EXPANDING REMDESIVIR’S THERAPEUTIC SPECTRUM FROM ANTIVIRAL PROPERTIES TO ANTICANCER ACTIVITY THROUGH MTOR INHIBITION

Öz

Objective: The dysregulation of the mammalian target of rapamycin (mTOR) pathway is a prominent feature of various cancers, rendering it an attractive target for therapeutic intervention. While some mTOR inhibitors have been employed in cancer treatment, their use is often associated with significant complications. Here, we propose a novel approach to drug repurposing, focusing on Remdesivir, a known antiviral agent, as a potential mTOR inhibitor for cancer therapy.

Material and Method: In this study to evaluate the effect of Remdesivir on mTOR patway we performed in silico molecular docking and in vitro experiments including MTT, ELISA, qPCR, and Western Blotting with Caco2 colorectal cancer cells.

Result and Discussion: Through computational analyses, we conducted in-silico screenings to identify Remdesivir's interaction with the mTOR protein. Our findings suggest promising binding affinity and molecular interactions, indicating the potential for Remdesivir to inhibit mTOR activity. To validate this hypothesis, we performed molecular experiments using Caco2 colorectal cancer cells to investigate Remdesivir's ability to suppress epithelial-mesenchymal transition (EMT), a critical process in cancer metastasis, following mTOR inhibition. Our study represents a significant advancement in identifying new therapeutic targets using computational methodologies. Repurposing Remdesivir as an mTOR inhibitor offers a cost-effective and expedited approach to drug development, leveraging its known safety profile. Additionally, our findings suggest the potential for Remdesivir to reduce cancer progression by targeting the mTOR pathway and suppressing   EMT-associated   processes.   Overall,   this  study   underscores   the   promise  of computational drug repurposing in expediting the discovery of targeted therapies. The successful validation of Remdesivir as an mTOR inhibitor paves the way for advanced preclinical and clinical investigations, providing a fresh perspective on cancer treatment and therapeutic innovation.

Anahtar Kelimeler

• Anticancer drug development
• drug repurposing
• mTOR inhibition
• remdesivir bioactivity

REMDESİVİRİN TERAPÖTİK SPEKTRUMUNUN MTOR İNHİBİSYONU ARACILIĞIYLA ANTIVİRAL ÖZELLİKLERDEN ANTİKANSER AKTİVİTESİNE GENİŞLETİLMESİ

Öz

Amaç: Memelilerde rapamisin hedefi (mTOR) yolunun düzensizliği, çeşitli kanser türlerinde belirgin bir özelliktir ve bu da onu terapötik müdahaleler için cazip bir hedef haline getirir. Bazı mTOR inhibitörleri kanser tedavisinde kullanılmış olsa da bu ilaçların kullanımı genellikle önemli komplikasyonlarla ilişkilidir. Bu çalışmada, ilaç yeniden konumlandırmaya yönelik yeni bir yaklaşım öneriyoruz: bilinen bir antiviral ajan olan Remdesivir'in, kanser tedavisinde potansiyel bir mTOR inhibitörü olarak değerlendirilmesi.

Gereç ve Yöntem: Bu çalışmada Remdesivir'in mTOR yolağı üzerindeki etkisini değerlendirmek için in silico moleküler kenetlenme (docking) ve in vitro Caco2 kolorektal kanser hücreleri ile MTT, ELISA, qPCR ve Western Blotting yöntemleri ile analiz edilmiştir.

