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Metabolomic Profiles in Patients with Cervical Cancer Undergoing Cisplatin and Radiation Therapy

  • Seo-Yeon Choi (College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University) ;
  • Suin Kim (College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University) ;
  • Ji-Young Jeon (Center for Clinical Pharmacology, Jeonbuk National University Hospital) ;
  • Min-Gul Kim (Center for Clinical Pharmacology, Jeonbuk National University Hospital) ;
  • Sun-Young Lee (Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital) ;
  • Kwang-Hee Shin (College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University)
  • Received : 2023.09.12
  • Accepted : 2023.11.30
  • Published : 2024.05.01

Abstract

This study was aimed to evaluate endogenous metabolic changes before and after cisplatin and radiation therapy in patients with cervical cancer via untargeted metabolomic analysis using plasma samples. A total of 13 cervical cancer patients were enrolled in this study. Plasma samples were collected from each patient on two occasions: approximately one week before therapy (P1) and after completion of cisplatin and radiation therapy (P2). Of the 13 patients, 12 patients received both cisplatin and radiation therapy, whereas one patient received radiation therapy alone. The samples were analyzed using the Ultimate 3000 coupled with Q ExactiveTM Focus Hybrid Quadrupole-OrbitrapTM mass spectrometry (Thermo Fisher Scientific, Waltham, MA, USA). Chromatographic separation utilized a Kinetex C18 column 2.1×100 mm (2.6 ㎛) (Phenomenex, Torrance, CA, USA), and the temperature was maintained at 40℃. Following P2, there were statistically significant increases in the concentrations of indoxyl sulfate, phenylacetylglutamine, Lysophosphatidyethanolamine (LysoPE) (18:1), and indole-3-acetic acid compared with the concentrations observed at P1. Specifically, in the human papillomavirus (HPV) noninfection group, indoxyl sulfate, LysoPE (18:1), and phenylacetylglutamine showed statistically significant increases at P2 compared with P1. No significant changes in metabolite concentrations were observed in the HPV infection group. Indoxyl sulfate, LysoPE (18:1), phenylacetylglutamine, and indole-3-acetic acid were significantly increased following cisplatin and radiation therapy.

Keywords

Acknowledgement

This paper was supported by Fund of Biomedical Research Institute, Jeonbuk National University Hospital. This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. RS-2023-00251397) and the 4TH BK21 project (Educational Research Group for Platform development of management of emerging infectious disease) funded by the Korean ministry of education (5199990614732).

