Integrated Network Pharmacology and Metabolomics to Dissect the Mechanisms of Naringin for Treating Cervical Cancer


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Abstract

Introduction:Cervical cancer is one of the malignant cancers with high mortality among women worldwide. Although vaccines and early detection have reduced cervical cancer mortality, it remains a malignancy with a high mortality rate in women.

Objective:We aimed to develop a novel integrated strategy that combines metabolomics with network pharmacology to explore the therapeutic mechanisms of naringin in cervical cancer. The mechanism of naringin intervention in cervical cancer was initially clarified by metabolomics and network pharmacology.

Methods:The method of LC-MS and network pharmacology for the detection and identification of potential biomarkers and the mechanisms of action of naringin was used. The metabolites were detected and identified based on ultra-high-performance liquid chromatography coupled with Quadrupole- Exactive Orbitrap MS (UHPLC-Q-Exactive Orbitrap MS) and followed by the network pharmacology analysis.

Results:In network pharmacology, naringin played a synergetic role through regulatory shared pathways, such as steroid hormone biosynthesis, sphingolipid signaling pathway and arachidonic acid metabolism, etc. Besides, the metabolomics analysis showed that 20 differential metabolites and 10 metabolic pathways were mainly involved in the therapeutic effect of naringin on cervical cancer. The result showed that naringin treatment for cervical cancer mainly occurs through the following metabolic pathways: amino acid metabolism and arachidonic acid metabolism.

Conclusion:This work provided valuable information and a scientific basis for further studies of naringin in the treatment of cervical cancer.

About the authors

Ziwei Yin

Department of HBP Surgery Ⅱ, The Second Affiliated Hospital, School of Medicine, South China University of Technology

Email: info@benthamscience.net

Xuefeng Hua

Department of HBP Surgery Ⅱ, The Second Affiliated Hospital, School of Medicine, South China University of Technology

Email: info@benthamscience.net

Minqiang Lu

Department of HBP Surgery Ⅱ, The Second Affiliated Hospital, School of Medicine, South China University of Technology

