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The AAPS Journal

, 20:9 | Cite as

Transporter-Mediated Interaction Between Platinum Drugs and Sorafenib at the Cellular Level

  • Verena Schneider
  • Selim Chaib
  • Claudia Spanier
  • Mandy Knapp
  • Violeta Moscvin
  • Laura Scordovillo
  • Alessandra Ewertz
  • Ulrich Jaehde
  • Ganna V. Kalayda
Research Article
First Online:

Abstract

Combining the multikinase inhibitor sorafenib with the platinum-based chemotherapy of solid tumors was expected to improve treatment outcome. However, in many clinical trials, no benefit from sorafenib addition to the platinum-containing regimen could be demonstrated. Moreover, in some studies, decreased survival of ovarian cancer patients as well as non-small cell lung cancer patients with squamous cell histology was observed. The aim of this study was to investigate the cellular mechanisms of the pharmacological interaction between platinum drugs and sorafenib in different cancer cell lines. The interaction was characterized by combination index analysis, platinum accumulation and DNA platination were determined using flameless atomic absorption spectrometry, and protein expression was assessed with Western blot. In the sensitive A2780 ovarian carcinoma and H520 squamous cell lung carcinoma cell lines, sorafenib induced downregulation of Na+,K+-ATPase. In A2780 cells, the kinase inhibitor also decreased the expression of copper transporter 1 (CTR1). As a result, sorafenib treatment led to a diminished cellular accumulation of cisplatin and carboplatin and to a decrease in DNA platination in these cell lines. This was not the case in the cisplatin-resistant A2780cis ovarian carcinoma and H522 lung adenocarcinoma cell lines featuring lower basal expression of the above-mentioned transporters. In all cell lines studied, an antagonistic interaction between platinum drugs and sorafenib was found. Our results suggest that sorafenib impairs cisplatin and carboplatin uptake through downregulation of CTR1 and/or Na+,K+-ATPase resulting in reduction of DNA platination. This effect is not observed in cancer cells with defects in platinum accumulation.

KEY WORDS

antagonism copper transporter 1 Na+,K+-ATPase platinum accumulation 
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Supplementary material

