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Investigation of Antitumor Effects of Sorafenib and Lapatinib Alone and in Combination on MCF-7 Breast Cancer Cells

  • Kacan, Turgut (Department of Medical Oncology, Cumhuriyet University) ;
  • Altun, Ahmet (Department of Pharmacology, Sivas Numune Hospital) ;
  • Altun, Gulsah Gultekin (Department of Internal Medicine, Sivas Numune Hospital) ;
  • Kacan, Selen Baloglu (Department of Internal Medicine, Sivas Numune Hospital) ;
  • Sarac, Bulent (Department of Pharmacology, Sivas Numune Hospital) ;
  • Seker, Mehmet Metin (Department of Medical Oncology, Cumhuriyet University) ;
  • Bahceci, Aykut (Department of Medical Oncology, Cumhuriyet University) ;
  • Babacan, Nalan (Department of Medical Oncology, Cumhuriyet University)
  • Published : 2014.04.01

Abstract

Background: Breast cancer evolution and tumor progression are controlled by complex interactions between steroid receptors and growth factor receptor signaling. Aberrant growth factor receptor signaling can augment or suppress estrogen receptor function in hormone-dependent breast cancer cells. Thus, we aimed to investigate antitumor effects of sorafenib and lapatinib alone and in combination on MCF-7 breast cancer cells. Materials and Methods: Cytotoxicity of the sorafenib and lapatinib was tested in MCF-7 cells by XTT assays. 50, 25, 12.5 and $6.25{\mu}M$ concentrations of sorafenib and 200, 100, 50 and $25{\mu}M$ concentrations of lapatinib were administered alone and in combination. Results were evaluated as absorbance at 450nM and $IC_{50}$ values are calculated according to the absorbance data Results: Both sorafenib and lapatinib showed concentration dependent cytotoxic effects on MCF-7 cells. Sorafenib exerted cytotoxic effects with an $IC_{50}$ value of $32.0{\mu}M$; in contrast with lapatinib the $IC_{50}$ was $136.6{\mu}M$. When sorafenib and lapatinib combined, lapatinib increased cytotoxic effects of sorafenib at its ineffective concentrations. Also at the concentrations where both drugs had cytotoxic effects, combination show strong anticancer effects and killed approximately 70 percent of breast cancer cells. Conclusions: Combinations of tyrosine kinase inhibitors and cytotoxic agents or molecular targeted therapy has been successful for many types of cancer. The present study shows that both sorafenib and lapatinib alone are effective in the treatment of breast cancer. Also a combination of these two agents may be a promising therapeutic option in treatment of breast cancer.

