Lapatinib bleomisin ile oluşturulmuş deneysel skleroderma modelinde dermal fibrozu önler ve iyileştirir
Öz
Amaç: Skleroderma, endotelyal hasar ve diffüz interstisyel fibroz ile karakterize bir bağ dokusu hastalığıdır.Lapatinib, 4-anilinoquinoline türevi olan bir tirozin kinaz inhibitörüdür. Böylece, MAPK ve PI3K gibi önemli pek çok yolağın akışını durdurur. Sonuç olarak, hücre siklus ilerlemesi, apoptoz, anjiogenez ve hücre adhezyonunu etkilemektedir.Çalışmamızın amacı, bleomisin (BLM) ile oluşturulmuş deneysel skleroderma modelinde lapatinib uygulamalarının profilaktik ve teröpatik etkinliklerinin belirlenmesidir
Materyal ve Metot: Çalışmaya ortalama 6 hafta yaşında ve 20-25 gram ağırlıklarında, 6 eşit gruba ayrıldı (her grupta n=10).Bleomisin uygulanmayacak olan kontrol grubu farelere (grup A ve grup D), her gün sc fosfat ile tamponlanmış salin (FTS) uygulandı. BLM, FTS içerisinde çözündürülerek, B ve C grubundaki farelere 3 hafta boyunca, E ve F grubundaki farelere 6 hafta boyunca her gün sc 100 L (100 g) dozunda uygulandı. A, B ve C grup fareler 3. hafta; D, E ve F grubu fareler 6. hafta sonunda sakrifiye edildi ve yapılacak analizler için doku örnekleri alındı. Doku TGF-β1, ve fibronektin-1 mRNA ekspresyonları RT-PCR yöntemi ile belirlendi.
Bulgular: Tekrarlanan subkutan BLM uygulamaları sonucunda; erken ve geç evrede, dermal inflamatuar hücre infiltrasyonu, dermal fibroz ve dermal kalınlıkta artış meydana geldi. Benzer şekilde TGF-β1 ve fibronektin-1 mRNA ekspresyonları belirgin artı. Lapatinibin hem profilaktik hem de teröpatik uygulamalarında TGF-β1, ve fibronektin-1 mRNA ekspresyonları belirgin azaldı. Ek olarak, histopatolojik olarak dermal nekro inflamasyon ve dermal fibrozda gerileme tespit edildi.
Sonuç: Lapatinib BLM ile uyarılmış dermal fibroz modelinde anti-fibrotik etkiler sergileyebilmektedir.
Anahtar Kelimeler
Kaynakça
- Allanore,Y., Simms, R., Distler, O., Trojanowska, M., Pope, J., Denton, CP., et al. (2015). Systemic sclerosis. Nat Rev Dis Primers, 1 (1). https://doi.org/10.1038/nrdp.2015.2
- Arteaga, CL., (2001). The epidermal growth factor receptor: From mutant oncogene in nonhuman cancers to therapeutic target in human neoplasia. J ClinOncol, 19(18), 32-40.
- Camp, ER., Summy, J., Bauer, TW., Liu, W., Gallick, GE., Ellis, LM.., et al .(2005). Molecular mechanisms of resistance to therapies targeting the epidermal growth factor receptor.Clin Cancer Res,11(1), 397-405.
- Cutulo, M., Soldano, S., Smith, V., (2019) Pathophysiology of systemic sclerosis: current understanding and new insights. Expert Rev Clin Immunol,15(7), 753-764.
- Diaz, R., Nguewa, PA., Parrondo, R., Perez-Stable C., Manrique, I., Redrado, M., et al (2010). Antitumor and antiangiogenic effect of the dual EGFR and HER-2 tyrosine kinase inhibitor lapatinib in a lung cancer model. BMC Cancer,10:188.
- Gonçalves, JG., Canale, D., De Bragança, AC., Seguro, AC., Shimizu, MHM., Volpini, RA., et al. (2021). The Blockade of TACE-Dependent EGF Receptor Activation by Losartan-Erlotinib Combination Attenuates Renal Fibrosis Formation in 5/6-Nephrectomized Rats Under Vitamin D Deficiency. Front Med (Lausanne), 7:60915. Gu, YS., Kong, J., Cheema, GS., Keen, CL., Wick, G., Gershwin, ME., (2008). The immunobiology of systemic sclerosis. Semin Arthritis Rheum, 38:132-160.
- Hirata, A., Ogawa, S., Kometani, T., Kuwano, T., Naito, S., Kuwano, M., et al. (2002). ZD1839 (Iressa) induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinase. Cancer Res, 62:2554-2560.