References

  1. Badaracco, G., Savarese, A., Micheli, A., Rizzo, C., Paolini, F., Carosi, M., Cutillo, G., Vizza, E., Arcangeli, G. and Venuti, A. (2010) Persistence of HPV after radio-chemotherapy in locally advanced cervical cancer. Oncol. Rep. 23, 1093-1099.
  2. Barrios, C., Spector, T. D. and Menni, C. (2016) Blood, urine and faecal metabolite profiles in the study of adult renal disease. Arch. Biochem. Biophys. 589, 81-92. https://doi.org/10.1016/j.abb.2015.10.006
  3. Bourmaud, A., Gallien, S. and Domon, B. (2016) Parallel reaction monitoring using quadrupole-Orbitrap mass spectrometer: principle and applications. Proteomics 16, 2146-2159. https://doi.org/10.1002/pmic.201500543
  4. Brown, A., Kumar, S. and Tchounwou, P. B. (2019) Cisplatin-based chemotherapy of human cancers. J. Cancer Sci. Ther. 11, 97.
  5. Chen, H., Zhang, J., Zhou, H., Zhu, Y., Liang, Y., Zhu, P. and Zhang, Q. (2022) UHPLC-HRMS-based serum lipisdomics reveals novel biomarkers to assist in the discrimination between colorectal adenoma and cancer. Front. Oncol. 12, 934145.
  6. Chen, L., Ding, H., Zhu, Y., Guo, Y., Tang, Y., Xie, K., Zhang, G., Dai, G., Gao, Y. and Zhang, T. (2023) Untargeted and targeted metabolomics identify metabolite biomarkers for Salmonella enteritidis in chicken meat. Food Chem. 409, 135294.
  7. Chen, W.-L., Wang, J.-H., Zhao, A.-H., Xu, X., Wang, Y.-H., Chen, T.-L., Li, J.-M., Mi, J.-Q., Zhu, Y.-M. and Liu, Y.-F. (2014) A distinct glucose metabolism signature of acute myeloid leukemia with prognostic value. Blood 124, 1645-1654. https://doi.org/10.1182/blood-2014-02-554204
  8. Cheng, T.-H., Ma, M.-C., Liao, M.-T., Zheng, C.-M., Lu, K.-C., Liao, C.-H., Hou, Y.-C., Liu, W.-C. and Lu, C.-L. (2020) Indoxyl sulfate, a tubular toxin, contributes to the development of chronic kidney disease. Toxins 12, 684.
  9. Chhonker, Y. S., Kanvinde, S., Ahmad, R., Singh, A. B., Oupicky, D. and Murry, D. J. (2021) Simultaneous quantitation of lipid biomarkers for inflammatory bowel disease using LC-MS/MS. Metabolites 11, 106.
  10. Dasari, S., Wudayagiri, R. and Valluru, L. (2015) Cervical cancer: biomarkers for diagnosis and treatment. Clin. Chim. Acta 445, 7-11. https://doi.org/10.1016/j.cca.2015.03.005
  11. Ezaki, T., Nishiumi, S., Azuma, T. and Yoshida, M. (2017) Metabolomics for the early detection of cisplatin-induced nephrotoxicity. Toxicol. Res. 6, 843-853. https://doi.org/10.1039/C7TX00171A
  12. Gadducci, A., Tana, R., Cosio, S. and Genazzani, A. R. (2008) The serum assay of tumour markers in the prognostic evaluation, treatment monitoring and follow-up of patients with cervical cancer: a review of the literature. Crit. Rev. Oncol. Hematol. 66, 10-20. https://doi.org/10.1016/j.critrevonc.2007.09.002
  13. Ghosh, S. (2019) Cisplatin: the first metal based anticancer drug. Bioorg. Chem. 88, 102925.
  14. Hascitha, J., Priya, R., Jayavelu, S., Dhandapani, H., Selvaluxmy, G., Singh, S. S. and Rajkumar, T. (2016) Analysis of Kynurenine/Tryptophan ratio and expression of IDO1 and 2 mRNA in tumour tissue of cervical cancer patients. Clin. Biochem. 49, 919-924. https://doi.org/10.1016/j.clinbiochem.2016.04.008
  15. Holditch, S. J., Brown, C. N., Lombardi, A. M., Nguyen, K. N. and Edelstein, C. L. (2019) Recent advances in models, mechanisms, biomarkers, and interventions in cisplatin-induced acute kidney injury. Int. J. Mol. Sci. 20, 3011.
  16. Ji, Y., Yin, W., Liang, Y., Sun, L., Yin, Y. and Zhang, W. (2020) Antiinflammatory and anti-oxidative activity of indole-3-acetic acid involves induction of HO-1 and neutralization of free radicals in RAW264.7 cells. Int. J. Mol. Sci. 21, 1579.
  17. Khan, I., Nam, M., Kwon, M., Seo, S.-S., Jung, S., Han, J. S., Hwang, G.-S. and Kim, M. K. (2019) LC/MS-based polar metabolite profiling identified unique biomarker signatures for cervical cancer and cervical intraepithelial neoplasia using global and targeted metabolomics. Cancers 11, 511.
  18. Kihara, Y., Mizuno, H. and Chun, J. (2015) Lysophospholipid receptors in drug discovery. Exp. Cell Res. 333, 171-177. https://doi.org/10.1016/j.yexcr.2014.11.020
  19. Kwon, B. (2023) A metabolite of the gut microbiota: a facilitator of chemotherapy efficacy in cancer. Signal Transduct. Target. Ther. 8, 238.
  20. Lee, J. H., Kim, D., Oh, Y. S. and Jun, H.-S. (2019) Lysophosphatidic acid signaling in diabetic nephropathy. Int. J. Mol. Sci. 20, 2850.
  21. Liu, H., Han, Y., Mi, R., Zhang, Y., Su, G., Wang, H., Zhou, X., Liu, X. and Zhu, B. (2011) Identification of cervical cancer proteins associated with treatment with paclitaxel and cisplatin in patients. Int. J. Gynecol. Cancer 21, 1452-1457. https://doi.org/10.1097/IGC.0b013e31822491d0
  22. Mokhtarani, M., Diaz, G., Rhead, W., Lichter-Konecki, U., Bartley, J., Feigenbaum, A., Longo, N., Berquist, W., Berry, S. and Gallagher, R. (2012) Urinary phenylacetylglutamine as dosing biomarker for patients with urea cycle disorders. Mol. Genet. Metab. 107, 308-314. https://doi.org/10.1016/j.ymgme.2012.08.006
