Kemoterapi öncesi hücre içi homeostazının değiştirilmesinin prostat kanser hücre sağkalımına ve kanser kök hücre profiline etkisi
Küçük Resim Yok
Tarih
2023
Yazarlar
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Trakya Üniversitesi
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Kemoterapi, günümüzde kanser tedavisinde başvurulan en önemli terapi seçeneklerinden birisidir. Bununla birlikte, kemoterapötik ajanların yan etkileri ve ilaç direnci gelişimi hastanın yaşam süresini kısıtlayan sorunların başında gelmektedir. Taksol grubu kemoterapi ajanları, androjen deprivasyon tedavisine yanıt vermeyen kastrasyon-dirençli prostat kanseri terapisinde başvurulan temel bir yöntemdir. Ancak, bu hastaların önemli bir kısmında taksol tedavisine cevap oluşmayarak ilaç direnci gelişebilmekte, metastaz ve nüksle sonuçlanabilmektedir. Bu tez çalışmasının amacı, taksol tedavisi öncesi PCa hücrelerinin kemoterapiye duyarlılığını artırmaktır. Böylece daha düşük taksol dozu ile daha etkili terapi sağlayarak ilacın yan etkilerinin azaltılması hedeflenmektedir. Tümör kütlesinde az sayıda bulunan kanser kök hücreleri terapi direnci gelişimi ve metastazdan sorumlu tutulur. Bu sebeple, tedavi öncesinde gerçekleştirilen uygulamaların kanser kök hücrelerini de elimine etmesi planlanmıştır. Çalışmada kanser kök hücrelerine seçicilik gösteren salinomisin hücre içi potasyum (K+) iyon dengesini, Wnt yolağı inhibitörü de hücresel proliferasyon işlevini bozmak amacıyla kullanılarak kanser hücrelerinin kabazitaksel tedavisine olan duyarlılığı artırılmıştır. Araştırmada insan kastrasyon-dirençli prostat kanseri PC3 hücre serisi kullanılmıştır. Hücreler 0,5 µM salinomisin ve 6,25 µM Wnt yolağı inhibitörü kombinasyonu ile ön uygulama (48 saat) sonrası yeni nesil taksol kabazitaksel ile (48 saat) tedavi edilmiştir. Hücre sağkalımı, apoptoz ve hücre döngüsü analizleri sırasıyla MTT testi, anneksin V kullanılarak sitometrik yöntemle belirlenmiştir. Hücre göçü, yara iyileşmesi deneyi ile değerlendirilmiştir. Tedaviler sonrası kanser kök hücre pluripotensi gücü ve başlıca hücre içi sinyal yolak analizleri kantitatif PCR ve Western blot tekniği ile analiz edilmiştir. Elde edilen veriler, PCa tedavisinde kemoterapi etkinliğini artırması, ilaç direnci ve nüks riskini düşürmesi yönünde literatüre katkı sağlamıştır.
Chemotherapy is one of the most important treatment options used in cancer therapy today. However, the side effects of chemotherapeutic agents and the development of drug resistance are major problems that limit the patient's lifespan. Taxane-based chemotherapy agents are a fundamental method used in the treatment of castration-resistant prostate cancer that does not respond to androgen deprivation therapy. However, a significant portion of these patients may develop drug resistance and result in metastasis and relapse due to a lack of response to taxane treatment. The aim of this thesis is to increase the sensitivity of prostate cancer cells to chemotherapy prior to taxane treatment, aiming to provide a more effective therapy with a lower taxane dosage and reduce the side effects of the drug. Cancer stem cells (CSCs), which are found in small numbers in tumor masses, are held responsible for the development of treatment resistance and metastasis. Therefore, the interventions performed before treatment are planned to eliminate CSCs as well. In the study, salinomycin, which exhibits selectivity towards cancer stem cells, was used to disrupt intracellular potassium (K+) ion balance, while a Wnt pathway inhibitor was used to disrupt cellular proliferation function, aiming to increase the sensitivity of cancer cells to cabazitaxel treatment. The human castration-resistant prostate cancer PC3 cells were used in the research. The cells were treated with a combination of 0.5 µM salinomycin and 6.25 µM Wnt pathway inhibitor after pre-treatment (48 hours) and then treated with the new generation taxane, cabazitaxel (48 hours). Cell survival, apoptosis, and cell cycle analyses were determined by the MTT test, flow cytometric method using annexin V, respectively. Cell migration was evaluated using a wound healing experiment. The pluripotency of CSCs and major intracellular signaling pathway analyses were quantitatively analyzed using PCR and Western blot techniques after treatments. The obtained data have contributed to the literature by increasing the effectiveness of chemotherapy in PCa treatment and reducing drug resistance and the risk of relapse.
Chemotherapy is one of the most important treatment options used in cancer therapy today. However, the side effects of chemotherapeutic agents and the development of drug resistance are major problems that limit the patient's lifespan. Taxane-based chemotherapy agents are a fundamental method used in the treatment of castration-resistant prostate cancer that does not respond to androgen deprivation therapy. However, a significant portion of these patients may develop drug resistance and result in metastasis and relapse due to a lack of response to taxane treatment. The aim of this thesis is to increase the sensitivity of prostate cancer cells to chemotherapy prior to taxane treatment, aiming to provide a more effective therapy with a lower taxane dosage and reduce the side effects of the drug. Cancer stem cells (CSCs), which are found in small numbers in tumor masses, are held responsible for the development of treatment resistance and metastasis. Therefore, the interventions performed before treatment are planned to eliminate CSCs as well. In the study, salinomycin, which exhibits selectivity towards cancer stem cells, was used to disrupt intracellular potassium (K+) ion balance, while a Wnt pathway inhibitor was used to disrupt cellular proliferation function, aiming to increase the sensitivity of cancer cells to cabazitaxel treatment. The human castration-resistant prostate cancer PC3 cells were used in the research. The cells were treated with a combination of 0.5 µM salinomycin and 6.25 µM Wnt pathway inhibitor after pre-treatment (48 hours) and then treated with the new generation taxane, cabazitaxel (48 hours). Cell survival, apoptosis, and cell cycle analyses were determined by the MTT test, flow cytometric method using annexin V, respectively. Cell migration was evaluated using a wound healing experiment. The pluripotency of CSCs and major intracellular signaling pathway analyses were quantitatively analyzed using PCR and Western blot techniques after treatments. The obtained data have contributed to the literature by increasing the effectiveness of chemotherapy in PCa treatment and reducing drug resistance and the risk of relapse.
Açıklama
Doktora
Anahtar Kelimeler
Biyoteknoloji, Biotechnology ; Genetik