- Huang, HL., Chen, YC., Huang, YC., Yang, KC., Pan, Hy., Shih, SP., et al. (2011). Lapatinib Induces Autophagy, Apoptosis and Megakaryocytic Differentiation in Chronic Myelogenous Leukemia K562 Cells PLoS ONE PLoS One, 6:29014. Hughes, M., Herrick, AL. (2019). Systemic sclerosis. Br J Hosp Med (London), 80(9):530-536.
- Krieg, T., Abraham, D., Lafyatis, R. (2007). Fibrosis in connective tissue disease: the role of the myofibroblast and fibroblast-epithelial cell interactions. Arthritis Res.Ther; 9:4.
- Kuryliszyn-Moskal, A.(2004). Soluble adhesion molecules VCAM-1, sE-selectin, vascular endothelial growth factor (VEGF) and endothelin-1 in patients with systemic sclerosis: relationship to organ systemic involvement. Clin Rheumato, 24, 111-116.
- Li, L., Cai, L., Zheng, L., Hu, Y., Yuan, W., Guo, Z., Li W.,et al. (2018). Gefitinib Inhibits Bleomycin-Induced Pulmonary Fibrosis via Alleviating the Oxidative Damage in Mice. Oxid Med Cell Longev, 8249693.
- Mostmans, Y., Cutolo, M., Giddelo, C., Decuman, S., Melsens, K., Declercq, H., et al. (2017). The role of endothelial cells in the vasculopathy of systemic sclerosis: A systematic review. Autoimmun Rev, 16(8):774-786.
- Postlethwaite, AE., Shigemitsu, H., Kanangat, S. (2004). Cellular origins of fibroblasts: possible implications for organ fibrosis in systemic sclerosis. CurrOpinRheumatol,16,733-738.
- Rayego-Mateos, S., Morgado-Pascual, JL., Rodrigues-Diez, RR., Rodrigues-Diez, R., Falke, LL., Mezzano, S,et al. (2018). Connective tissue growth factor induces renal fibrosis via epidermal growth factor receptor activation. J Pathol., 244(2):227-241.
- Rusnak, DW., Lackey, K., Affleck, K., Wood, ER., Alligood, KJ., Rhodes, N., et al. (2001). The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo. Mol Cancer Ther, 1:85-94.
- Schroeder, RL., Stevens, CL.,Sridhar, J. (2014). Small molecule tyrosine kinase inhibitors of ErbB2/HER2/Neu in the treatment of aggressive breast cancer. Molecules, 19:15196-15212.
- Schlessinger, J., (2000). Cell Signaling by Receptor Tyrosine Kinases. Cell, 103:211-225.
- Slamon DJ., Clark GM., Wong SG., Levin WJ., Ullrich A., McGuire WL., et al. (1987). Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science, 235:177-182.
- Spector NL., Xia W., Burris H. (2005). Study of the biologic effects of lapatinib a reversible inhibitor of ErbB1 and ErbB2 tyrosine kinases, on tumor growth and survival pathways in patients with advanced malignancies. J ClinOncol, 23:2502-2512.
- Sritmatkandada P., Loomis R., Carbone R., Sritmankandada S., Lacy J. (2008). Combined proteasome and Bel-2 inhibition stimulates apoptosis and inhibits growth in EBV-transformed lymphocytes:a potential therapeutic approach to EBV-associated lympho profiferative diseases. Eur J Haematol, 80:407-418.
- Son SS., Hwang S., Park JH., Ko Y., Yun SI., Lee JH., et al. (2021). Invivosilencing of amphiregulinby a noveleffective Self-Assembled-Micelleinhibitory RNA ameliorates renal fibrosis via inhibition of EGFR signals. SciRep, 11(1):2191.
- Taskar KS., Rudraraju V., Mittapalli RK., Samala R., Thorsheim HR., Lockman J., et al. (2012). Lapatinib distribution in HER2 overexpressing experimental brain metastases of breast cancer. Pharm Res, 9:70-81.
- Wang L., Liu N., Xiong C., Xu L., Shi Y., Qiu A,, et al. (2016). Inhibition of EGF Receptor Blocksthe Development and Progression of Peritoneal Fibrosis. J Am SocNephrol, 27(9):2631-44.
- Wood ER., Truesdale AT., Nonaka S., McDonald OB. (2004). A unique structure for epidermal growth factor receptor bound to GW572016 (lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res, 64:6652-6659.
- Van C., Giaccone G., Hoekman K. (2005). Epidermal growth factor receptor and angiogenesis: Opportunities for combined anticancer strategies. Int J Cancer, 117:883-888.
- Varga J., Pasche B. (2009). Transforming growth factor beta as a therapeutic target in systemic sclerosis. Nat Rev Rheumatol, 5:200-206.
