Bortezomib dirençli multiple myeloma kanser hücre hatlarında hücre döngüsü kontrol noktaları ile ilişkili ilaç dirençliliğinin araştırılması
Yükleniyor...
Dosyalar
Tarih
2021
Yazarlar
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Aksaray Üniversitesi Fen Bilimleri Enstitüsü
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Multiple Myeloma (MM), kemik iliğinde malign plazma hücrelerinin birikmesiyle ile karakterize olan hematolojik bir kanser türüdür. Bortezomib multiple myeloma tedavisinde klinikte kullanılan en etkin kemoterapötik ilaçlardan biridir. Fakat kanser tedavisi sürecinde bortezomibe karşı dirençlilik sıklıkla karşılaşılan bir durumdur. Tümör hücrelerinde, ilaç taşıma proteinlerinin sentezinin artması, apoptozisin baskılanması ve hücre döngüsü kontrolünde yer alan düzenleme faktörlerindeki değişikler kemoterapötik ilaçlara karşı direnç oluşmasına sebep olan en önemli mekanizmalardır. Bu nedenle çalışmamızda, multiple myeloma kanser hücrelerinde gelişen bortezomib dirençliğinin hücre döngüsü kontrol noktalarında bulunan cyclin genleri ile ilişkisi araştırılmıştır. Bu çalışmada, multiple myeloma KMS-28 (bortezomibe hassas) ve KMS-20 (bortezomibe dirençli) hücre hatları çoğaltıldı. MTT testi uygulanarak her iki hücre hattı için bortezomibin IC50 değerleri saptandı. Hücre hatlarından RNA izolasyonu yapılarak cDNA sentezi gerçekleştirildi ve hücre döngüsü düzenleyici faktörleri olan Cyclin D1, Cyclin D2, Cyclin A1, Cyclin E1 ve Cyclin B1 genlerinin ifade düzeyleri Real-time PCR ile analiz edildi. Elde ettiğimiz bulgulara göre Cyclin A1 geninin bortezomibe hassas hücrelerde ifade edilmeyip, bortezomibe dirençli hücrelerdeki yüksek ifadesi (overekspresyon) bu genin multiple myelomada bortezomib dirençliliğinin gelişiminde doğrudan rolünün olduğunu göstermiştir. Cyclin D1 geni KMS-28'de aşırı ifade edilirken, KMS-20'de ise baskılanmıştır. Cyclin D1 genindeki bu değişikliklerin bortezomib dirençliliğine neden olabilceği düşünülmektedir. Sonuç olarak, multiple myelomada ilaç dirençliliğine yol açan mekanizmaların aydınlatılması, hastalığın moleküler düzeyde anlaşılmasını sağlayacak ve MM ile ilgili daha etkili tedavi seçeneklerinin oluşturulmasını olanak tanıyacaktır.
Multiple Myeloma (MM) is a type of hematological cancer characterized by the accumulation of malignant plasma cells in the bone marrow. Bortezomib is one of the most effective chemotherapeutic drugs used clinically in the treatment of multiple myeloma. However, resistance to bortezomib is a frequently encountered situation during the cancer treatment process. In tumor cells, increased synthesis of drug transport proteins, suppression of apoptosis and changes in regulation factors involved in cell cycle control are the most important mechanisms that cause resistance to chemotherapeutic drugs. Therefore, in our study, the relationship between bortezomib resistance in multiple myeloma cancer cells and cyclin genes at cell cycle checkpoints was investigated. In this study, multiple myeloma KMS-28 (bortezomib-sensitive) and KMS-20 (bortezomib-resistant) cell lines were propagated. Bortezomib IC50 values were determined for both cell lines by applying the MTT test. cDNA synthesis was performed by RNA isolation from cell lines and the expression levels of the cell cycle regulatory factors Cyclin D1, Cyclin D2, Cyclin A1, Cyclin E1 and Cyclin B1 genes were analyzed by Real-Time PCR. According to our findings, the Cyclin A1 gene is not expressed at all in bortezomib-sensitive cells, and its high expression (overexpression) in bortezomib-resistant cells has shown that this gene has a direct role in the development of bortezomib resistance in multiple myeloma. The Cyclin D1 gene is overexpressed in KMS-28 and suppressed in KMS-20. It is thought that these changes in the Cyclin D1 gene may cause bortezomib resistance. In conclusion, elucidating the mechanisms leading to drug resistance in multiple myeloma will provide an understanding of the disease at the molecular level and will enable more effective treatment options for MM.
Multiple Myeloma (MM) is a type of hematological cancer characterized by the accumulation of malignant plasma cells in the bone marrow. Bortezomib is one of the most effective chemotherapeutic drugs used clinically in the treatment of multiple myeloma. However, resistance to bortezomib is a frequently encountered situation during the cancer treatment process. In tumor cells, increased synthesis of drug transport proteins, suppression of apoptosis and changes in regulation factors involved in cell cycle control are the most important mechanisms that cause resistance to chemotherapeutic drugs. Therefore, in our study, the relationship between bortezomib resistance in multiple myeloma cancer cells and cyclin genes at cell cycle checkpoints was investigated. In this study, multiple myeloma KMS-28 (bortezomib-sensitive) and KMS-20 (bortezomib-resistant) cell lines were propagated. Bortezomib IC50 values were determined for both cell lines by applying the MTT test. cDNA synthesis was performed by RNA isolation from cell lines and the expression levels of the cell cycle regulatory factors Cyclin D1, Cyclin D2, Cyclin A1, Cyclin E1 and Cyclin B1 genes were analyzed by Real-Time PCR. According to our findings, the Cyclin A1 gene is not expressed at all in bortezomib-sensitive cells, and its high expression (overexpression) in bortezomib-resistant cells has shown that this gene has a direct role in the development of bortezomib resistance in multiple myeloma. The Cyclin D1 gene is overexpressed in KMS-28 and suppressed in KMS-20. It is thought that these changes in the Cyclin D1 gene may cause bortezomib resistance. In conclusion, elucidating the mechanisms leading to drug resistance in multiple myeloma will provide an understanding of the disease at the molecular level and will enable more effective treatment options for MM.
Açıklama
Anahtar Kelimeler
Multiple Myeloma, Bortezomib, Kanser, İlaç Dirençliliği, Hücre Döngüsü Siklin Genleri, Multiple Myeloma, Bortezomib, Cancer, Drug-Resistance, Cell Cycle Cyclin Genes
