HSP27 inhibitörü brivudin'in bortezomible birlikte multiple myeloma tedavisinde kullanılabilirliğinin araştırılması
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Dosyalar
Tarih
2022
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Yayıncı
Aksaray Üniversitesi Fen Bilimleri Enstitüsü
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Multiple myeloma (MM) fonksiyonel olmayan monoklonal immunoglobilin üretiminden sorumlu malign plasma hücrelerinin kemik iliğinde birikmesiyle karakterize edilen hematolojik bir kanserdir. Son yıllarda myeloma hücrelerinde aşırı üretildiği rapor edilen ısı şok protein ailesinin küçük üyesi HSP27 şaperonun hem MM patogenezinde hem de tedaviye direnç gelişmesinde rol oynadığı gösterilmiştir. Myeloma tedavisinde özellikle bortezomib gibi proteasome inhibitörleri ile büyük ilerlemeler kaydedilmesine karşın, MM kinikte halen tam olarak tedavi edilemeyen bir kanser türüdür. Bu çalışmanın amacı klinikte antiviral tedavi için kullanılan biruvidinin bortezomible birlikte myeloma tedavisinde kullanılabilirliğini araştırmaktır. Bu amaç için brivudin (BRVD) ve bortezomibin (BZM) tek başına ve kombine olarak U266 ve RPMI-8226 insan myeloma hücre hatlarındaki sitotoksisiteleri MTT test kullanarak saptandı. BZM ve BRVD'nin her iki hücre hattında 48 saatteki IC50 dozları hesaplandı. BZM'in IC50 dozunda sabit, BRVD konsantrasyonunun değiştirildiği kombine ilaç uygulamalarının U266 ve RPMI-8226 hücre hatlarındaki sitotoksitesi belirlendi. BZM-BRVD etkileşimini değerlendirmek için kombinasyon indeks (CI) analizi yapıldı. Ayrıca BRVD ve BZM uygulamasının U266 ve RPMI-8226 hücre hatlarında HSP27 gen ifadesi üzerine etkisi real time RT-PCR yöntemi kullanarak araştırıldı. Sonuçta BRVD'nin IC50 değeri 48 saat için U266 ve RPMI-8226 hücre hatlarında sırasıyla 24.39 ?M ve 18,83 ?M olarak bulundu. BZM'in IC50 değeri ise 48 saat için U266 ve RPMI-8226 hücre hatlarında sırasıyla 13,75 nM ve 11,22 nM olarak bulundu. BZM'in IC50 dozu ile BRVD'nin 3.75, 7.5, 15 ve 30 ?M dozları kombine edildiğinde, BZM + 3.75 ?M BRVD kombinasyonunun her iki hücre hatında additif etkiye (CI=1), diğer tüm BRVD konsantrasyonlarının ise BZM'le birlikte doza bağlı olarak artan sinerjistik etkiye neden olduğu bulundu (CI<1). Ayrıca, BRVD'nin her iki hücre hatında HSP27 gen ifade düzeyinde kontrole göre anlamlı bir düşüşe neden olduğu saptandı (p<0.05). İlginç olarak BZM'in de her iki hücre hattında HSP27 gen ifade düzeyinde kontrole göre anlamlı bir azalmaya neden olduğunu bulundu (p<0.05). Sonuç olarak biz BRVD-BZM kombinasyonunun MM tedavisinde kullanılabileceğini ve tedavinin etkiliğinde HSP27 gen ifade düzeyinin baskılanmasının rol alabileceğini önerdik.
