Academic Journal
CB-RAF600E-1 exerts efficacy in vemurafenib-resistant and non-resistant-melanoma cells via dual inhibition of RAS/RAF/MEK/ERK and PI3K/Akt signaling pathways
| العنوان: | CB-RAF600E-1 exerts efficacy in vemurafenib-resistant and non-resistant-melanoma cells via dual inhibition of RAS/RAF/MEK/ERK and PI3K/Akt signaling pathways |
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| المؤلفون: | Mesfer Al Shahrani, Prasanna Rajagopalan, Mohammad Abohassan, Mohammad Alshahrani, Yasser Alraey |
| المصدر: | Saudi Journal of Biological Sciences, Vol 29, Iss 6, Pp 103285- (2022) |
| بيانات النشر: | Elsevier |
| سنة النشر: | 2022 |
| المجموعة: | Directory of Open Access Journals: DOAJ Articles |
| مصطلحات موضوعية: | High throughput, BRAFV600E, ERK, Akt, Melanoma, Vemurafenib, Biology (General), QH301-705.5 |
| الوصف: | Background and Aim: Predicting novel dual inhibitors to combat adverse effects such as the development of resistance to vemurafenib in melanoma treatment due to the reactivation of MAPK and PI3K/AKT signaling pathways is studied to help in reversal of cancer symptoms.Reversal of cancer symptoms in melanoma associated with vemurafenib resistance is driven by reactivation of MAPK and PI3K/Akt signaling pathways. Novel dual inhibitors targeting these proteins would be beneficial to combat resistance. Methods: High-throughput virtual screening of the ChemBridge library against B-RAFV600E and Akt was performed using an automated protocol with the AutoDock VINA program. Luminescence and time-resolved fluorescence kits were used to measure enzyme activities. The MTT assay was used to determine proliferation in normal and vemurafenib-resistant A375 cells. Flow cytometry was used to examine apoptosis, cell cycle, and phosphorylation of ERK/Akt signaling pathway. Results: High-throughput screening from the ChemBridge library identified 15 compounds with high binding energy towards B-RAFV600E; among these, CB-RAF600E-1 had the highest ΔGbinding score −11.9 kcal/mol. The compound also had a high affinity towards Akt, with a ΔGbinding score of −11.5 kcal/mol. CB-RAF600E-1 dose-dependently inhibited both B-RAFV600E and Akt with IC50 values of 635 nM and 154.3 nM, respectively. The compound effectively controlled the proliferations of normal and vemurafenib-resistant A375 cells, with GI50 values of 222.3 nM and 230.5 nM, respectively. A dose-dependent increase in the sub G0/G1 phase of the cell cycle and total apoptosis was observed following compound treatment in both normal and vemurafenib-resistant melanoma cells. Treatment with CB-RAF600E-1 decreased the pERK/pAkt dual-positive populations in normal and vemurafenib-resistant A375 cells. Conclusion: CB-RAF600E-1, identified as a novel dual inhibitor effective against normal and vemurafenib-resistant melanoma cells, requires further attention for development as an effective ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 1319-562X |
| Relation: | http://www.sciencedirect.com/science/article/pii/S1319562X22002017; https://doaj.org/toc/1319-562X; https://doaj.org/article/bccf224f52894445a76f53fa315aa65a |
| DOI: | 10.1016/j.sjbs.2022.103285 |
| الاتاحة: | https://doi.org/10.1016/j.sjbs.2022.103285 https://doaj.org/article/bccf224f52894445a76f53fa315aa65a |
| رقم الانضمام: | edsbas.FCD70493 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 1319562X |
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| DOI: | 10.1016/j.sjbs.2022.103285 |