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References

  1. 1.
    Galluzzi L, Senovilla L, Vitale I, Michels J, Martins I, Kepp O, et al. Molecular mechanisms of cisplatin resistance. Oncogene. 2012;31(15):1869–83.  https://doi.org/10.1038/onc.2011.384.CrossRefPubMedGoogle Scholar
  2. 2.
    Brozovic A, Osmak M. Activation of mitogen-activated protein kinases by cisplatin and their role in cisplatin-resistance. Cancer Lett. 2007;251(1):1–16.  https://doi.org/10.1016/j.canlet.2006.10.007.CrossRefPubMedGoogle Scholar
  3. 3.
    Hayakawa J, Ohmichi M, Kurachi H, Ikegami H, Kimura A, Matsuoka T, et al. Inhibition of extracellular signal-regulated protein kinase or c-Jun N-terminal protein kinase cascade, differentially activated by cisplatin, sensitizes human ovarian cancer cell line. J Biol Chem. 1999;274(44):31648–54.  https://doi.org/10.1074/jbc.274.44.31648.CrossRefPubMedGoogle Scholar
  4. 4.
    Villedieu M, Deslandes E, Duval M, Héron J-F, Gauduchon P, Poulain L. Acquisition of chemoresistance following discontinuous exposures to cisplatin is associated in ovarian carcinoma cells with progressive alteration of FAK, ERK and p38 activation in response to treatment. Gynecol Oncol. 2006;101(3):507–19.  https://doi.org/10.1016/j.ygyno.2005.11.017.CrossRefPubMedGoogle Scholar
  5. 5.
    Dal Lago L, D'Hondt V, Awada A. Selected combination therapy with sorafenib: a review of clinical data and perspectives in advanced solid tumors. Oncologist. 2008;13(8):845–58.  https://doi.org/10.1634/theoncologist.2007-0233.CrossRefPubMedGoogle Scholar
  6. 6.
    Flaherty KT, Schiller J, Schuchter LM, Liu G, Tuveson DA, Redlinger M, et al. A phase I trial of the oral, multikinase inhibitor sorafenib in combination with carboplatin and paclitaxel. Clin Cancer Res. 2008;14(15):4836–42.  https://doi.org/10.1158/1078-0432.CCR-07-4123.CrossRefPubMedGoogle Scholar
  7. 7.
    Kim C, Lee J-L, Choi YH, Kang BW, Ryu M-H, Chang HM, et al. Phase I dose-finding study of sorafenib in combination with capecitabine and cisplatin as a first-line treatment in patients with advanced gastric cancer. Investig New Drugs. 2012;30(1):306–15.  https://doi.org/10.1007/s10637-010-9531-2.CrossRefGoogle Scholar
  8. 8.
    Scagliotti G, Novello S, von Pawel J, Reck M, Pereira JR, Thomas M, et al. Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer. J Clin Oncol. 2010;28(11):1835–42.  https://doi.org/10.1200/JCO.2009.26.1321.CrossRefPubMedGoogle Scholar
  9. 9.
    Flaherty KT, Lee SJ, Zhao F, Schuchter LM, Flaherty L, Kefford R, et al. Phase III trial of carboplatin and paclitaxel with or without sorafenib in metastatic melanoma. J Clin Oncol. 2013;31(3):373–9.  https://doi.org/10.1200/JCO.2012.42.1529.CrossRefPubMedGoogle Scholar
  10. 10.
    Hainsworth JD, Thompson DS, Bismayer JA, Gian VG, Merritt WM, Whorf RC, et al. Paclitaxel/carboplatin with or without sorafenib in the first-line treatment of patients with stage III/IV epithelial ovarian cancer: a randomized phase II study of the Sarah Cannon research institute. Cancer Med. 2015;4(5):673–81.  https://doi.org/10.1002/cam4.376.CrossRefPubMedGoogle Scholar
  11. 11.
    Hauschild A, Agarwala SS, Trefzer U, Hogg D, Robert C, Hersey P, et al. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol. 2009;27(17):2823–30.  https://doi.org/10.1200/JCO.2007.15.7636.CrossRefPubMedGoogle Scholar
  12. 12.
    Pölcher M, Eckhardt M, Coch C, Wolfgarten M, Kübler K, Hartmann G, et al. Sorafenib in combination with carboplatin and paclitaxel as neoadjuvant chemotherapy in patients with advanced ovarian cancer. Cancer Chemother Pharmacol. 2010;66(1):203–7.  https://doi.org/10.1007/s00280-010-1276-2.CrossRefPubMedGoogle Scholar
  13. 13.
    Okamoto I, Miyazaki M, Morinaga R, Kaneda H, Ueda S, Hasegawa Y, et al. Phase I clinical and pharmacokinetic study of sorafenib in combination with carboplatin and paclitaxel in patients with advanced non-small cell lung cancer. Investig New Drugs. 2010;28(6):844–53.  https://doi.org/10.1007/s10637-009-9321-x.CrossRefGoogle Scholar
  14. 14.
    Heim M, Scharifi M, Zisowsky J, Jaehde U, Voliotis D, Seeber S, et al. The Raf kinase inhibitor BAY 43-9006 reduces cellular uptake of platinum compounds and cytotoxicity in human colorectal carcinoma cell lines. Anti-Cancer Drugs. 2005;16(2):129–36.  https://doi.org/10.1097/00001813-200502000-00003.CrossRefPubMedGoogle Scholar
