Vol 6, No 3 (2021)
Original article
Published online: 2021-08-05

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Influence of dexamethasone and doxorubicin on inhibition of hypoxia- -induced metastatic potential in HepG2 cell line

Agnieszka Mlicka1, Tomasz Aleksiewicz1, Maciej Rydzkowski1, Paweł Niewiadomski1, Wioletta Zielińska2, Marta Hałas-Wiśniewska2, Klaudia Mikołajczyk2, Magdalena Izdebska2
Medical Research Journal 2021;6(3):194-203.


One of the commonly applied methods in the case of median to advance stages of liver cancer is the transarterial chemoembolization (TACE) procedure. It involves the administration of relatively high doses of cytostatics to the tumour-supplying artery followed by the embolization of the vessel. It limits the drug action almost only to the tumour mass. However, this also reduces the availability of oxygen, which stimulates cell migration. Therefore, the study aimed to assess how the introduction of an additional drug — dexamethasone and its combination with doxorubicin will impact the viability and migration of HepG2 cells under hypoxia-mimic conditions. To assess the basic response of the cells to the drugs and evaluate the interaction between them MTT assay and apoptosis assay were used. To analyse the migratory potential transwell migration assay was applied. Epithelial-mesenchymal transition (EMT) markers and apoptosis-related proteins were studied using Western blot assay. Hypoxia-mimic conditions were induced using pretreatment with cobalt chloride. The obtained results suggest that the developed doxorubicin: dexamethasone combination limits hypoxia-induced increase in the migratory potential of HCC cells, which is connected with the inhibition of the EMT process and directing cells to death on the cellular level.