Author for correspondence.
Email: info@benthamscience.net

References

  1. Pimple, S.A.; Mishra, G.A. Global strategies for cervical cancer prevention and screening. Minerva Ginecol., 2019, 71(4), 313-320. doi: 10.23736/S0026-4784.19.04397-1 PMID: 30808155
  2. Johnson, C.A.; James, D.; Marzan, A.; Armaos, M. Cervical cancer: An overview of pathophysiology and management. Semin. Oncol. Nurs., 2019, 35(2), 166-174. doi: 10.1016/j.soncn.2019.02.003 PMID: 30878194
  3. Koh, W.J.; Abu-Rustum, N.R.; Bean, S.; Bradley, K.; Campos, S.M.; Cho, K.R.; Chon, H.S.; Chu, C.; Clark, R.; Cohn, D.; Crispens, M.A.; Damast, S.; Dorigo, O.; Eifel, P.J.; Fisher, C.M.; Frederick, P.; Gaffney, D.K.; Han, E.; Huh, W.K.; Lurain, J.R., III; Mariani, A.; Mutch, D.; Nagel, C.; Nekhlyudov, L.; Fader, A.N.; Remmenga, S.W.; Reynolds, R.K.; Tillmanns, T.; Ueda, S.; Wyse, E.; Yashar, C.M.; McMillian, N.R.; Scavone, J.L. Cervical cancer, version 3.2019, NCCN clinical practice guidelines in oncology. J. Natl. Compr. Canc. Netw., 2019, 17(1), 64-84. doi: 10.6004/jnccn.2019.0001 PMID: 30659131
  4. Ramírez, A.; Vera, E.; Gamboa-Domínguez, A.; Lambert, P.; Gariglio, P.; Camacho, J. Calcium-activated potassium channels as potential early markers of human cervical cancer. Oncol. Lett., 2018, 15(5), 7249-7254. PMID: 29725443
  5. Arbyn, M.; Weiderpass, E.; Bruni, L.; de Sanjosé, S.; Saraiya, M.; Ferlay, J.; Bray, F. Estimates of incidence and mortality of cervical cancer in 2018: A worldwide analysis. Lancet Glob. Health, 2020, 8(2), e191-e203. doi: 10.1016/S2214-109X(19)30482-6 PMID: 31812369
  6. Da Silva, D.M.; Enserro, D.M.; Mayadev, J.S.; Skeate, J.G.; Matsuo, K.; Pham, H.Q.; Lankes, H.A.; Moxley, K.M.; Ghamande, S.A.; Lin, Y.G.; Schilder, R.J.; Birrer, M.J.; Kast, W.M. Immune activation in patients with locally advanced cervical cancer treated with ipilimumab following definitive chemoradiation (GOG-9929). Clin. Cancer Res., 2020, 26(21), 5621-5630. doi: 10.1158/1078-0432.CCR-20-0776 PMID: 32816895
  7. Zhang, L.; Zheng, C.; Cao, J.; Luo, S. Efficacy of paclitaxel, carboplatin, and bevacizumab for cervical cancer. Medicine (Baltimore), 2020, 99(24), e20558. doi: 10.1097/MD.0000000000020558 PMID: 32541479
  8. Kashafi, E.; Moradzadeh, M.; Mohamadkhani, A.; Erfanian, S. Kaempferol increases apoptosis in human cervical cancer HeLa cells via PI3K/AKT and telomerase pathways. Biomed. Pharmacother., 2017, 89, 573-577. doi: 10.1016/j.biopha.2017.02.061 PMID: 28258039
  9. Reyes-Farias, M.; Carrasco-Pozo, C. The anti-cancer effect of quercetin: Molecular implications in cancer metabolism. Int. J. Mol. Sci., 2019, 20(13), 3177. doi: 10.3390/ijms20133177 PMID: 31261749
  10. Imran, M.; Aslam Gondal, T.; Atif, M.; Shahbaz, M.; Batool Qaisarani, T.; Hanif Mughal, M.; Salehi, B.; Martorell, M.; Sharifi-Rad, J. Apigenin as an anticancer agent. Phytother. Res., 2020, 34(8), 1812-1828. doi: 10.1002/ptr.6647 PMID: 32059077
  11. Zhou, J.; Xia, L.; Zhang, Y. Naringin inhibits thyroid cancer cell proliferation and induces cell apoptosis through repressing PI3K/AKT pathway. Pathol. Res. Pract., 2019, 215(12), 152707. doi: 10.1016/j.prp.2019.152707 PMID: 31727500
  12. Hambardikar, V.R.; Mandlik, D.S. Protective effect of naringin ameliorates TNBS‐induced colitis in rats via improving antioxidant status and pro-inflammatory cytokines. Immunopharmacol. Immunotoxicol., 2022, 44(3), 373-386. doi: 10.1080/08923973.2022.2049813 PMID: 35254187
  13. Deenonpoe, R.; Prayong, P.; Thippamom, N.; Meephansan, J.; Na-Bangchang, K. Anti-inflammatory effect of naringin and sericin combination on human peripheral blood mononuclear cells (hPBMCs) from patient with psoriasis. BMC Complement. Altern. Med., 2019, 19(1), 168. doi: 10.1186/s12906-019-2535-3 PMID: 31291937
  14. Aroui, S.; Fetoui, H.; Kenani, A. Natural dietary compound naringin inhibits glioblastoma cancer neoangiogenesis. BMC Pharmacol. Toxicol., 2020, 21(1), 46. doi: 10.1186/s40360-020-00426-1 PMID: 32576255
