercellular cell adhesion molecule-1 (icam-1) in lung cancer: Implications for disease progression and prognosis. Anticancer Res., 2014, 34(9), 4665-4672.
[PMID: 25202042]
[35]
Wang, M.; Liao, Q.; Zou, P. PRKCZ-AS1 promotes the tumorigenesis of lung adenocarcinoma via sponging miR-766-5p to modulate MAPK1. Cancer Biol. Ther., 2020, 21(4), 364-371.
[http://dx.doi.org/10.1080/15384047.2019.1702402] [PMID: 31939714]
[36]
Ai, C.; Zhang, J.; Lian, S.; Ma, J.; Győrffy, B.; Qian, Z.; Han, Y.; Feng, Q. FOXM1 functions collaboratively with PLAU to promote gastric cancer progression. J. Cancer, 2020, 11(4), 788-794.
[http://dx.doi.org/10.7150/jca.37323] [PMID: 31949481]
[37]
Bassères, D.S.; Ebbs, A.; Levantini, E.; Baldwin, A.S. Requirement of the NF-kappaB subunit p65/RelA for K-Ras-induced lung tumorigenesis. Cancer Res., 2010, 70(9), 3537-3546.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-4290] [PMID: 20406971]
[38]
Zhao, C.C.; Han, Q.J.; Ying, H.Y.; Gu, X.X.; Yang, N.; Li, L.Y.; Zhang, Q.Z. TNFSF15 facilitates differentiation and polarization of macrophages toward M1 phenotype to inhibit tumor growth. OncoImmunology, 2022, 11(1), 2032918.
[http://dx.doi.org/10.1080/2162402X.2022.2032918] [PMID: 35127254]
[39]
Eustace, B.K.; Sakurai, T.; Stewart, J.K.; Yimlamai, D.; Unger, C.; Zehetmeier, C.; Lain, B.; Torella, C.; Henning, S.W.; Beste, G.; Scroggins, B.T.; Neckers, L.; Ilag, L.L.; Jay, D.G. Functional proteomic screens reveal an essential extracellular role for hsp90α in cancer cell invasiveness. Nat. Cell Biol., 2004, 6(6), 507-514.
[http://dx.doi.org/10.1038/ncb1131] [PMID: 15146192]
[40]
McCready, J.; Sims, J.D.; Chan, D.; Jay, D.G. Secretion of extracellular hsp90α via exosomes increases cancer cell motility: A role for plasminogen activation. BMC Cancer, 2010, 10(1), 294.
[http://dx.doi.org/10.1186/1471-2407-10-294] [PMID: 20553606]
[41]
Chen, W.S.; Chen, C.C.; Chen, L.L.; Lee, C.C.; Huang, T.S. Secreted heat shock protein 90α (HSP90α) induces nuclear factor-κB-mediated TCF12 protein expression to down-regulate E-cadherin and to enhance colorectal cancer cell migration and invasion. J. Biol. Chem., 2013, 288(13), 9001-9010.
[http://dx.doi.org/10.1074/jbc.M112.437897] [PMID: 23386606]
[42]
Hou, Q.; Chen, S.; An, Q.; Li, B.; Fu, Y.; Luo, Y. Extracellular Hsp90α promotes tumor lymphangiogenesis and lymph node metastasis in breast cancer. Int. J. Mol. Sci., 2021, 22(14), 7747.
[http://dx.doi.org/10.3390/ijms22147747]
[43]
Shi, Y.; Liu, X.; Lou, J.; Han, X.; Zhang, L.; Wang, Q.; Li, B.; Dong, M.; Zhang, Y. Plasma levels of heat shock protein 90 alpha associated with lung cancer development and treatment responses. Clin. Cancer Res., 2014, 20(23), 6016-6022.