Keywords

Tyrosine kinase inhibitor;sorafenib;lapatinib;breast cancer

References

  1. Viale G, Rotmensz N, Maisonneuve P, et al (2009). Invasive ductal carcinoma of the breast with the triple-negative phenotype: prognostic implications of EGFR immunoreactivity. Breast Cancer Res Treat, 116, 317-28. https://doi.org/10.1007/s10549-008-0206-z
  2. Stoica GE, Franke TF, Wellstein A, et al (2003). Estradiol rapidly activates Akt via the ErbB2 signaling pathway. Mol Endocrinol, 17, 818-30. https://doi.org/10.1210/me.2002-0330
  3. Takimoto CH, Awada A (2008). Safety and anti-tumor activity of sorafenib (Nexavar) in combination with other anti-cancer agents: a review of clinical trials. Cancer Chemother Pharmacol, 61, 535-48. https://doi.org/10.1007/s00280-007-0639-9
  4. Tozlu S, Girault I, Vacher S, et al (2006). Identification of novel genes that co-cluster with estrogen receptor alpha in breast tumor biopsy specimens, using a large-scale real-time reverse transcription-PCR approach. Endocr Relat Cancer, 13, 1109-20. https://doi.org/10.1677/erc.1.01120
  5. Young H, Baum R, Cremerius U, et al (1999). Measurement of clinical and subclinical tumour response using (18F)-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European Organization for Research and Treatment of Cancer (EORTC) PET Study Group. Eur J Cancer, 35, 1773-82. https://doi.org/10.1016/S0959-8049(99)00229-4
  6. Zubeda S, Kaipa PR, Shaik NA, et al (2013). Her-2/neu status: a neglected marker of prognostication and management of breast cancer patients in India.. Asian Pac J Cancer Prev, 14, 2231-5. https://doi.org/10.7314/APJCP.2013.14.4.2231
  7. Saeki T, Cristiano A, Lynch MJ, et al (1991). Regulation by estrogen through the 5'-flanking region of the transforming growth factor alpha gene. Mol Endocrinol, 5, 1955-63. https://doi.org/10.1210/mend-5-12-1955
  8. Park BJ, Whichard ZL, Corey SJ (2012). Dasatinib synergizes with both cytotoxic and signal transduction inhibitors in heterogeneous breast cancer cell lines-lessons for design of combination targeted therapy. Cancer Lett, 320, 104-10. https://doi.org/10.1016/j.canlet.2012.01.039
  9. Polli JW, Humphreys JE, Harmon KA, et al (2008). The role of efflux and uptake transporters in [N-{3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl] amino}methyl)-2-furyl]-4-quinazolinamine (GW572016, lapatinib) disposition and drug interactions. Drug Metab Dispos, 36, 695-701. https://doi.org/10.1124/dmd.107.018374
  10. Rusnak DW, Affleck K, Cockerill SG, et al (2001). The characterization of novel, dual ErbB-2/EGFR, tyrosine kinase inhibitors: potential therapy for cancer. Cancer Res, 61, 7196-203.
  11. Salomon DS, Brandt R, Ciardiello F, Normanno N (1995). Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol, 19, 183-232. https://doi.org/10.1016/1040-8428(94)00144-I
  12. Shou J, Massarweh, S, Osborne C, et al (2004). Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J Natl Cancer Inst, 96, 926-35. https://doi.org/10.1093/jnci/djh166
  13. Simonelli M, Zucali PA, Lorenzi E, et al (2013). Phase I pharmacokinetic and pharmacodynamic study of lapatinib in combination with sorafenib in patients with advanced refractory solid tumors. Eur J Cancer, 49, 989-98. https://doi.org/10.1016/j.ejca.2012.10.016
  14. Sini P, Wyder L, Schnell C, et al (2005). The antitumor and antiangiogenic activity of vascular endothelial growth factor receptor inhibition is potentiated by ErbB1 blockade. Clin Cancer Res, 11, 4521-32. https://doi.org/10.1158/1078-0432.CCR-04-1954
  15. Llovet JM, Ricci S, Mazzaferro V, et al (2008). Sorafenib in advanced hepatocellular carcinoma. N Engl J Med, 359, 378-90. https://doi.org/10.1056/NEJMoa0708857
  16. Kong HH, Sibaud V, Chanco Turner ML, et al (2008). Sorafenib-induced eruptive melanocytic lesions. Arch Dermatol, 144, 820-2.
  17. Lee AV, Guler BL, Sun X, et al (2000). Oestrogen receptor is a critical component required for insulin-like growth factor (IGF)-mediated signalling and growth in MCF-7 cells. Eur J Cancer, 36, 109-10. https://doi.org/10.1016/S0959-8049(00)00264-1
  18. Liu AN, Sun P, Liu JN, et al (2012). Clinicopathologic characteristics and prognostic factors in patients with operable HER-2 overexpressing breast cancer. Asian Pac J Cancer Prev, 13, 1197-201. https://doi.org/10.7314/APJCP.2012.13.4.1197
  19. Macfarlane R, Seal M, Speers C, et al (2012). Molecular alterations between the primary breast cancer and the subsequent locoregional/metastatic tumor. Oncologist, 17, 172-8. https://doi.org/10.1634/theoncologist.2011-0127
  20. Mackey JR, Kerbel RS, Gelmon KA, et al (2012). Controlling angiogenesis in breast cancer: a systematic review of anti-angiogenic trials. Cancer Treat Rev, 38, 673-88. https://doi.org/10.1016/j.ctrv.2011.12.002
  21. Martinelli E, Troiani T, Morgillo F, et al (2010). Synergistic antitumor activity of sorafenib in combination with epidermal growth factor receptor inhibitors in colorectal and lung cancer cells. Clin Cancer Res, 16, 4990-5001. https://doi.org/10.1158/1078-0432.CCR-10-0923