  15. 15.
    Alley MC, Scudiero DA, Monks A, Hursey ML, Czerwinski MJ, Fine DL, et al. Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Res. 1988;48(3):589–601.PubMedGoogle Scholar
  16. 16.
    Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzym Regul. 1984;22:27–55.  https://doi.org/10.1016/0065-2571(84)90007-4.CrossRefGoogle Scholar
  17. 17.
    Buß I, Kalayda GV, Lindauer A, Reithofer MR, Galanski M, Keppler BK, et al. Effect of reactivity on cellular accumulation and cytotoxicity of oxaliplatin analogues. J Biol Inorg Chem. 2012;17(5):699–708.  https://doi.org/10.1007/s00775-012-0889-9.CrossRefPubMedGoogle Scholar
  18. 18.
    Wu Z, Liu Q, Liang X, Yang X, Wang N, Wang X, et al. Reactivity of platinum-based antitumor drugs towards a Met- and His-rich 20mer peptide corresponding to the N-terminal domain of human copper transporter 1. J Biol Inorg Chem. 2009;14(8):1313–23.  https://doi.org/10.1007/s00775-009-0576-7.CrossRefPubMedGoogle Scholar
  19. 19.
    Los G, Verdegaal E, Noteborn HP, Ruevekamp M, de Graeff A, Meesters EW, et al. Cellular pharmacokinetics of carboplatin and cisplatin in relation to their cytotoxic action. Biochem Pharmacol. 1991;42(2):357–63.  https://doi.org/10.1016/0006-2952(91)90723-I.CrossRefPubMedGoogle Scholar
  20. 20.
    Knox RJ, Friedlos F, Lydall DA, Roberts JJ. Mechanism of cytotoxicity of anticancer platinum drugs: evidence that cis-diamminedichloroplatinum(II) and cis-diammine-(1,1-cyclobutanedicarboxylato)-platinum(II) differ only in the kinetics of their interaction with DNA. Cancer Res. 1986;46(4 Pt 2):1972–9.PubMedGoogle Scholar
  21. 21.
    Smith PK, Krohn RI, Hermanson GT, Mallia AK, Gartner FH, Provenzano MD, et al. Measurement of protein using bicinchoninic acid. Anal Biochem. 1985;150(1):76–85.  https://doi.org/10.1016/0003-2697(85)90442-7.CrossRefPubMedGoogle Scholar
  22. 22.
    Holzer AK, Varki NM, Le QT, Gibson MA, Naredi P, Howell SB. Expression of the human copper influx transporter 1 in normal and malignant human tissues. J Histochem Cytochem. 2006;54(9):1041–9.  https://doi.org/10.1369/jhc.6A6970.2006.CrossRefPubMedGoogle Scholar
  23. 23.
    Crouch SP, Kozlowski R, Slater KJ, Fletcher J. The use of ATP bioluminescence as a measure of cell proliferation and cytotoxicity. J Immunol Methods. 1993;160(1):81–8.  https://doi.org/10.1016/0022-1759(93)90011-U.CrossRefPubMedGoogle Scholar
  24. 24.
    Will Y, Dykens JA, Nadanaciva S, Hirakawa B, Jamieson J, Marroquin LD, et al. Effect of the multitargeted tyrosine kinase inhibitors imatinib, dasatinib, sunitinib, and sorafenib on mitochondrial function in isolated rat heart mitochondria and H9c2 cells. Toxicol Sci. 2008;106(1):153–61.  https://doi.org/10.1093/toxsci/kfn157.CrossRefPubMedGoogle Scholar
  25. 25.
    Strumberg D, Clark JW, Awada A, Moore MJ, Richly H, Hendlisz A, et al. Safety, pharmacokinetics, and preliminary antitumor activity of sorafenib: a review of four phase I trials in patients with advanced refractory solid tumors. Oncologist. 2007;12(4):426–37.  https://doi.org/10.1634/theoncologist.12-4-426.CrossRefPubMedGoogle Scholar
  26. 26.
    Schneider V, Krieger ML, Bendas G, Jaehde U, Kalayda GV. Contribution of intracellular ATP to cisplatin resistance of tumor cells. J Biol Inorg Chem. 2013;18(2):165–74.  https://doi.org/10.1007/s00775-012-0960-6.CrossRefPubMedGoogle Scholar
  27. 27.
    Zisowsky J, Koegel S, Leyers S, Devarakonda K, Kassack MU, Osmak M, et al. Relevance of drug uptake and efflux for cisplatin sensitivity of tumor cells. Biochem Pharmacol. 2007;73(2):298–307.  https://doi.org/10.1016/j.bcp.2006.10.003.CrossRefPubMedGoogle Scholar
  28. 28.
    Howell SB, Safaei R, Larson CA, Sailor MJ. Copper transporters and the cellular pharmacology of the platinum-containing cancer drugs. Mol Pharmacol. 2010;77(6):887–94.  https://doi.org/10.1124/mol.109.063172.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Andrews PA, Mann SC, Huynh HH, Albright KD. Role of the Na+, K(+)-adenosine triphosphatase in the accumulation of cis-diamminedichloroplatinum(II) in human ovarian carcinoma cells. Cancer Res. 1991;51(14):3677–81.PubMedGoogle Scholar
  30. 30.
