Combination therapy with  Selenourea and Ethacrynic acid targeting GST inhibition and reveals  some apoptosis-cleaved proteins in breast cancer

Berna Özdem; Işıl Yıldırım

Makale detayları

Combination therapy with Selenourea and Ethacrynic acid targeting GST inhibition and reveals some apoptosis-cleaved proteins in breast cancer

Yazarlar:

Berna Özdem | Işıl Yıldırım

Yayıncı:

Kocaeli University

Ana Başlıklar:

Enzimler | Hücre Gelişimi | Proliferasyon ve Ölümü

Dergi:

Acta Medica Nicomedia Vol.8 Issue 2, pp.202-211

Belge Tipi:

Makale

Yayın Tarihi:

6/2025

Belge Dili:

İngilizce

Document ID (Org No.):

2001353783

pISSN:

2717-8994

Anahtar kelimeler:

Özet:

 Abstract Abstract Objective: Glutathione S-transferase GST participates in the maintenance of cellular redox homeostasis through several mechanisms. At the same time, GST enzyme causes the development of resistance, especially chemotherapeutic drugs. This development of resistance is associated with altered drug permeability and increased levels of Glutathione GSH and GST enzymes in the cell. Therefore, compounds or drug-like drugs that GSTs as their target are important for preclinical and clinical studies. In particular, molecular docking new ligands to a protein target by virtual screening efficiently represents drug metabolism enzymes. We hypothesized that inhibition of GST by selenourea and Etacrynic acid combination sensitizes breast cancer cells to apoptotic signaling by altering redox homeostasis, leading to the identification of specific apoptosis-cleaved proteins that drive cell death pathways. Methods: This study was carried out to demonstrate the binding and inhibition effect of selenourea compound to glutathione S-transferase enzymes GSTs for the structure-based design is the biggest obstacle. So, different GST enzyme sub-types of appropriate molecular docking were used. Also, we analyzed cell proliferation with MTS and protein expression with western blot analysis of combination therapy with selenourea and Etacrynic acid to target GST inhibition and revealed apoptosis-cleaved proteins in estrogen positive MCF7 cell and non-estrogenic MDA-MB-231breast cancer. Results: In the results, it was found that selenourea acts through targeting by indirect S-glutathionylation modification of cysteine residues in target proteins, although its polar covalent bond, hydrogen bond, and ionic interaction bind to other amino acids in all sub-types of GST. The combination of selenourea and etacrynic acid dose-dependently inhibited cell proliferation. Selenourea and Etacrynic acid combination exhibited important statistical difference in both cell p0.0001. Selenourea only exhibited 52  and 50  inhibition on MDA-MB-231 and MCF7 cell, while Selenourea and Etacrynic acid combination exhibited 41 and 38 inhibition on MDA-MB-231 cell and MCF7 cell, respectively. Conclusions: This work may be provided a practical guide and useful insights into new therapeutics. This could be considered a very promising strategy for the development of new antineoplastic drugs. Targeting identified proteins, in combination with GST inhibition, enhances therapeutic efficacy.

 Abstract Abstract Objective: Glutathione S-transferase GST participates in the maintenance of cellular redox homeostasis through several mechanisms. At the same time, GST enzyme causes the development of resistance, especially chemotherapeutic drugs. This development of resistance is associated with altered drug permeability and increased levels of Glutathione GSH and GST enzymes in the cell. Therefore, compounds or drug-like drugs that GSTs as their target are important for preclinical and clinical studies. In particular, molecular docking new ligands to a protein target by virtual screening efficiently represents drug metabolism enzymes. We hypothesized that inhibition of GST by selenourea and Etacrynic acid combination sensitizes breast cancer cells to apoptotic signaling by altering redox homeostasis, leading to the identification of specific apoptosis-cleaved proteins that drive cell death pathways. Methods: This study was carried out to demonstrate the binding and inhibition effect of selenourea compound to glutathione S-transferase enzymes GSTs for the structure-based design is the biggest obstacle. So, different GST enzyme sub-types of appropriate molecular docking were used. Also, we analyzed cell proliferation with MTS and protein expression with western blot analysis of combination therapy with selenourea and Etacrynic acid to target GST inhibition and revealed apoptosis-cleaved proteins in estrogen positive MCF7 cell and non-estrogenic MDA-MB-231breast cancer. Results: In the results, it was found that selenourea acts through targeting by indirect S-glutathionylation modification of cysteine residues in target proteins, although its polar covalent bond, hydrogen bond, and ionic interaction bind to other amino acids in all sub-types of GST. The combination of selenourea and etacrynic acid dose-dependently inhibited cell proliferation. Selenourea and Etacrynic acid combination exhibited important statistical difference in both cell p0.0001. Selenourea only exhibited 52  and 50  inhibition on MDA-MB-231 and MCF7 cell, while Selenourea and Etacrynic acid combination exhibited 41 and 38 inhibition on MDA-MB-231 cell and MCF7 cell, respectively. Conclusions: This work may be provided a practical guide and useful insights into new therapeutics. This could be considered a very promising strategy for the development of new antineoplastic drugs. Targeting identified proteins, in combination with GST inhibition, enhances therapeutic efficacy.