[http://dx.doi.org/10.1158/1078-0432.CCR-14-0174] [PMID: 25316816]
[44]
Wang, Y.; Seyed Barghi, S.M.; Yang, Y.; Akhavan-Sigari, R. Value of HSP90α in lung cancer diagnosis and recurrence prediction: A cohort study. Oncol. Res. Treat., 2021, 44(11), 583-589.
[http://dx.doi.org/10.1159/000519277] [PMID: 34547748]
[45]
Ju, W.; Wang, X.; Shi, H.; Chen, W.; Belinsky, S.A.; Lin, Y. A critical role of luteolin-induced reactive oxygen species in blockage of tumor necrosis factor-activated nuclear factor-kappaB pathway and sensitization of apoptosis in lung cancer cells. Mol. Pharmacol., 2007, 71(5), 1381-1388.
[http://dx.doi.org/10.1124/mol.106.032185] [PMID: 17296806]
[46]
Yan, J.; Wang, Q.; Zheng, X.; Sun, H.; Zhou, Y.; Li, D.; Lin, Y.; Wang, X. Luteolin enhances TNF-related apoptosis-inducing ligand’s anticancer activity in a lung cancer xenograft mouse model. Biochem. Biophys. Res. Commun., 2012, 417(2), 842-846.
[http://dx.doi.org/10.1016/j.bbrc.2011.12.055] [PMID: 22206675]
[47]
Chen, K.C.; Chen, C.Y.; Lin, C.J.; Yang, T.Y.; Chen, T.H.; Wu, L.C.; Wu, C.C. Luteolin attenuates TGF-β1-induced epithelial–mesenchymal transition of lung cancer cells by interfering in the PI3K/Akt–NF-κB–Snail pathway. Life Sci., 2013, 93(24), 924-933.
[http://dx.doi.org/10.1016/j.lfs.2013.10.004] [PMID: 24140887]
[48]
Ruan, J.; Zhang, L.; Yan, L.; Liu, Y.; Yue, Z.; Chen, L.; Wang, A.Y.; Chen, W.; Zheng, S.; Wang, S.; Lu, Y. Inhibition of hypoxia-induced epithelial mesenchymal transition by luteolin in non-small cell lung cancer cells. Mol. Med. Rep., 2012, 6(1), 232-238.
[PMID: 22552526]
[49]
Theoharides, T.C. COVID-19, pulmonary mast cells, cytokine storms, and beneficial actions of luteolin. Biofactors, 2020, 46(3), 306-308.
[http://dx.doi.org/10.1002/biof.1633] [PMID: 32339387]
[50]
Shawan, M.M.A.K.; Halder, S.K.; Hasan, M.A. Luteolin and abyssinone II as potential inhibitors of SARS-CoV-2: An in silico molecular modeling approach in battling the COVID-19 outbreak. Bull. Natl. Res. Cent., 2021, 45(1), 27.
[http://dx.doi.org/10.1186/s42269-020-00479-6] [PMID: 33495684]
[51]
Theoharides, T.C.; Cholevas, C.; Polyzoidis, K.; Politis, A. Long-COVID syndrome-associated brain fog and chemofog: Luteolin to the rescue. Biofactors, 2021, 47(2), 232-241.
[http://dx.doi.org/10.1002/biof.1726] [PMID: 33847020]
[52]
Cao, X.; Wang, B. Targeted PD-L1 PLGA/liposomes-mediated luteolin therapy for effective liver cancer cell treatment. J. Biomater. Appl., 2021, 36(5), 843-850.
[http://dx.doi.org/10.1177/08853282211017701] [PMID: 34000859]
[53]
Tu, D.G.; Lin, W.T.; Yu, C.C.; Lee, S.S.; Peng, C.Y.; Lin, T.; Yu, C.H. Chemotherapeutic effects of luteolin on radio-sensitivity enhancement and interleukin-6/signal transducer and activator of transcription 3 signaling repression of oral cancer stem cells. J. Formos. Med. Assoc., 2016, 115(12), 1032-1038.
[http://dx.doi.org/10.1016/j.jfma.2016.08.009] [PMID: 27742160]

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