The Effects of Iodinated Radiographic Contrast Media on Multidrug-resistant K562/Dox Cells: Mitochondria Impairment and P-glycoprotein Inhibition

  • Benjamaporn Supawat
  • Chatchanok Udomtanakunchai
  • Suchart Kothan
  • Montree TungjaiEmail author
Original Paper


Iodinated radiographic contrast media is used in cancer radiography for cancer diagnosis. The aim of this present study was to examine five iodinated radiographic contrast media (IRCM) (i.e., iohexol, iopamidol, iobitridol, ioxaglate, and iodixanol) in terms of their cytotoxicity, mitochondria membrane potential (ΔΨm), and P-glycoprotein function in multidrug resistant K562/Dox cancer cells and corresponding sensitive cancer cells. The cytotoxicity was determined by colorimetric resazurin reduction assay. The ΔΨm and P-glycoprotein function was measured using a noninvasive functional spectrofluorometry. Rhodamine B, fluorescence probe, was used to estimate ΔΨm. The kinetic of P-glycoprotein-mediated efflux pirarubicin was used to monitor P-glycoprotein function in multidrug resistant (MDR) cancer cells. The results showed that ioxaglate and iodixanol show similar efficacy in MDR cancer cells and for their corresponding sensitive cancer cells. Iopamidol, iohexol, and iobitridol showed higher efficacy in MDR cancer cells than for the corresponding sensitive cancer cells by approximately 2 fold. The results also showed no significant change in the |ΔΨm| values in treated K562 and K562/Dox cancer cells when compared to the non-treated K562 and K562/Dox cancer cells. However, there were notable changes detected for iobitridol and iodixanol at 50 mgI/mL. Similarly, the results showed significant differences in P-glycoprotein function of K562/Dox cancer cells after treatment with IRCM when compared to the non-treated K562/Dox cancer cells, with iohexol and iodixanol being the notable exceptions once again. In this present study, IRCM exhibited cytotoxicity on MDR cancer cells and their corresponding sensitive cancer cells. IRCM also showed potential as an anticancer agent in the future.


Iodinated radiographic contrast media P-glycoprotein Multidrug resistance Cancer 



This research was supported by a Faculty of Associated Medical Sciences, Chiang Mai University, Thailand