    Planells-Cases R, Lutter D, Guyader C, Gerhards NM, Ullrich F, Elger DA, et al. Subunit composition of VRAC channels determines substrate specificity and cellular resistance to Pt-based anti-cancer drugs. EMBO J. 2015;34:2993–3008.  10.15252/embj.201592409.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Geier A, Macias RI, Bettinger D, Weiss J, Bantel H, Jahn D, et al. The lack of the organic cation transporter OCT1 at the plasma membrane of tumor cells precludes a positive response to sorafenib in patients with hepatocellular carcinoma. Oncotarget. 2017;  10.18632/oncotarget.15029.
  32. 32.
    Zhang S, Lovejoy KS, Shima JE, Lagpacan LL, Shu Y, Lapuk A, et al. Organic cation transporters are determinants of oxaliplatin cytotoxicity. Cancer Res. 2006;66(17):8847–57.  https://doi.org/10.1158/0008-5472.CAN-06-0769.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Larson CA, Blair BG, Safaei R, Howell SB. The role of the mammalian copper transporter 1 in the cellular accumulation of platinum-based drugs. Mol Pharmacol. 2009;75(2):324–30.  https://doi.org/10.1124/mol.108.052381.CrossRefPubMedGoogle Scholar
  34. 34.
    Tsai C-Y, Finley JC, Ali SS, Patel HH, Howell SB. Copper influx transporter 1 is required for FGF, PDGF and EGF-induced MAPK signaling. Biochem Pharmacol. 2012;84(8):1007–13.  https://doi.org/10.1016/j.bcp.2012.07.014.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Turski ML, Brady DC, Kim HJ, Kim B-E, Nose Y, Counter CM, et al. A novel role for copper in Ras/mitogen-activated protein kinase signaling. Mol Cell Biol. 2012;32(7):1284–95.  https://doi.org/10.1128/MCB.05722-11.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Jentsch TJ. VRACs and other ion channels and transporters in the regulation of cell volume and beyond. Nat Rev Mol Cell Biol. 2016;17(5):293–307.  https://doi.org/10.1038/nrm.2016.29.CrossRefPubMedGoogle Scholar
  37. 37.
    Sorensen BH, Nielsen D, Thorsteinsdottir UA, Hoffmann EK, Lambert IH. Downregulation of LRRC8A protects human ovarian and alveolar carcinoma cells against cisplatin-induced expression of p53, MDM2, p21Waf1/Cip1, and Caspase-9/-3 activation. Am J Physiol Cell Physiol. 2016;310(11):C857–73.  https://doi.org/10.1152/ajpcell.00256.2015.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Amran D, Sancho P, Fernandez C, Esteban D, Ramos AM, de Blas E, et al. Pharmacological inhibitors of extracellular signal-regulated protein kinases attenuate the apoptotic action of cisplatin in human myeloid leukemia cells via glutathione-independent reduction in intracellular drug accumulation. Biochim Biophys Acta. 1743;2005(3):269–79.  https://doi.org/10.1016/j.bbamcr.2004.10.009.Google Scholar
  39. 39.
    Song IS, Savaraj N, Siddik ZH, Liu P, Wei Y, Wu CJ, et al. Role of human copper transporter Ctr1 in the transport of platinum-based antitumor agents in cisplatin-sensitive and cisplatin-resistant cells. Mol Cancer Ther. 2004;3(12):1543–9.PubMedGoogle Scholar
  40. 40.
    Kurokawa T, He G, Siddik ZH. Protein kinase inhibitors emodin and dichloro-ribofuranosylbenzimidazole modulate the cellular accumulation and cytotoxicity of cisplatin in a schedule-dependent manner. Cancer Chemother Pharmacol. 2010;65(3):427–36.  https://doi.org/10.1007/s00280-009-1045-2.CrossRefPubMedGoogle Scholar
  41. 41.
    Zhou Y, Tozzi F, Chen J, Fan F, Xia L, Wang J, et al. Intracellular ATP levels are a pivotal determinant of chemoresistance in colon cancer cells. Cancer Res. 2012;72(1):304–14.  https://doi.org/10.1158/0008-5472.CAN-11-1674.CrossRefPubMedGoogle Scholar
  42. 42.
    Meijer TW, Schuurbiers OC, Kaanders JH, Looijen-Salamon MG, de Geus-Oei L-F, Verhagen AF, et al. Differences in metabolism between adeno- and squamous cell non-small cell lung carcinomas: spatial distribution and prognostic value of GLUT1 and MCT4. Lung Cancer. 2012;76(3):316–23.  https://doi.org/10.1016/j.lungcan.2011.11.006.CrossRefPubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2017

Authors and Affiliations

  • Verena Schneider
    • 1
  • Selim Chaib
    • 1
  • Claudia Spanier
    • 1
  • Mandy Knapp
    • 1
  • Violeta Moscvin
    • 1
  • Laura Scordovillo
    • 1
  • Alessandra Ewertz
    • 1
  • Ulrich Jaehde
    • 1
  • Ganna V. Kalayda
    • 1
  1. 1.Department of Clinical Pharmacy, Institute of PharmacyUniversity of BonnBonnGermany

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