- Yamamoto T. (2002). Animal model of sclerotic skin induced by bleomycin: a clue to the pathogenesis of and therapy for scleroderma? ClinI Immunol, 102:209-216.
Lapatinib prevents and ameliorates dermal fibrosis in bleomycin induced experimental scleroderma model
Öz
Background: Scleroderma is a connective tissue disease characterized by endothelial damage and diffuse interstitial fibrosis. Lapatinib, a tyrosine kinase inhibitor, is a 4-anilinoquinol derivative. It inhibits many important signalling pathways including MAPK and PI3K. As a result, it affects cell cycle progression, apoptosis, angiogenesis and cell adhesion.
Materials and Methods: Mice with an average age of 6 weeks and a weight of 20-25 g were divided into 6 equal groups (n=10 in each group). Mice in the control group (group A and group D), which were not treated with bleomycin (BLM), received sc phosphate buffered saline (PBS) daily. BLM was dissolved in FTS and administered to mice in groups B and C for 3 weeks, and to mice in groups E and F at a dose of sc 100 L (100 g) daily for 6 weeks. Mice in groups A, B and C were sacrificed at the end of week 3; mice in groups D, E and F were sacrificed at the end of week 6 and tissue samples were collected for further analysis. The mRNA expressions of TGF-β1 and fibronectin-1 were determined by RT-PCR.
Results: Repeated subcutaneous administration of BLM caused dermal inflammatory cell infiltration, increased skin thickness and dermal fibrosis at early and late stages. TGF-β1 and fibronectin-1 mRNA expressions were also evidently increased. In both prophylactic and therapeutic applications of lapatinib, TGF-β1 and fibronectin-1mRNA expressions decreased markedly. In addition, histopathological dermal necro- inflammation and fibrosis were reduced.
Conclusions: Lapatinib may exert anti-fibrotic effects in BLM-induced dermal fibrosis model. Studies show that lapatinib is a potential therapeutic agent, but it needs to be confirmed with in vivo studies.
Anahtar Kelimeler
Kaynakça
- Allanore,Y., Simms, R., Distler, O., Trojanowska, M., Pope, J., Denton, CP., et al. (2015). Systemic sclerosis. Nat Rev Dis Primers, 1 (1). https://doi.org/10.1038/nrdp.2015.2
- Arteaga, CL., (2001). The epidermal growth factor receptor: From mutant oncogene in nonhuman cancers to therapeutic target in human neoplasia. J ClinOncol, 19(18), 32-40.
- Camp, ER., Summy, J., Bauer, TW., Liu, W., Gallick, GE., Ellis, LM.., et al .(2005). Molecular mechanisms of resistance to therapies targeting the epidermal growth factor receptor.Clin Cancer Res,11(1), 397-405.
- Cutulo, M., Soldano, S., Smith, V., (2019) Pathophysiology of systemic sclerosis: current understanding and new insights. Expert Rev Clin Immunol,15(7), 753-764.
- Diaz, R., Nguewa, PA., Parrondo, R., Perez-Stable C., Manrique, I., Redrado, M., et al (2010). Antitumor and antiangiogenic effect of the dual EGFR and HER-2 tyrosine kinase inhibitor lapatinib in a lung cancer model. BMC Cancer,10:188.
- Gonçalves, JG., Canale, D., De Bragança, AC., Seguro, AC., Shimizu, MHM., Volpini, RA., et al. (2021). The Blockade of TACE-Dependent EGF Receptor Activation by Losartan-Erlotinib Combination Attenuates Renal Fibrosis Formation in 5/6-Nephrectomized Rats Under Vitamin D Deficiency. Front Med (Lausanne), 7:60915. Gu, YS., Kong, J., Cheema, GS., Keen, CL., Wick, G., Gershwin, ME., (2008). The immunobiology of systemic sclerosis. Semin Arthritis Rheum, 38:132-160.
- Hirata, A., Ogawa, S., Kometani, T., Kuwano, T., Naito, S., Kuwano, M., et al. (2002). ZD1839 (Iressa) induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinase. Cancer Res, 62:2554-2560.
- Huang, HL., Chen, YC., Huang, YC., Yang, KC., Pan, Hy., Shih, SP., et al. (2011). Lapatinib Induces Autophagy, Apoptosis and Megakaryocytic Differentiation in Chronic Myelogenous Leukemia K562 Cells PLoS ONE PLoS One, 6:29014. Hughes, M., Herrick, AL. (2019). Systemic sclerosis. Br J Hosp Med (London), 80(9):530-536.
- Krieg, T., Abraham, D., Lafyatis, R. (2007). Fibrosis in connective tissue disease: the role of the myofibroblast and fibroblast-epithelial cell interactions. Arthritis Res.Ther; 9:4.