Sonuç ve Tartışma: Hesaplamalı analizler yoluyla, Remdesivir’in mTOR proteini ile etkileşimini belirlemek amacıyla in-silico taramalar gerçekleştirdik. Bulgularımız, Remdesivir’in mTOR aktivitesini inhibe etme potansiyelini ortaya koyan umut verici bağlanma afinitesi ve moleküler etkileşimler göstermektedir. Bu hipotezi doğrulamak için, mTOR inhibisyonu sonrasında kanser metastazında kritik bir süreç olan epitel-mezenkimal geçişi (EMT) baskılayıp baskılamadığını incelemek üzere Caco2 kolorektal kanser hücreleri kullanılarak moleküler deneyler gerçekleştirildi. Çalışmamız, hesaplamalı yöntemlerle yeni terapötik hedeflerin belirlenmesinde önemli bir ilerleme sunmaktadır. Remdesivir’in mTOR inhibitörü olarak yeniden konumlandırılması, bilinen güvenlik profili sayesinde maliyet etkin ve hızlandırılmış bir ilaç geliştirme yaklaşımı sunmaktadır. Ayrıca, bulgularımız Remdesivir’in mTOR yolaklarını hedefleyerek ve EMT ile ilişkili süreçleri baskılayarak kanser ilerlemesini azaltma potansiyeline sahip olduğunu göstermektedir. Genel olarak, bu çalışma, hedefe yönelik tedavilerin keşfini hızlandırmada hesaplamalı ilaç yeniden konumlandırmanın vaatlerini vurgulamaktadır. Remdesivir’in mTOR inhibitörü olarak başarılı şekilde doğrulanması, ileri düzey preklinik ve klinik araştırmaların önünü açmakta ve kanser tedavisinde yenilikçi bir bakış açısı sunmaktadır.

Anahtar Kelimeler

• Antikanser ilaç geliştirme
• ilaç yeniden hedefleme
• mTOR inhibisyonu
• remdesivir biyoaktivitesi

Kaynakça

1. 1. Afrin, H., Salazar, C.J., Kazi, M., et al. (2022). Methods of screening, monitoring and management of cardiac toxicity induced by chemotherapeutics. Chinese Chemical Letters, 33(6), 2773-2782. [CrossRef]
2. 2. Siegel, R.L., Miller, K.D., Fuchs, H.E., et al. (2021). Erratum to “cancer statistics, 2021”. CA:A Cancer Journal for Clinicians, 71(4), 359-359. [CrossRef]
3. 3. Alshehri, S., Imam, S.S., Rizwanullah, M.D., et al. (2021). Progress of cancer nanotechnology as diagnostics, therapeutics, and theranostics nanomedicine: Preclinical promise and translational challenges. Pharmaceutics, 13(1), 24. [CrossRef]
4. 4. Feng, T.T., Zheng, L., Liu, F., et al. (2016). Growth factor progranulin promotes tumorigenesis of cervical cancer via PI3K/Akt/mTOR signaling pathway. Oncotarget, 7(36), 58381-58395. [CrossRef]
5. 5. Li, X.Y., Yang, Q.F., Yu, H.Y., et al. (2014). LIF promotes tumorigenesis and metastasis of breast cancer through the AKT-mTOR pathway. Oncotarget, 5(3), 788-801. [CrossRef]
6. 6. Rousseau, B., Guillemin, A., Duvoux, C., et al. (2019). Optimal oncologic management and mTOR inhibitor introduction are safe and improve survival in kidney and liver allograft recipients with carcinoma. International Journal of Cancer, 144(4), 886-896. [CrossRef]
7. 7. Yu, S.W., Shen, G.X., Khor, T.O., et al. (2008). Curcumin inhibits Akt/mammalian target of rapamycin signaling through protein phosphatase-dependent mechanism. Molecular Cancer Therapeutics, 7(9), 2609-2620. [CrossRef]
8. 8. Papavassiliou, K.A., Zoi, I., Gargalionis, A.N., et al. (2019). Polycystin-1 affects cancer cell behaviour and interacts with mTOR and Jak signalling pathways in cancer cell lines. Journal of Cellular and Molecular Medicine, 23(9), 6215-6227. [CrossRef]