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Jemal, A., Siegel, R., Ward, E., Hao, Y., Xu, J., Murray, T., & Thun, M. J. (2008). Cancer statistics, 2008. CA: A Cancer Journal for Clinicians, 58(2), 71–96.Google Scholar
  2. 2.
    SiegelR., Naishadham, DJemal, A. (2012). Cancer statistics for Hispanics/Latinos, 2012. CA: A Cancer Journal for Clinicians, 62(5), 283–298.Google Scholar
  3. 3.
    Siegel, R. L., Miller, K. D., & Jemal, A. (2015). Cancer statistics, 2015. CA: A Cancer Journal for Clinicians, 65(1), 5–29.Google Scholar
  4. 4.
    Ferlay, J., Soerjomataram, I., Dikshit, R., Eser, S., Mathers, C., Rebelo, M., Parkin, D. M., Forman, D., & Bray, F. (2015). Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. International Journal of Cancer, 136(5), E359–386.CrossRefGoogle Scholar
  5. 5.
    Siegel, R. L., Miller, K. D., & Jemal, A. (2018). Cancer statistics, 2018. CA: A Cancer Journal for Clinicians, 68(1), 7–30.Google Scholar
  6. 6.
    Chang, X. B. (2010). Molecular mechanism of ATP-dependent solute transport by multidrug resistance-associated protein 1. Methods in Molecular Biology, 596, 223–249.CrossRefGoogle Scholar
  7. 7.
    Applied Radiologyaisner, D. L., Marshall, C. B. (2012). Molecular pathology of non-small cell lung cancer: a practical guide. American Journal of Clinical Pathology, 138(3), 332–346.CrossRefGoogle Scholar
  8. 8.
    Khan, M., Maryam, A., Mehmood, T., Zhang, Y., & Ma, T. (2015). Enhancing activity of anticancer drugs in multidrug resistant tumors by modulating p-glycoprotein through dietary nutraceuticals. Asian Pacific Journal of Cancer Prevention, 16(16), 6831–6839.CrossRefGoogle Scholar
  9. 9.
    Mitscher, L. A., Pillai, S. P., Gentry, E. J., & Shankel, D. M. (1999). Multiple drug resistance. Medicinal Research Reviews, 19(6), 477–496.CrossRefGoogle Scholar
  10. 10.
    Goldstein, L. G., Pastanb, I., & Gottesman, M. M. (1992). Multidrug resistance in human cancer. Critical Reviews in Oncology/Hematology, 12, 11.CrossRefGoogle Scholar
  11. 11.
    Marie, J. P., Zittoun, R., & Sikic, B. I. (1991). Multidrug resistance (mdr1) gene expression in adult acute leukemias: correlations with treatment outcome and in vitro drug sensitivity. Blood, 78(3), 586–592.Google Scholar
  12. 12.
    Nobili, S., Landini, I., Mazzei, T., & Mini, E. (2012). Overcoming tumor multidrug resistance using drugs able to evade P-glycoprotein or to exploit its expression. Medicinal Research Reviews, 32(6), 1220–1262.CrossRefGoogle Scholar
  13. 13.
    Tan, B., Piwnica-Worms, D., & Ratner, L. (2000). Multidrug resistance transporters and modulation. Current Opinion in Oncology, 12(5), 450–458.CrossRefGoogle Scholar
  14. 14.
    Palmeira, A., Sousa, E., Vasconcelos, M. H., & Pinto, M. M. (2012). Three decades of P-gp inhibitors: skimming through several generations and scaffolds. Current Medicinal Chemistry, 19(13), 1946–2025.CrossRefGoogle Scholar
  15. 15.
    Dickinson, M. C., & Kam, P. C. (2008). Intravascular iodinated contrast media and the anaesthetist. Anaesthesia, 63(6), 626–634.CrossRefGoogle Scholar
  16. 16.
    Thomsen, H. S., & Morcos, S. K. (2000). Radiographic contrast media. BJU International, 86(Suppl 1), 1–10.Google Scholar
  17. 17.
    Andreucci, M., Faga, T., Pisani, A., Sabbatini, M., Russo, D., & Michael, A. (2014). The choice of the iodinated radiographic contrast media to prevent contrast-induced nephropathy. Advances in Nephrology, 2014, 11.CrossRefGoogle Scholar
  18. 18.
    Snitwongse Na Ayudhya, S., & Mankhetkorn, S. (2009). Diatrizoate, iopromide and iotrolan enhanced cytotoxicity of daunorubicin in multidrug resistant K562/adr cells: Impaired the mitochondrial and inhibited the P-glycoprotein function. American Journal of Applied Sciences, 6(3), 484–491.CrossRefGoogle Scholar
  19. 19.
    Reungpatthanaphong, P., & Mankhetkorn, S. (2002). Modulation of multidrug resistance by artemisinin, artesunate and dihydroartemisinin in K562/adr and GLC4/adr resistant cell lines. Biological and Pharmaceutical Bulletin, 25(12), 1555–1561.CrossRefGoogle Scholar
  20. 20.
    Reungpatthanaphong, P., Dechsupa, S., Meesungnoen, J., Loetchutinat, C., & Mankhetkorn, S. (2003). Rhodamine B as a mitochondrial probe for measurement and monitoring of mitochondrial membrane potential in drug-sensitive and resistant cells. Journal of Biochemical and Biophysical Methods, 57(1), 1–16.CrossRefGoogle Scholar
  21. 21.
    Kothan, S., Dechsupa, S., Leger, G., Moretti, J. L., Vergote, J., & Mankhetkorn, S. (2004). Spontaneous mitochondrial membrane potential change during apoptotic induction by quercetin in K562 and K562/adr cells. Canadian Journal of Physiology and Pharmacology, 82(12), 1084–1090.CrossRefGoogle Scholar
  22. 22.
    Tungjai, M., Phathakanon, N., & Rithidech, K. N. (2017). Effects of medical diagnostic low-dose X rays on human lymphocytes: mitochondrial membrane potential, apoptosis and cell cycle. Health Physics, 112(5), 458–464.CrossRefGoogle Scholar
  23. 23.
    Ko, G. J., Bae, S. Y., Hong, Y. A., Pyo, H. J., & Kwon, Y. J. (2016). Radiocontrast-induced nephropathy is attenuated by autophagy through regulation of apoptosis and inflammation. Human and Experimental Toxicology, 35(7), 724–736.CrossRefGoogle Scholar