  15. Zhu, H.; Zou, X.; Lin, S.; Hu, X.; Gao, J. Effects of naringin on reversing cisplatin resistance and the Wnt/β -catenin pathway in human ovarian cancer SKOV3/CDDP cells. J. Int. Med. Res., 2020, 48(10) doi: 10.1177/0300060519887869 PMID: 33086930
  16. Yoshinaga, A.; Kajiya, N.; Oishi, K.; Kamada, Y.; Ikeda, A.; Chigwechokha, P.K.; Kibe, T.; Kishida, M.; Kishida, S.; Komatsu, M.; Shiozaki, K. NEU3 inhibitory effect of naringin suppresses cancer cell growth by attenuation of EGFR signaling through GM3 ganglioside accumulation. Eur. J. Pharmacol., 2016, 782, 21-29. doi: 10.1016/j.ejphar.2016.04.035 PMID: 27105818
  17. Zeng, L.; Zhen, Y.; Chen, Y.; Zou, L.; Zhang, Y.; Hu, F.; Feng, J.; Shen, J.; Wei, B. Naringin inhibits growth and induces apoptosis by a mechanism dependent on reduced activation of NF-κB/COX-2-caspase-1 pathway in HeLa cervical cancer cells. Int. J. Oncol., 2014, 45(5), 1929-1936. doi: 10.3892/ijo.2014.2617 PMID: 25174821
  18. Lin, R.; Hu, X.; Chen, S.; Shi, Q.; Chen, H. Naringin induces endoplasmic reticulum stress-mediated apoptosis, inhibits β-catenin pathway and arrests cell cycle in cervical cancer cells. Acta Biochim. Pol., 2020, 67(2), 181-188. PMID: 32343512
  19. Liu, X.; Yang, X.; Chen, F.; Chen, D. Combined application of Doxorubicin and Naringin enhances the antitumor efficiency and attenuates the toxicity of Doxorubicin in HeLa cervical cancer cells. Int. J. Clin. Exp. Pathol., 2017, 10(7), 7303-7311. PMID: 31966570
  20. Ramesh, E.; Alshatwi, A.A. Naringin induces death receptor and mitochondria-mediated apoptosis in human cervical cancer (SiHa) cells. Food Chem. Toxicol., 2013, 51, 97-105. doi: 10.1016/j.fct.2012.07.033 PMID: 22847135
  21. Posey, E.A.; Bazer, F.W.; Wu, G. Amino Acids in Nutrition and Health: Amino Acids in Gene Expression, Metabolic Regulation, and Exercising Performance; Wu, G., Ed.; Springer International Publishing: Cham, 2021, pp. 151-166. doi: 10.1007/978-3-030-74180-8_9
  22. Vissers, Y.L.J.; Dejong, C.H.C.; Luiking, Y.C.; Fearon, K.C.H.; von Meyenfeldt, M.F.; Deutz, N.E.P. Plasma arginine concentrations are reduced in cancer patients: Evidence for arginine deficiency? Am. J. Clin. Nutr., 2005, 81(5), 1142-1146. doi: 10.1093/ajcn/81.5.1142 PMID: 15883440
  23. Liu, W.; Hancock, C.N.; Fischer, J.W.; Harman, M.; Phang, J.M. Proline biosynthesis augments tumor cell growth and aerobic glycolysis: involvement of pyridine nucleotides. Sci. Rep., 2015, 5(1), 17206. doi: 10.1038/srep17206 PMID: 26598224
  24. Khan, I.; Nam, M.; Kwon, M.; Seo, S.; Jung, S.; Han, J.S.; Hwang, G.S.; Kim, M.K. LC/MS-based polar metabolite profiling identified unique biomarker signatures for cervical cancer and cervical intraepithelial neoplasia using global and targeted metabolomics. Cancers, 2019, 11(4), 511. doi: 10.3390/cancers11040511 PMID: 30974861
  25. Yarla, N.S.; Bishayee, A.; Sethi, G.; Reddanna, P.; Kalle, A.M.; Dhananjaya, B.L.; Dowluru, K.S.V.G.K.; Chintala, R.; Duddukuri, G.R. Targeting arachidonic acid pathway by natural products for cancer prevention and therapy. Semin. Cancer Biol., 2016, 40-41, 48-81. doi: 10.1016/j.semcancer.2016.02.001 PMID: 26853158
  26. Bae, S.; Kim, M.K.; Kim, H.S.; Moon, Y.A. Arachidonic acid induces ER stress and apoptosis in HT-29 human colon cancer cells. Anim. Cells Syst., 2020, 24(5), 260-266. doi: 10.1080/19768354.2020.1813805 PMID: 33209199
  27. Kori, M.; Yalcin Arga, K. Potential biomarkers and therapeutic targets in cervical cancer: Insights from the meta-analysis of transcriptomics data within network biomedicine perspective. PLoS One, 2018, 13(7), e0200717. doi: 10.1371/journal.pone.0200717 PMID: 30020984
  28. Chang, C.C.; Lee, W.S.; Hsieh, H.G.; Chuang, C.L.; Huang, H.C.; Lee, F.Y.; Lee, S.D. Selective cyclooxygenase inhibition by SC-560 improves hepatopulmonary syndrome in cirrhotic rats. PLoS One, 2017, 12(6), e0179809. doi: 10.1371/journal.pone.0179809 PMID: 28632747

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