Multiple myeloma (MM) is a hematological cancer characterized by the accumulation of malignant plasma cells responsible for the production of nonfunctional monoclonal immunoglobulin in the bone marrow. HSP27, a small member of the heat shock protein family, has shown to play a role in both the pathogenesis of MM and the development of resistance to therapy. Although great progress has been made in the myeloma treatment especially with proteasome inhibitors such as bortezomib, MM cannot be fully cured in clinical practice. The aim of this study is to investigate the usability of biruvidin, an antiviral drug, in the treatment of myeloma combined with bortezomib. For this purpose, we detected the cytotoxicity of brivudine (BRVD) and bortezomib (BZM) alone or in combination in U266 and RPMI-8226 human myeloma cell lines using the MTT test. We calculated the IC50 doses at 48 hours for both cell lines of BZM and BRVD. We determined the cytotoxicity in U266 and RPMI-8226 cell lines by keeping the BZM constant at the IC50 dose and changing the BRVD concentration. We performed combination index (CI) analysis to evaluate the BZM-BRVD interaction. We also investigated the effect of BRVD and BZM application on HSP27 gene expression in U266 and RPMI-8226 cell lines using real time RT-PCR method. As a result, we found the IC50 dose of BRVD at 48 hours to be 24.39 ?M and 18.83 ?M, respectively. We found the IC50 value of BZM as 13.75 nM and 11.22 nM for 48 hours in U266 and RPMI-8226 cell lines, respectively. When the IC50 dose of BZM and the 3.75, 7.5, 15 and 30 ?M doses of BRVD are combined, the combination of BZM + 3.75 ?M BRVD has an additive effect (CI=1) on both cell lines, while all other BRVD concentrations with BZM caused an dose-dependent increased synergistic effect (CI<1). In addition, we showed that BRVD caused a significant decrease in HSP27 gene expression level in both cell lines compared to the control (p<0.05). Interestingly, we found that BZM caused a significant decrease in HSP27 gene expression level in both cell lines compared to the control (p<0.05). As a result, we suggested that the combination of BRVD-BZM can be used in the treatment of MM and suppression of the HSP27 gene expression level may play a role in the effectiveness of the treatment.
Multiple myeloma (MM) is a hematological cancer characterized by the accumulation of malignant plasma cells responsible for the production of nonfunctional monoclonal immunoglobulin in the bone marrow. HSP27, a small member of the heat shock protein family, has shown to play a role in both the pathogenesis of MM and the development of resistance to therapy. Although great progress has been made in the myeloma treatment especially with proteasome inhibitors such as bortezomib, MM cannot be fully cured in clinical practice. The aim of this study is to investigate the usability of biruvidin, an antiviral drug, in the treatment of myeloma combined with bortezomib. For this purpose, we detected the cytotoxicity of brivudine (BRVD) and bortezomib (BZM) alone or in combination in U266 and RPMI-8226 human myeloma cell lines using the MTT test. We calculated the IC50 doses at 48 hours for both cell lines of BZM and BRVD. We determined the cytotoxicity in U266 and RPMI-8226 cell lines by keeping the BZM constant at the IC50 dose and changing the BRVD concentration. We performed combination index (CI) analysis to evaluate the BZM-BRVD interaction. We also investigated the effect of BRVD and BZM application on HSP27 gene expression in U266 and RPMI-8226 cell lines using real time RT-PCR method. As a result, we found the IC50 dose of BRVD at 48 hours to be 24.39 ?M and 18.83 ?M, respectively. We found the IC50 value of BZM as 13.75 nM and 11.22 nM for 48 hours in U266 and RPMI-8226 cell lines, respectively. When the IC50 dose of BZM and the 3.75, 7.5, 15 and 30 ?M doses of BRVD are combined, the combination of BZM + 3.75 ?M BRVD has an additive effect (CI=1) on both cell lines, while all other BRVD concentrations with BZM caused an dose-dependent increased synergistic effect (CI<1). In addition, we showed that BRVD caused a significant decrease in HSP27 gene expression level in both cell lines compared to the control (p<0.05). Interestingly, we found that BZM caused a significant decrease in HSP27 gene expression level in both cell lines compared to the control (p<0.05). As a result, we suggested that the combination of BRVD-BZM can be used in the treatment of MM and suppression of the HSP27 gene expression level may play a role in the effectiveness of the treatment.
Açıklama
Anahtar Kelimeler
HSP27, Brivudin, Bortezomib, Multiple Myeloma