  24. 24.
    Tongqiang, L., Shaopeng, L., Xiaofang, Y., Nana, S., Xialian, X., Jiachang, H., Ting, Z., & Xiaoqiang, D. (2016). Salvianolic acid B prevents iodinated contrast media-induced acute renal injury in rats via the PI3K/Akt/Nrf2 pathway. Oxidative Medicine and Cellular Longevity, 2016, 7079487.CrossRefGoogle Scholar
  25. 25.
    Sawmiller, C. J., Powell, R. J., Quader, M., Dudrick, S. J., & Sumpio, B. E. (1998). The differential effect of contrast agents on endothelial cell and smooth muscle cell growth in vitro. Journal of Vascular Surgery, 27(6), 1128–1140.CrossRefGoogle Scholar
  26. 26.
    Zhao, Y., Tao, Z., Xu, Z., Tao, Z., Chen, B., Wang, L., Li, C., Chen, L., Jia, Q., Jia, E., Zhu, T., & Yang, Z. (2011). Toxic effects of a high dose of non-ionic iodinated contrast media on renal glomerular and aortic endothelial cells in aged rats in vivo. Toxicology Letters, 202(3), 253–260.CrossRefGoogle Scholar
  27. 27.
    Lee, S. Y., Rhee, C. M., Leung, A. M., Braverman, L. E., Brent, G. A., & Pearce, E. N. (2015). A review: radiographic iodinated contrast media-induced thyroid dysfunction. Journal of Clinical Endocrinology and Metabolism, 100(2), 376–383.CrossRefGoogle Scholar
  28. 28.
    Lei, R., Zhao, F., Tang, C. Y., Luo, M., Yang, S. K., Cheng, W., Li, X. W., & Duan, S. B. (2018). Mitophagy plays a protective role in iodinated contrast-induced acute renal tubular epithelial cells injury. Cellular Physiology and Biochemistry, 46(3), 975–985.CrossRefGoogle Scholar
  29. 29.
    Liu, N., Lei, R., Tang, M. M., Cheng, W., Luo, M., Xu, Q., & Duan, S. B. (2017). Autophagy is activated to protect renal tubular epithelial cells against iodinated contrast mediainduced cytotoxicity. Mol Med Rep, 16(6), 8277–8282.CrossRefGoogle Scholar
  30. 30.
    Ronda, N., Poti, F., Palmisano, A., Gatti, R., Orlandini, G., Maggiore, U., Cabassi, A., Regolisti, G., & Fiaccadori, E. (2013). Effects of the radiocontrast agent iodixanol on endothelial cell morphology and function. Vascular Pharmacology, 58(1-2), 39–47.CrossRefGoogle Scholar
  31. 31.
    Fanning, N. F., Manning, B. J., Buckley, J., & Redmond, H. P. (2002). Iodinated contrast media induce neutrophil apoptosis through a mitochondrial and caspase mediated pathway. British Journal of Radiology, 75(899), 861–873.CrossRefGoogle Scholar
  32. 32.
    Hayakawa, K., Nakamura, T., & Shimizu, Y. (1999). Role of hemolysis in potassium release by iodinated contrast medium. European Radiology, 9(7), 1357–1361.CrossRefGoogle Scholar
  33. 33.
    Kim, K. H., Park, J. Y., Park, H. S., Kuh, S. U., Chin, D. K., Kim, K. S., & Cho, Y. E. (2015). Which iodinated contrast media is the least cytotoxic to human disc cells? Spine J, 15(5), 1021–1027.CrossRefGoogle Scholar
  34. 34.
    Kerl, J. M., Nguyen, S. A., Lazarchick, J., Powell, J. W., Oswald, M. W., Alvi, F., Costello, P., Vogl, T. J., & Schoepf, U. J. (2008). Iodinated contrast media: effect of osmolarity and injection temperature on erythrocyte morphology in vitro. Acta Radiologica, 49(3), 337–343.CrossRefGoogle Scholar
  35. 35.
    Mannechez, A., Reungpatthanaphong, P., De Certaines, J. D., Leray, G., & Le Moyec, L. (2005). Proton NMR visible mobile lipid signals in sensitive and multidrug-resistant K562 cells are modulated by rafts. Cancer Cell International, 5(1), 2.CrossRefGoogle Scholar
  36. 36.
    Reungpatthanaphong, P., Marbeuf-Gueye, C., Le Moyec, L., Salerno, M., & Garnier-Suillerot, A. (2004). Decrease of P-glycoprotein activity in K562/ADR cells by MbetaCD and filipin and lack of effect induced by cholesterol oxidase indicate that this transporter is not located in rafts. Journal of Bioenergetics and Biomembranes, 36(6), 533–543.CrossRefGoogle Scholar
  37. 37.
    Franke, R. P., Scharnweber, T., Fuhrmann, R., Wenzel, F., Kruger, A., Mrowietz, C., & Jung, F. (2014). Effect of radiographic contrast media on the spectrin/band3-network of the membrane skeleton of erythrocytes. PloS ONE, 9(2), e89512CrossRefGoogle Scholar
  38. 38.
    Franke, R. P., Kruger, A., Scharnweber, T., Wenzel, F., & Jung, F. (2014). Effects of radiographic contrast media on the micromorphology of the junctional complex of erythrocytes visualized by immunocytology. International Journal of Molecular Sciences, 15(9), 16134–16152.CrossRefGoogle Scholar
  39. 39.
    Gerka, U., Frankeb, Rp, & Jungc, F. (2015). Effect of radiographic contrast media (Iodixanol, Iobitridol) on hemolysis. Journal of Cellular Biotechnology, 1, 179–182. 2016.CrossRefGoogle Scholar
  40. 40.
    Losco, P., Nash, G., Stone, P., & Ventre, J. (2001). Comparison of the effects of radiographic contrast media on dehydration and filterability of red blood cells from donors homozygous for hemoglobin A or hemoglobin S. American Journal of Hematology, 68(3), 149–158.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Benjamaporn Supawat
    • 1
    • 2
  • Chatchanok Udomtanakunchai
    • 1
  • Suchart Kothan
    • 1
  • Montree Tungjai
    • 1
    Email author
  1. 1.Department of Radiologic Technology, Faculty of Associated Medical SciencesChiang Mai UniversityChiang MaiThailand
  2. 2.Graduate SchoolChiang Mai UniversityChiang MaiThailand

Personalised recommendations