 Abstract Abstract Objective: Glutathione S-transferase GST participates in the maintenance of cellular redox homeostasis through several mechanisms. At the same time, GST enzyme causes the development of resistance, especially chemotherapeutic drugs. This development of resistance is associated with altered drug permeability and increased levels of Glutathione GSH and GST enzymes in the cell. Therefore, compounds or drug-like drugs that GSTs as their target are important for preclinical and clinical studies. In particular, molecular docking new ligands to a protein target by virtual screening efficiently represents drug metabolism enzymes. We hypothesized that inhibition of GST by selenourea and Etacrynic acid combination sensitizes breast cancer cells to apoptotic signaling by altering redox homeostasis, leading to the identification of specific apoptosis-cleaved proteins that drive cell death pathways. Methods: This study was carried out to demonstrate the binding and inhibition effect of selenourea compound to glutathione S-transferase enzymes GSTs for the structure-based design is the biggest obstacle. So, different GST enzyme sub-types of appropriate molecular docking were used. Also, we analyzed cell proliferation with MTS and protein expression with western blot analysis of combination therapy with selenourea and Etacrynic acid to target GST inhibition and revealed apoptosis-cleaved proteins in estrogen positive MCF7 cell and non-estrogenic MDA-MB-231breast cancer. Results: In the results, it was found that selenourea acts through targeting by indirect S-glutathionylation modification of cysteine residues in target proteins, although its polar covalent bond, hydrogen bond, and ionic interaction bind to other amino acids in all sub-types of GST. The combination of selenourea and etacrynic acid dose-dependently inhibited cell proliferation. Selenourea and Etacrynic acid combination exhibited important statistical difference in both cell p0.0001. Selenourea only exhibited 52  and 50  inhibition on MDA-MB-231 and MCF7 cell, while Selenourea and Etacrynic acid combination exhibited 41 and 38 inhibition on MDA-MB-231 cell and MCF7 cell, respectively. Conclusions: This work may be provided a practical guide and useful insights into new therapeutics. This could be considered a very promising strategy for the development of new antineoplastic drugs. Targeting identified proteins, in combination with GST inhibition, enhances therapeutic efficacy.

