Hela serviks kanseri hücrelerinde aflibercept, platin ve IL-6 inhibisyonu kombinasyonunun hücre canlılığı ve IL-6/STAT3 sinyal yolağında etkisi
Küçük Resim Yok
Tarih
2022
Yazarlar
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Ege Üniversitesi, Tıp Fakültesi
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Rahim ağzı kanseri, kadınlarda kanser ölümlerinin önde gelen nedenlerinden biridir. Dünya genelinde kadınlarda en sık görülen dördüncü malignitedir. Vakaların çoğu insan papilloma virüsü (HPV) enfeksiyonundan kaynaklanır. Tedavisinde, cerrahi müdahale erken evre; kemoradyoterapi ileri evre hastalara uygulanır. Yaygın veya nükseden rahim ağzı kanserinde tedavi seçenekleri kısıtlıdır; kemoterapi kullanılır ve ilaç direnci mevcut olabilir. Anjiogenezisin tümör gelişim ve yayılımdaki rolü ortaya konulunca, kemoterapiye anjiogenez inhibitörleri eklenerek yeni tedavi seçenekleri ortaya çıkmıştır. HPV pozitif rahim ağzı kanseri hücrelerinde IL-6 ekspresyonu artmıştır. HPV'nin kodladığı E6 proteini, pro-enflamatuar sitokin Interleukin 6 (IL-6) 'nın otokrin aktivasyonu aracılığıyla proto-onkojenik transkripsiyon faktörü STAT3'ün aktivitesini arttırır. IL-6 ekspresyonu, STAT3 üzerinden vasküler epitel büyüme faktörüne (VEGF) bağımlı anjiyogenezi indükleyerek tümör proliferasyonunu destekler. VEGF ailesinin üyeleri, en güçlü proanjiyojenik faktörlerdir, kanser hücreleri tarafından üretilir ve insan tümörlerinin invazif ve metastatik potansiyeli ile ilgilidir. VEGF inhibitörü Bevacizumab rahim ağzı kanseri tedavisinde onay alan ilk antianjiojenik ilaçtır. IL-6/JAK/STAT sinyal yolağı hedeflenerek STAT3 aktivasyonunu önlemenin, rahim ağzı kanserinde terapötik fayda sağlayabileceği düşündürmektedir. Aflibercept, VEGF-A'nın tüm formlarını, VEGF-B'yi ve plasental büyüme faktörünü hedefleyerek anjiyogenezi bloke eden, rekombinant, tuzak reseptör füzyon proteinidir. İnsan VEGF reseptörü VEGFR-1, VEGFR-2 ile IgG1 üzerinden etki eder. Çalışmamızda HELA rahim ağzı kanseri hücrelerinde (HPV18 + servikal epitelyal adenokarsinom) Aflibercept, Platin ve IL-6 İnhibitörü Kombinasyonunun Hücre Canlılığı ve İL-6/Stat Sinyal Yolağında Etkisi araştırılacaktır. Il-6 inhibitörü kullanılarak STAT3 üzerinden VEGF ekspresyonunun azalması ve Aflibercept kullanılarak VEGF inhibisyonu amaçlanmaktadır. Rahim ağzı kanseri hücrelerinde kemoterapiye ek bu iki ajanın kombinasyonunun kullanımı ile ilgili preklinik çalışma bulunmamaktadır. Elde edilecek veriler tedaviye yönelik klinik çalışmalara ön ayak olacaktır.
Cervical cancer is one of the leading causes of cancer death in women. It is the fourth most common malignancy in women worldwide. Most cases are caused by human papillomavirus (HPV) infection. In the treatment, surgical intervention perform in the early stage of desease; Chemoradiotherapy is applied to advanced stage patients. Treatment options for extensive or recurrent cervical cancer are limited; chemotherapy is used and drug resistance may be present. When the role of angiogenesis in tumor development and spread was revealed, inhibitors of angiogenesis was added to chemotherapy and new treatment options have emerged. IL-6 expression is increased in HPV positive cervical cancer cells. The HPV-encoded E6 protein increases the activity of the proto-oncogenic transcription factor STAT3 through autocrine activation of the pro-inflammatory cytokine Interleukin 6 (IL-6). IL-6 expression promotes tumor proliferation by inducing vascular epithelial growth factor (VEGF)-dependent angiogenesis via STAT3. Members of the VEGF family are the most potent proangiogenic factors, produced by cancer cells and are related to the invasive and metastatic potential of human tumors. VEGF inhibitor Bevacizumab is the first antiangiogenic drug approved for the treatment of cervical cancer. This suggests that inhibiting STAT3 activation by targeting the IL-6/JAK/STAT signaling pathway may provide therapeutic benefit in cervical cancer. Aflibercept is a recombinant decoy receptor fusion protein that blocks angiogenesis by targeting all forms of VEGF-A, VEGF-B and placental growth factor. The human VEGF acts via VEGFR-1, VEGFR- 2 receptors and IgG1. In our study, the Effect of Aflibercept, Platinum and IL-6 Inhibitor Combination on Cell Viability and IL-6/Stat Signaling Pathway in HELA cervical cancer cells (HPV18 + cervical epithelial adenocarcinoma) will be investigated. It is aimed to decrease VEGF expression via STAT3 by using IL-6 inhibitor and to inhibit VEGF by using Aflibercept. There are no preclinical studies on the use of the combination of these two agents in addition to chemotherapy in cervical cancer cells. The data to be obtained will lead to clinical studies for treatment.
Cervical cancer is one of the leading causes of cancer death in women. It is the fourth most common malignancy in women worldwide. Most cases are caused by human papillomavirus (HPV) infection. In the treatment, surgical intervention perform in the early stage of desease; Chemoradiotherapy is applied to advanced stage patients. Treatment options for extensive or recurrent cervical cancer are limited; chemotherapy is used and drug resistance may be present. When the role of angiogenesis in tumor development and spread was revealed, inhibitors of angiogenesis was added to chemotherapy and new treatment options have emerged. IL-6 expression is increased in HPV positive cervical cancer cells. The HPV-encoded E6 protein increases the activity of the proto-oncogenic transcription factor STAT3 through autocrine activation of the pro-inflammatory cytokine Interleukin 6 (IL-6). IL-6 expression promotes tumor proliferation by inducing vascular epithelial growth factor (VEGF)-dependent angiogenesis via STAT3. Members of the VEGF family are the most potent proangiogenic factors, produced by cancer cells and are related to the invasive and metastatic potential of human tumors. VEGF inhibitor Bevacizumab is the first antiangiogenic drug approved for the treatment of cervical cancer. This suggests that inhibiting STAT3 activation by targeting the IL-6/JAK/STAT signaling pathway may provide therapeutic benefit in cervical cancer. Aflibercept is a recombinant decoy receptor fusion protein that blocks angiogenesis by targeting all forms of VEGF-A, VEGF-B and placental growth factor. The human VEGF acts via VEGFR-1, VEGFR- 2 receptors and IgG1. In our study, the Effect of Aflibercept, Platinum and IL-6 Inhibitor Combination on Cell Viability and IL-6/Stat Signaling Pathway in HELA cervical cancer cells (HPV18 + cervical epithelial adenocarcinoma) will be investigated. It is aimed to decrease VEGF expression via STAT3 by using IL-6 inhibitor and to inhibit VEGF by using Aflibercept. There are no preclinical studies on the use of the combination of these two agents in addition to chemotherapy in cervical cancer cells. The data to be obtained will lead to clinical studies for treatment.
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