MCF-7 Hücrelerinde ATP‐Bağlayıcı Kaset Taşıyıcıları Aracılı Kemorezistansın PhTAD-Sübstitüe Dihidropirol Bileşikleri ile Modülasyonu

Year 2022, , 77 - 85, 22.04.2022

Burak Yazgan , Seda Mesci , Maşuk Akşahın , Arif Ayar , Melek Gül , Tuba Yıldırım

https://doi.org/10.46332/aemj.896830

Abstract

Amaç: ABC proteinleri, antibiyotikler ve ilaçlar gibi birçok substratı taşır. ABC'lerin artması kanserde kemorezistansa yol açmak-tadır.
Bu bilgiler ışığında, çalışmamızda hem PhTAD türevli dihidropirol bileşiklerinin MCF7 hücrelerinde ABC Transporterların gen ekspresyonları üzerindeki etkisini hem de bu bileşikler için insan ABCB1 yapısını hedef alan öngörücü moleküler bağlanma bölgelerini araştırmayı planladık.
Araçlar ve Yöntem: MCF-7 hücrelerindeki ABCB1, ABCC3, ABCC10, ABCC11 ve ABCG2'nin mRNA ekspresyon seviyeleri qPCR ile ölçülmüştür. Moleküler kenetlenme testleri hem AutoDock Tools 4.2 hem de PyMOL 2.4 programları ile gerçekleştirilmiştir. Ayrıca etkileşim analizi ProteinsPlus web servisi üzerinden yapılmıştır.
Tartışma: Bulgularımız, PhTAD ikameli dihidropirol içeren moleküllerin, kanser kemoresiztansının potansiyel bir düzenleyicisi olan ABC Transporterları etkilediğini göstermektedir.
Sonuç: Sonuçlarımız, bileşik (B) I, BII, BIII, BV, BVIII ve BXII'nin ABCB1'i artırdığını, BIV, BVI, BVII, BX, BIX, BXI, BXIII ve BXIV'ün ise ABCB1'i azalttığını ortaya koymuştur. Ayrıca, BI, BIV, BVI ve BVIII, ABCC3'ü yukarı regüle etmesine rağmen, BVII, BX, BXII, BXIII ve BXIV, ABCC3'ü aşağı regüle eder. Ayrıca, tüm bileşikler ABCC10 ekspresyonunu arttırmıştır. Tersine, ABCC11’in ekspresyonu ise tüm bileşikler tarafından azaltılmıştır. Ayrıca BII, BV ve BVI, ABCG2'yi artırırken, BI, BVII, BVIII, BIX, BX, BXI, BXII, BXIII ve BXIV, ABCG2'yi azaltmıştır. Bunun yanında ABCB1, ABCC3, ABCC11 ve ABCG2 miktarları, BVII, BIX, BX, BXI, BXIII ve BXIV ile paralel olarak azalmıştır. Ayrıca, yüksek bağlanma enerjisine sahip BXI ve BXIV'ün moleküler kenetlenme hesaplama sonuçları, ABCB1'in sıkı bir şekilde modüle edildiğini göstermiştir. Özellikle bu bileşikler, ABCB1 üzerindeki birçok hidrojen bağlama ve hidrofobik bölge ile etkileşime girmektedir.

Keywords

Meme kanseri, PhTAD-dihidropirol, kemorezistans, ABCB1, ABCC3

Thanks

Yazarlar, Amasya Üniversitesi Merkez Araştırma Laboratuvarı'na (AUMAULAB) tesislerini kullanma konusundaki anlayışları için teşekkür eder.

ATP‐Binding Cassette Transporters Mediated Chemoresistance in MCF-7 Cells: Modulation by PhTAD-Substituted Dihydropyrrole Compounds

Abstract

Purpose: ABC proteins transport many substrates such as antibiotics and drugs. Increase of ABCs lead chemoresistance in can-cer.
In view of this information, in our study, we planned to investigate both PhTAD-substituted dihydropyrrole compound's impact on gene expressions of ABC Transporters in the MCF7 cells, and predictive molecular binding sites target on human ABCB1 structure for these compounds.
Materials and Methods: The mRNA expression levels of ABCB1, ABCC3, ABCC10, ABCC11, and ABCG2 in the MCF-7 cell were measured by qPCR. Molecular docking assays were realized with both the AutoDock Tools 4.2 and PyMOL 2.4. Also, the interaction analysis was performed by ProteinsPlus web service.
Results: Our results revealed that CI, CII, CIII, CV, CVIII, and CXII increased ABCB1 while compound CIV, CVI, CVII, CX, CIX, CXI, CXIII, and CXIV decreased ABCB1. Besides, CI, CIV, CVI, and CVIII upregulate ABCC3, although CVII, CX, CXII, CXIII, and CXIV downregulate ABCC3. Moreover, ABCC10 expression is induced by all compounds. Conversely, ABCC11 expression is reduced by all compounds. Furthermore, CII, CV, and CVI increased ABCG2, while CI, CVII, CVIII, CIX, CX, CXI, CXII, CXIII, and CXIV decreased ABCG2. Also, ABCB1, ABCC3, ABCC11, and ABCG2 parallelly reduced by CVII, CIX, CX, CXI, CXIII, and CXIV. Also, the molecular docking calculation results of CXI and CXIV with high binding energy have shown that tightly modulated ABCB1. Especially, these compounds interact with many hydrogen bonding and hydrophobic site on ABCB1.
Conclusion: Our findings indicate that the PhTAD-substituted dihydropyrol containing molecules affect ABC transporters as a potential regulator of cancer chemoresistance.

Keywords

Breast Cancer, PhTAD-Dihydropyrrole, Chemoresistance, ABCB1, ABCC3

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