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  1. Galle PR, Tovoli F, Foerster F, et al. The treatment of intermediate stage tumours beyond TACE: From surgery to systemic therapy. J Hepatol. 2017; 67(1): 173–183.
  2. El Fouly A, Ertle J, El Dorry A, et al. In intermediate stage hepatocellular carcinoma: radioembolization with yttrium 90 or chemoembolization? Liver Int. 2015; 35(2): 627–635.
  3. Boulin M, Delhom E, Pierredon-Foulongne MA, et al. Transarterial chemoembolization for hepatocellular carcinoma: An old method, now flavor of the day. Diagn Interv Imaging. 2015; 96(6): 607–615.
  4. Asghar U, Meyer T. Are there opportunities for chemotherapy in the treatment of hepatocellular cancer? J Hepatol. 2012; 56(3): 686–695.
  5. Lau CK, Yang ZF, Ho DW, et al. An Akt/hypoxia-inducible factor-1alpha/platelet-derived growth factor-BB autocrine loop mediates hypoxia-induced chemoresistance in liver cancer cells and tumorigenic hepatic progenitor cells. Clin Cancer Res. 2009; 15(10): 3462–3471.
  6. De Francesco EM, Maggiolini M, Musti AM. Crosstalk between Notch, HIF-1α and GPER in Breast Cancer EMT. Int J Mol Sci. 2018; 19(7).
  7. Roche J. Erratum: Roche, J. The Epithelial-to-Mesenchymal Transition in Cancer. Cancers, 2018, 10, 52. Cancers (Basel). 2018; 10(3).
  8. Simko V, Takacova M, Debreova M, et al. Dexamethasone downregulates expression of carbonic anhydrase IX via HIF-1α and NF-κB-dependent mechanisms. Int J Oncol. 2016; 49(4): 1277–1288.
  9. Chou TC. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev. 2006; 58(3): 621–681.
  10. Krajewski A, Gagat M, Żuryń A, et al. Cyclin F is involved in response to cisplatin treatment in melanoma cell lines. Oncol Rep. 2020; 43(3): 765–772.
  11. Lencioni R, Petruzzi P, Crocetti L. Chemoembolization of hepatocellular carcinoma. Semin Intervent Radiol. 2013; 30(1): 3–11.
  12. Choi BJ, Park SA, Lee SY, et al. Hypoxia induces epithelial-mesenchymal transition in colorectal cancer cells through ubiquitin-specific protease 47-mediated stabilization of Snail: A potential role of Sox9. Sci Rep. 2017; 7(1): 15918.
  13. Li HL, Ji WB, Zhao R, et al. Poor prognosis for hepatocellular carcinoma with transarterial chemoembolization pre-transplantation: retrospective analysis. World J Gastroenterol. 2015; 21(12): 3599–3606.
  14. Buschauer S, Koch A, Wiggermann P, et al. Hepatocellular carcinoma cells surviving doxorubicin treatment exhibit increased migratory potential and resistance to doxorubicin re-treatment . Oncol Lett. 2018; 15(4): 4635–4640.
  15. Kim JHo, Hwang YJ, Han SH, et al. Dexamethasone inhibits hypoxia-induced epithelial-mesenchymal transition in colon cancer. World J Gastroenterol. 2015; 21(34): 9887–9899.
  16. Hassoun H, Reich L, Klimek VM, et al. Doxorubicin and dexamethasone followed by thalidomide and dexamethasone is an effective well tolerated initial therapy for multiple myeloma. Br J Haematol. 2006; 132(2): 155–161.
  17. Chaikomon K, Chattong S, Chaiya T, et al. Doxorubicin-conjugated dexamethasone induced MCF-7 apoptosis without entering the nucleus and able to overcome MDR-1-induced resistance. Drug Des Devel Ther. 2018; 12: 2361–2369.
  18. Ogasawara S, Chiba T, Ooka Y, et al. A randomized placebo-controlled trial of prophylactic dexamethasone for transcatheter arterial chemoembolization. Hepatology. 2018; 67(2): 575–585.
  19. Dubbelboer IR, Pavlovic N, Heindryckx F, et al. Liver cancer cell lines treated with doxorubicin under normoxia and hypoxia: cell viability and oncologic protein profile. Cancers (Basel). 2019; 11(7).
  20. He J, Zhou J, Yang W, et al. Dexamethasone affects cell growth/apoptosis/chemosensitivity of colon cancer via glucocorticoid receptor α/NF-κB. Oncotarget. 2017; 8(40): 67670–67683.
  21. Chen YX, Wang Y, Fu CC, et al. Dexamethasone enhances cell resistance to chemotherapy by increasing adhesion to extracellular matrix in human ovarian cancer cells. Endocr Relat Cancer. 2010; 17(1): 39–50.
  22. Wang LJ, Li J, Hao FR, et al. Dexamethasone suppresses the growth of human non-small cell lung cancer via inducing estrogen sulfotransferase and inactivating estrogen. Acta Pharmacol Sin. 2016; 37(6): 845–856.
  23. Ou XW, Wang RX, Kang MF, et al. Hypoxia promotes migration and invasion of gastric cancer cells by activating HIF-1α and inhibiting NDRG2 associated signaling pathway. Eur Rev Med Pharmacol Sci. 2018; 22(23): 8237–8247.
  24. Lee JW, Ko J, Ju C, et al. Hypoxia signaling in human diseases and therapeutic targets. Exp Mol Med. 2019; 51(6): 1–13.
  25. Muñoz-Sánchez J, Chánez-Cárdenas ME, Orozco-Ibarra M, et al. Aged garlic extract and S-allylcysteine prevent apoptotic cell death in a chemical hypoxia model. Biol Res. 2016; 49(4): 7–570.
  26. Guan Y, Chen J, Zhan Y, et al. Effects of dexamethasone on C6 cell proliferation, migration and invasion through the upregulation of AQP1. Oncol Lett. 2018; 15(5): 7595–7602.
  27. Wu Y, Xia R, Dai C, et al. Dexamethasone inhibits the proliferation of tumor cells. Cancer Manag Res. 2019; 11: 1141–1154.
  28. Zhang XD, Dong XQ, Xu JL, et al. Hypoxia promotes epithelial-mesenchymal transition of hepatocellular carcinoma cells via inducing Twist1 expression. Eur Rev Med Pharmacol Sci. 2017; 21(13): 3061–3068.
  29. Strouhalova K, Přechová M, Gandalovičová A, et al. Vimentin Intermediate Filaments as Potential Target for Cancer Treatment. Cancers (Basel). 2020; 12(1).
  30. Zhang Qi, Bai X, Chen W, et al. Wnt/β-catenin signaling enhances hypoxia-induced epithelial-mesenchymal transition in hepatocellular carcinoma via crosstalk with hif-1α signaling. Carcinogenesis. 2013; 34(5): 962–973.