- Kuryliszyn-Moskal, A.(2004). Soluble adhesion molecules VCAM-1, sE-selectin, vascular endothelial growth factor (VEGF) and endothelin-1 in patients with systemic sclerosis: relationship to organ systemic involvement. Clin Rheumato, 24, 111-116.
- Li, L., Cai, L., Zheng, L., Hu, Y., Yuan, W., Guo, Z., Li W.,et al. (2018). Gefitinib Inhibits Bleomycin-Induced Pulmonary Fibrosis via Alleviating the Oxidative Damage in Mice. Oxid Med Cell Longev, 8249693.
- Mostmans, Y., Cutolo, M., Giddelo, C., Decuman, S., Melsens, K., Declercq, H., et al. (2017). The role of endothelial cells in the vasculopathy of systemic sclerosis: A systematic review. Autoimmun Rev, 16(8):774-786.
- Postlethwaite, AE., Shigemitsu, H., Kanangat, S. (2004). Cellular origins of fibroblasts: possible implications for organ fibrosis in systemic sclerosis. CurrOpinRheumatol,16,733-738.
- Rayego-Mateos, S., Morgado-Pascual, JL., Rodrigues-Diez, RR., Rodrigues-Diez, R., Falke, LL., Mezzano, S,et al. (2018). Connective tissue growth factor induces renal fibrosis via epidermal growth factor receptor activation. J Pathol., 244(2):227-241.
- Rusnak, DW., Lackey, K., Affleck, K., Wood, ER., Alligood, KJ., Rhodes, N., et al. (2001). The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo. Mol Cancer Ther, 1:85-94.
- Schroeder, RL., Stevens, CL.,Sridhar, J. (2014). Small molecule tyrosine kinase inhibitors of ErbB2/HER2/Neu in the treatment of aggressive breast cancer. Molecules, 19:15196-15212.
- Schlessinger, J., (2000). Cell Signaling by Receptor Tyrosine Kinases. Cell, 103:211-225.
- Slamon DJ., Clark GM., Wong SG., Levin WJ., Ullrich A., McGuire WL., et al. (1987). Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science, 235:177-182.
- Spector NL., Xia W., Burris H. (2005). Study of the biologic effects of lapatinib a reversible inhibitor of ErbB1 and ErbB2 tyrosine kinases, on tumor growth and survival pathways in patients with advanced malignancies. J ClinOncol, 23:2502-2512.
- Sritmatkandada P., Loomis R., Carbone R., Sritmankandada S., Lacy J. (2008). Combined proteasome and Bel-2 inhibition stimulates apoptosis and inhibits growth in EBV-transformed lymphocytes:a potential therapeutic approach to EBV-associated lympho profiferative diseases. Eur J Haematol, 80:407-418.
- Son SS., Hwang S., Park JH., Ko Y., Yun SI., Lee JH., et al. (2021). Invivosilencing of amphiregulinby a noveleffective Self-Assembled-Micelleinhibitory RNA ameliorates renal fibrosis via inhibition of EGFR signals. SciRep, 11(1):2191.
- Taskar KS., Rudraraju V., Mittapalli RK., Samala R., Thorsheim HR., Lockman J., et al. (2012). Lapatinib distribution in HER2 overexpressing experimental brain metastases of breast cancer. Pharm Res, 9:70-81.
- Wang L., Liu N., Xiong C., Xu L., Shi Y., Qiu A,, et al. (2016). Inhibition of EGF Receptor Blocksthe Development and Progression of Peritoneal Fibrosis. J Am SocNephrol, 27(9):2631-44.
- Wood ER., Truesdale AT., Nonaka S., McDonald OB. (2004). A unique structure for epidermal growth factor receptor bound to GW572016 (lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res, 64:6652-6659.
- Van C., Giaccone G., Hoekman K. (2005). Epidermal growth factor receptor and angiogenesis: Opportunities for combined anticancer strategies. Int J Cancer, 117:883-888.
- Varga J., Pasche B. (2009). Transforming growth factor beta as a therapeutic target in systemic sclerosis. Nat Rev Rheumatol, 5:200-206.
- Yamamoto T. (2002). Animal model of sclerotic skin induced by bleomycin: a clue to the pathogenesis of and therapy for scleroderma? ClinI Immunol, 102:209-216.
Ayrıntılar
| Birincil Dil | İngilizce |
|---|---|
| Konular | Romatoloji ve Artrit |
| Bölüm | Araştırma Makaleleri |
| Yazarlar | |
| Yayımlanma Tarihi | 30 Nisan 2024 |
| Gönderilme Tarihi | 13 Aralık 2023 |
| Kabul Tarihi | 15 Mart 2024 |
| Yayımlandığı Sayı | Yıl 2024 Cilt: 3 Sayı: 1 |