  23. Morimoto, K., Tominaga, Y., Agatsuma, Y., Miyamoto, M., Kashiwagura, S., Takahashi, A., Sano, Y., Yano, K., Kakinuma, C. and Ogihara, T. (2018) Intestinal secretion of indoxyl sulfate as a possible compensatory excretion pathway in chronic kidney disease. Biopharm. Drug Dispos. 39, 328-334. https://doi.org/10.1002/bdd.2149
  24. O'Brien, F. J., Mair, R. D., Plummer, N. S., Meyer, T. W., Sutherland, S. M. and Sirich, T. L. (2020) Impaired tubular secretion of organic solutes in acute kidney injury. Kidney360 1, 724-730. https://doi.org/10.34067/KID.0001632020
  25. Pabla, N. and Dong, Z. (2008) Cisplatin nephrotoxicity: mechanisms and renoprotective strategies. Kidney Int. 73, 994-1007. https://doi.org/10.1038/sj.ki.5002786
  26. Paeslack, N., Mimmler, M., Becker, S., Gao, Z., Khuu, M. P., Mann, A., Malinarich, F., Regen, T. and Reinhardt, C. (2022) Microbiota-derived tryptophan metabolites in vascular inflammation and cardiovascular disease. Amino Acids 54, 1339-1356. https://doi.org/10.1007/s00726-022-03161-5
  27. Putral, L. N., Bywater, M. J., Gu, W., Saunders, N. A., Gabrielli, B. G., Leggatt, G. R. and McMillan, N. A. (2005) RNA interference against human papillomavirus oncogenes in cervical cancer cells results in increased sensitivity to cisplatin. Mol. pharmacol. 68, 1311-1319. https://doi.org/10.1124/mol.105.014191
  28. Schwickert, G., Walenta, S., Sundfor, K., Rofstad, E. K. and Mueller-Klieser, W. (1995) Correlation of high lactate levels in human cervical cancer with incidence of metastasis. Cancer Res. 55, 4757-4759.
  29. Shi, W., Yuan, X., Cui, K., Li, H., Fu, P., Rehman, S.-U., Shi, D., Liu, Q. and Li, Z. (2021) LC-MS/MS based metabolomics reveal candidate biomarkers and metabolic changes in different buffalo species. Animals 11, 560.
  30. Sui, Y., Yang, Y., Wang, J., Li, Y., Ma, H., Cai, H., Liu, X., Zhang, Y., Wang, S. and Li, Z. (2015) Lysophosphatidic acid inhibits apoptosis induced by cisplatin in cervical cancer cells. Biomed Res. Int. 2015, 598386.
  31. Tan, B., Chen, J., Qin, S., Liao, C., Zhang, Y., Wang, D., Li, S., Zhang, Z., Zhang, P. and Xu, F. (2021) Tryptophan pathway-targeted metabolomics study on the mechanism and intervention of cisplatininduced acute kidney injury in rats. Chem. Res. Toxicol. 34, 1759-1768. https://doi.org/10.1021/acs.chemrestox.1c00110
  32. Unami, A., Nishina, N., Terai, T., Sato, S., Tamura, T., Noda, K. and Mine, Y. (1996) Effects of cisplatin on erythropoietin production in rats. J. Toxicol. Sci. 21, 157-165. https://doi.org/10.2131/jts.21.3_157
  33. Velenosi, T. J., Krausz, K. W., Hamada, K., Dorsey, T. H., Ambs, S., Takahashi, S. and Gonzalez, F. J. (2022) Pharmacometabolomics reveals urinary diacetylspermine as a biomarker of doxorubicin effectiveness in triple negative breast cancer. NPJ Precision Oncol. 6, 70.
  34. Wei, Y., Wang, J., Chen, F., Li, X., Zhang, J., Shen, M., Tang, R. and Huang, Z. (2022) Serum abnormal metabolites for evaluating therapeutic response and prognosis of patients with multiple myeloma. Front. Oncol. 12, 808290.
  35. Wood, P. A. and Hrushesky, W. (1995) Cisplatin-associated anemia: an erythropoietin deficiency syndrome. J. Clin. Invest. 95, 1650-1659. https://doi.org/10.1172/JCI117840
  36. Xu, Y., Shen, Z., Wiper, D. W., Wu, M., Morton, R. E., Elson, P., Kennedy, A. W., Belinson, J., Markman, M. and Casey, G. (1998) Lysophosphatidic acid as a potential biomarker for ovarian and other gynecologic cancers. JAMA 280, 719-723. https://doi.org/10.1001/jama.280.8.719
  37. Yabuuchi, N., Hou, H., Gunda, N., Narita, Y., Jono, H. and Saito, H. (2021) Suppressed hepatic production of indoxyl sulfate attenuates cisplatin-induced acute kidney injury in sulfotransferase 1a1-deficient mice. Int. J. Mol. Sci. 22, 1764.
  38. Yamamoto, Y., Sakurai, T., Chen, Z., Furukawa, T., Gowda, S. G. B., Wu, Y., Nouso, K., Fujii, Y., Yoshikawa, Y., Chiba, H. and Hui, S. P. (2021) Analysis of serum lysophosphatidylethanolamine levels in patients with non-alcoholic fatty liver disease by liquid chromatography-tandem mass spectrometry. Anal. Bioanal. Chem. 413, 245-254. https://doi.org/10.1007/s00216-020-02996-9
  39. Yuan, C.-H., Filippova, M. and Duerksen-Hughes, P. (2012) Modulation of apoptotic pathways by human papillomaviruses (HPV): mechanisms and implications for therapy. Viruses 4, 3831-3850. https://doi.org/10.3390/v4123831
  40. Zhu, H., Luo, H., Zhang, W., Shen, Z., Hu, X. and Zhu, X. (2016) Molecular mechanisms of cisplatin resistance in cervical cancer. Drug Des. Devel. Ther. 10, 1885-1895.
  41. Zhu, Z.-J., Qi, Z., Zhang, J., Xue, W.-H., Li, L.-F., Shen, Z.-B., Li, Z.-Y., Yuan, Y.-L., Wang, W.-B. and Zhao, J. (2020) Untargeted metabolomics analysis of esophageal squamous cell carcinoma discovers dysregulated metabolic pathways and potential diagnostic biomarkers. J. Cancer 11, 3944-3954. https://doi.org/10.7150/jca.41733