  22. Mayer IA, Arteaga CL (2010). Does lapatinib work against HER2-negative breast cancers? Clin Cancer Res, 16, 1355-7. https://doi.org/10.1158/1078-0432.CCR-09-3223
  23. Meche A, Cimpean AM, Raica M (2009). Immunohistochemical expression and significance of epidermal growth factor receptor (EGFR) in breast cancer. Rom J Morphol Embryol, 50, 217-21.
  24. Osborne CK, Schiff R (2005). Estrogen-receptor biology: continuing progress and therapeutic implications. J Clin Oncol, 23, 1616-22. https://doi.org/10.1200/JCO.2005.10.036
  25. Geyer CE, Forster J, Lindquist D, Chan S, et al (2006). Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med, 355, 2733-43. https://doi.org/10.1056/NEJMoa064320
  26. Erlichman C, Boerner SA, Hallgren CG, et al (2001). The HER tyrosine kinase inhibitor CI1033 enhances cytotoxicity of 7-ethyl-10-hydroxycamptothecin and topotecan by inhibiting breast cancer resistance protein-mediated drug efflux. Cancer Res, 61, 739-48.
  27. Escudier B, Eisen T, Stadler WM, et al (2007). Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med, 356, 125-34. https://doi.org/10.1056/NEJMoa060655
  28. Finn RS, Press MF, Dering J, et al (2009). Estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 (HER2), and epidermal growth factor receptor expression and benefit from lapatinib in a randomized trial of paclitaxel with lapatinib or placebo as first-line treatment in HER2-negative or unknown metastatic breast cancer. J Clin Oncol, 27, 3908-15. https://doi.org/10.1200/JCO.2008.18.1925
  29. Hynes NE, MacDonald G (2009). ErbB receptors and signaling pathways in cancer. Curr Opin Cell Biol, 21, 177-84. https://doi.org/10.1016/j.ceb.2008.12.010
  30. Izadi P, Mehrdad N, Foruzandeh F, Reza NM (2012). Association of poor prognosis subtypes of breast cancer with estrogen receptor alpha methylation in Iranian women. Asian Pac J Cancer Prev, 13, 4113-7. https://doi.org/10.7314/APJCP.2012.13.8.4113
  31. Johnston S, Pippen JJr, Pivot X, et al (2009). Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol, 27, 5538-46. https://doi.org/10.1200/JCO.2009.23.3734
  32. Kerbel RS (2008). Tumor angiogenesis. N Engl J Med, 358, 2039-49. https://doi.org/10.1056/NEJMra0706596
  33. Dai CL, Tiwari AK, Wu CP, et al (2008). Lapatinib (Tykerb, GW572016) reverses multidrug resistance in cancer cells by inhibiting the activity of ATP-binding cassette subfamily B member 1 and G member 2. Cancer Res, 68, 7905-14. https://doi.org/10.1158/0008-5472.CAN-08-0499
  34. Ciardiello F, Bianco R, Damiano V, et al (2000). Antiangiogenic and antitumor activity of anti-epidermal growth factor receptor C225 monoclonal antibody in combination with vascular endothelial growth factor antisense oligonucleotide in human GEO colon cancer cells. Clin Cancer Res, 6, 3739-47.
  35. Collins LC, Martyniak A, Kandel MJ, et al (2009). Basal cytokeratin and epidermal growth factor receptor expression are not predictive of BRCA1 mutation status in women with triple-negative breast cancers. Am J Surg Pathol, 33, 1093-97 https://doi.org/10.1097/PAS.0b013e31819c1c93
  36. Coombes RC, Tat T, Miller ML, et al (2013). An open-label study of lapatinib in women with HER-2-negative early breast cancer: the lapatinib pre-surgical study (LPS study). Ann Oncol, 24, 924-30. https://doi.org/10.1093/annonc/mds594
  37. Boulay A, Breuleux M, Stephan C, et al (2008). The ret receptor tyrosine kinase pathway functionally interacts with the ERalpha pathway in breast cancer. Cancer Res, 68 3743-51. https://doi.org/10.1158/0008-5472.CAN-07-5100
  38. Arpino G, Wiechmann L, Osborne CK, Schiff R (2008). Crosstalk between the estrogen receptor and the HER tyrosine kinase receptor family: molecular mechanism and clinical implications for endocrine therapy resistance. Endocr Rev, 29, 217-33. https://doi.org/10.1210/er.2006-0045
  39. Bareford MD, Hamed HA, Tang Y, et al (2011). Sorafenib enhances pemetrexed cytotoxicity through an autophagy-dependent mechanism in cancer cells. Autophagy, 7, 1261-2. https://doi.org/10.4161/auto.7.10.17029
  40. Bonelli MA, Fumarola C, Alfieri RR, et al (2010) Synergistic activity of letrozole and sorafenib on breast cancer cells. Breast Cancer Res Treat, 124, 79-88. https://doi.org/10.1007/s10549-009-0714-5
  41. Brady-West DC and McGrowder DA (2011). Triple negative breast cancer: therapeutic and prognostic implications. Asian Pac J Cancer Prev, 12, 2139-43
  42. Cabuk D, Basaran G, Temomete M, et al (2014). Clinical outcome of Turkish metastatic breast cancer patients with currently available treatment modalities-singlecenter experience. Asian Pac J Cancer Prev, 15, 117-22. https://doi.org/10.7314/APJCP.2014.15.1.117
  43. Chan A, Miles DW, Pivot X (2010). Bevacizumab in combination with taxanes for the first-line treatment-of metastatic breast cancer. Ann Oncol, 21, 2305-15. https://doi.org/10.1093/annonc/mdq122
  44. Cheang MC, Voduc D, Bajdik C, et al (2008). Basal-like breast cancer defined by five biomarkers has superior prognostic value tham triple negative phenotype. Clin Cancer Res, 14, 368-76.

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