 Amaç: Glutatyon S-transferaz GST, çeşitli mekanizmalar aracılığıyla hücresel redoks homeostazının korunmasına katılır. Aynı zamanda GST enzimi, özellikle kemoterapötik ilaçlar olmak üzere direnç gelişimine neden olmaktadır. Bu direnç gelişimi, değişen ilaç geçirgenliği ve hücredeki Glutatyon GSH ve GST enzimlerinin seviyelerinin artmasıyla ilişkilidir. Bu nedenle, GSTlerin hedef olduğu bileşikler veya ilaç benzeri ilaçlar preklinik ve klinik çalışmalar için önemlidir. Özellikle, sanal tarama yoluyla yeni ligandların bir protein hedefine moleküler olarak yerleştirilmesi, ilaç metabolizması enzimlerini verimli bir şekilde temsil eder. GSTnin selenoüre ve Etakrinik asit kombinasyonu ile inhibisyonunun, redoks homeostazını değiştirerek meme kanseri hücrelerini apoptotik sinyale duyarlı hale getirdiğini ve hücre ölüm yollarını yönlendiren spesifik apoptoz bölünmüş proteinlerin tanımlanmasına yol açtığını varsaydık. Yöntemler: Bu çalışma, selenoüre bileşiğinin glutatyon S-transferaz enzimlerine GSTs bağlanma ve inhibisyon etkisini göstermek için gerçekleştirilmiştir. Bu nedenle, uygun moleküler yerleştirmenin farklı GST enzim alt tipleri kullanılmıştır. Ayrıca, GST inhibisyonunu hedeflemek için selenoüre ve Etakrinik asit ile kombinasyon tedavisinin MTS ile hücre proliferasyonunu ve western blot analizi ile protein ekspresyonunu analiz ettik ve östrojen pozitif MCF7 hücresinde ve östrojenik olmayan MDA-MB-231 meme kanserinde apoptozla parçalanan proteinleri ortaya çıkardık. Sonuçlar: Sonuçlarda, selenoürenin, polar kovalent bağı, hidrojen bağı ve iyonik etkileşimi GSTnin tüm alt tiplerindeki diğer amino asitlere bağlanmasına rağmen, hedef proteinlerdeki sistein kalıntılarının dolaylı S-glutatyonilasyon modifikasyonu ile hedefleme yoluyla etki ettiği bulunmuştur. Selenoüre ve etakrinik asit kombinasyonu hücre proliferasyonunu doza bağlı olarak inhibe etmiştir. Selenoüre ve Etakrinik asit kombinasyonu her iki hücrede de önemli istatistiksel farklılık sergilemiştir p0.0001. Selenoüre sadece MDA-MB-231 ve MCF7 hücreleri üzerinde 52 ve 50 inhibisyon gösterirken, Selenoüre ve Etakrinik asit kombinasyonu MDA-MB-231 hücresi ve MCF7 hücresi üzerinde sırasıyla 41 ve 38 inhibisyon göstermiştir. Sonuç: Sonuç olarak, bu kapsamlı inceleme ve derin öğrenme uygulaması, yeni terapötikler için pratik bir rehber ve faydalı bilgiler sağlayabilir. Bu, yeni antineoplastik ilaçların geliştirilmesi için çok umut verici bir strateji olarak düşünülebilir. Tanımlanan proteinlerin GST inhibisyonu ile birlikte hedeflenmesi, terapötik etkinliği artırır.

Makale detayları

Combination therapy with Selenourea and Ethacrynic acid targeting GST inhibition and reveals some apoptosis-cleaved proteins in breast cancer

Yazarlar:

Berna Özdem | Işıl Yıldırım

Yayıncı:

Kocaeli University

Ana Başlıklar:

Enzimler | Hücre Gelişimi | Proliferasyon ve Ölümü

Dergi:

Acta Medica Nicomedia Vol.8 Issue 2, pp.202-211

Belge Tipi:

Makale

Yayın Tarihi:

6/2025

Belge Dili:

İngilizce

Document ID (Org No.):

2001353783

pISSN:

2717-8994

Selenourea

GST

ADME analysis

protein-ligand interaction

signal pathway analysis.Selenourea

GST

ADME analizi

protein-ligand etkileşimi

sinyal yolu analizi.

Sayı

Makale detayları

Yazarlar: Berna Özdem | Işıl Yıldırım

Yayıncı: Kocaeli University

Ana Başlıklar: Enzimler | Hücre Gelişimi | Proliferasyon ve Ölümü

Dergi: Acta Medica Nicomedia Vol.8 Issue 2, pp.202-211

Belge Tipi: Makale

Yayın Tarihi: 6/2025

Belge Dili: İngilizce

Document ID (Org No.): 2001353783

pISSN: 2717-8994

Sayı

Yazarlar:

Berna Özdem | Işıl Yıldırım

Yayıncı:

Kocaeli University

Ana Başlıklar:

Enzimler | Hücre Gelişimi | Proliferasyon ve Ölümü

Dergi:

Acta Medica Nicomedia Vol.8 Issue 2, pp.202-211

Belge Tipi:

Makale

Yayın Tarihi:

6/2025

Belge Dili:

İngilizce

Document ID (Org No.):

2001353783

pISSN:

2717-8994