Temozolomid ve vismodegib kombinasyonunun beyin tümörü patogenezindeki rolünün moleküler boyutta incelenmesi
Küçük Resim Yok
Tarih
2015
Yazarlar
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Ege Üniversitesi
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Beyin tümörleri Dünya Sağlık Örgütü (WHO) tarafından belirlenen histopatolojik sınıflandırmaya göre I-IV arası değişen derecelerde isimlendirilir. Malign gliomlar en yaygın primer beyin tümörleridir. Glioblastom (GBM) en agresif formudur ve derece IV olarak sınıflandırılır. Kendilerini sürekli yenileme özelliğindeki olan ve etkili tümörijenik potansiyel sergileyen gliom kök hücrelerinin keşfi, GBM tedavisinin geliştirilmesinde kazanımlar sağlamıştır. Gliomların heterojen yapısı bu tip tümörlerin tedavisini zorlaştırmaktadır. Güncel tedavi stratejisi cerrahi müdahale, radyoterapi ve kemoterapiyi içermekle birlikte, hastaların ortalama sağkalım süresi 15 aydır. Temozolomid (TMZ), DNA alkilleyici kemoterapötik bir ajandır. İntrinsik ya da kazanılmış direnç, başarılı TMZ tedavisinin önünde ilaç etkinliğini sınırlayan bir engeldir. Embriyonik dönemde, hücresel büyüme ve farklılaşmada önemli rol oynayan Hedgehog (Hh) sinyal yolağı, GBM de dahil olmak üzere birçok kanser tipi ile ilişkilidir. Metastatik ya da bölgesel olarak ileri bazal hücreli karsinom tedavisi için FDA tarafından onaylanan ve bir Hh yolağı inhibitörü olan Vismodegib (VIS), normal hücrelerin proliferasyonunu engellemeden tümör hücrelerinin proliferasyonunu durdurur
Brain tumors are classified into four degrees (I-IV) according to their histopathological features. Malign gliomas are most common primary brain tumors. Glioblastoma (GBM) is the most aggressive form of glimas and classified as degree IV. The discovery of the glioma stem cells which have self-renewal ability and show efficient potential tumorogenic activity had provided benefits for the treatment of GBM. Treatment of gliomas are limited because of their heterogenity. Although the current treatment strategy consists of radiotherapy and chemotherapy, the average survival of patients remain 15 months. Temozolomide (TMZ) is a DNA alkylating chemoterapeutic agent. Intrinsic or acquired resistance is an obstacle for efficiency of drug in successful TMZ treatment. Hedgehog signaling pathway plays crucial roles in cellular growth and differentiation during embryonic period and is also associated with several cancer types, including GBM. Vismodegib (VIS) is a FDA approved Hh inhibitor that was designed for metastatic and basal cell carcinoma treatment. VIS inhibits the proliferation of tumor cells without inhibiting normal cells proliferation. Currently, it is considered that necrosis is a controlled and programmed cell death mechanism as apoptosis, for that reason it is named as programmed necrosis or necroptosis. The aim of this study is to detect the cytotoxic and apoptotic effects of combination of TMZ and VIS on human brain cancer stem cell and human neuronal stem cell lines and also to determine the chances in gene expressions levels related to necroptosis and Hh pathway. As a result, the combination of TMZ and VIS induced apoptosis on human brain cancer stem cell line. Significant changes on gene expressions which are related to necroptosis and Hh pathway were obtained. In this regard, we suggest that this approach may provide a novel strategy for brain cancer therapy.
Brain tumors are classified into four degrees (I-IV) according to their histopathological features. Malign gliomas are most common primary brain tumors. Glioblastoma (GBM) is the most aggressive form of glimas and classified as degree IV. The discovery of the glioma stem cells which have self-renewal ability and show efficient potential tumorogenic activity had provided benefits for the treatment of GBM. Treatment of gliomas are limited because of their heterogenity. Although the current treatment strategy consists of radiotherapy and chemotherapy, the average survival of patients remain 15 months. Temozolomide (TMZ) is a DNA alkylating chemoterapeutic agent. Intrinsic or acquired resistance is an obstacle for efficiency of drug in successful TMZ treatment. Hedgehog signaling pathway plays crucial roles in cellular growth and differentiation during embryonic period and is also associated with several cancer types, including GBM. Vismodegib (VIS) is a FDA approved Hh inhibitor that was designed for metastatic and basal cell carcinoma treatment. VIS inhibits the proliferation of tumor cells without inhibiting normal cells proliferation. Currently, it is considered that necrosis is a controlled and programmed cell death mechanism as apoptosis, for that reason it is named as programmed necrosis or necroptosis. The aim of this study is to detect the cytotoxic and apoptotic effects of combination of TMZ and VIS on human brain cancer stem cell and human neuronal stem cell lines and also to determine the chances in gene expressions levels related to necroptosis and Hh pathway. As a result, the combination of TMZ and VIS induced apoptosis on human brain cancer stem cell line. Significant changes on gene expressions which are related to necroptosis and Hh pathway were obtained. In this regard, we suggest that this approach may provide a novel strategy for brain cancer therapy.
Açıklama
Anahtar Kelimeler
Tıbbi Biyoloji, Medical Biology