9. 9. Wu, X.J., Li, S.H., Hu, X., et al. (2019). mTOR signaling upregulates CDC6 via suppressing miR-3178 and promotes the loading of DNA replication helicase. Scientific Reports, 9, 9805. [CrossRef]
10. 10. Dong, Y.Y., Gong, Y.X., Kuo, F.S., et al. (2022). Targeting the mTOR pathway in hurthle cell carcinoma results in potent antitumor activity. Molecular Cancer Therapeutics, 21(2), 382-394. [CrossRef]
11. 11. Morgan, T.M., Koreckij, T.D., Corey, E. (2009). Targeted therapy for advanced prostate cancer: Inhibition of the PI3K/Akt/mTOR pathway. Current Cancer Drug Targets, 9(2), 237-249. [CrossRef]
12. 12. German, S., Aslam, H.M., Saleem, S., et al. (2013). Carcinogenesis of PIK3CA. Hereditary Cancer in Clinical Practice, 11, 5. [CrossRef]
13. 13. Okui, T., Shimo, T., Fukazawa, T., et al. (2010). Antitumor effect of temsirolimus against oral squamous cell carcinoma associated with bone destruction. Molecular Cancer Therapeutics, 9(11), 2960-2969. [CrossRef]
14. 14. Matsubara, S., Ding, Q., Miyazaki, Y., et al. (2013). mTOR plays critical roles in pancreatic cancer stem cells through specific and stemness-related functions. Scientific Reports, 3, 3230. [CrossRef]
15. 15. Lee, Y.K., Lee, W.S., Kim, G.S., et al. (2010). Anthocyanins are novel AMPKα1 stimulators that suppress tumor growth by inhibiting mTOR phosphorylation. Oncology Reports, 24(6), 1471-1477. [CrossRef]
16. 16. McMahon, J.H., Udy, A., Peleg, A.Y. (2020). Remdesivir for the treatment of Covid-19-preliminary report. New England Journal of Medicine, 383(10), 992-993. [CrossRef]
17. 17. Frediansyah, A., Nainu, F., Dhama, K., et al. (2021). Remdesivir and its antiviral activity against COVID-19: A systematic review. Clinical Epidemiology and Global Health, 9, 123-127. [CrossRef]
18. 18. Lamb, Y.N. (2020). Remdesivir: First Approval. Drugs, 80(13), 1355-1363. [CrossRef]
19. 19. Malik, M.I., Zafar, S.A., Malik, M., et al. (2022). The utility of remdesivir in SARS-CoV-2: A single tertiary care center experience from a developing country. Exploratory Research in Clinical and Social Pharmacy, 5, 100107. [CrossRef]
20. 20. Doggrell, S.A. (2020). Remdesivir, a remedy or a ripple in severe COVID-19? Expert Opinion on Investigational Drugs, 29(11), 1195-1198. [CrossRef]
21. 21. Wakchaure, P.D., Ghosh, S., Ganguly, B. (2020). Revealing the inhibition mechanism of RNA-Dependent RNA Polymerase (RdRp) of SARS-CoV-2 by remdesivir and nucleotide analogues: A molecular dynamics simulation study. Journal of Physical Chemistry B, 124(47), 10641-10652. [CrossRef]
22. 22. Eberhardt, J., Santos-Martins, D., Tillack, A.F., et al. (2021). AutoDock Vina 1.2.0: New docking methods, expanded force field, and python bindings. Journal of Chemical Information and Modeling, 61(8), 3891-3898. [CrossRef]
23. 23. Trott, O., Olson, A.J. (2010). Software news and update autodock vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of Computational Chemistry, 31(2), 455-461. [CrossRef]
24. 24. Bui, B.P., Nguyen, P.L., Lee, K., et al. (2022). Hypoxia-Inducible Factor-1: A novel therapeutic target for the management of cancer, drug resistance, and cancer-related pain. Cancers, 14(24), 6054. [CrossRef]
25. 25. Ribatti, D., Tamma, R., Annese, T. (2020). Epithelial-mesenchymal transition in cancer: A historical overview. Translational Oncology, 13(6), 100773. [CrossRef]
26. 26. Levien, T.L., Baker, D.E. (2023). Remdesivir. Hospital Pharmacy, 58(5), 420-430. [CrossRef]
27. 27. Panwar, V., Singh, A., Bhatt, M., et al. (2023). Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease. Signal Transduction and Targeted Therapy, 8(1), 375. [CrossRef]
28. 28. Gomez-Pinillos, A., Ferrari, A.C. (2012). mTOR signaling pathway and mTOR inhibitors in cancer therapy. Hematology-Oncology Clinics of North America, 26(3), 483-505. [CrossRef]
29. 29. Pallet, N., Legendre, C. (2013). Adverse events associated with mTOR inhibitors. Expert Opinion on Drug Safety, 12(2), 177-186. [CrossRef]
30. 30. Zou, Z.L., Tao, T., Li, H.M., et al. (2020). mTOR signaling pathway and mTOR inhibitors in cancer: Progress and challenges. Cell and Bioscience, 10(1), 31. [CrossRef]