Significance of Targeting VEGFR-2 and Cyclin D1 in Luminal-A Breast Cancer
| العنوان: | Significance of Targeting VEGFR-2 and Cyclin D1 in Luminal-A Breast Cancer |
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| المؤلفون: | Muhammad Ahmed, Waleed H. Malki, Imran Shahid, Ashraf N. Abdalla, Mohammad Akbar Hossain, Amal Qattan |
| المصدر: | Molecules Volume 25 Issue 20 Molecules, Vol 25, Iss 4606, p 4606 (2020) |
| بيانات النشر: | Multidisciplinary Digital Publishing Institute, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | cyclin D1, Pharmaceutical Science, Pyridinium Compounds, Analytical Chemistry, chemistry.chemical_compound, 0302 clinical medicine, Drug Discovery, 0303 health sciences, biology, Cell Cycle, Indolizines, Middle Aged, Chemistry (miscellaneous), 030220 oncology & carcinogenesis, MCF-7 Cells, Molecular Medicine, medicine.drug, Adult, CDK2, kinase activity profiling, Breast Neoplasms, Hsp90, Article, Cell Line, Cyclic N-Oxides, lcsh:QD241-441, 03 medical and health sciences, Cyclin D1, lcsh:Organic chemistry, Cyclin-dependent kinase, medicine, Humans, HSP90 Heat-Shock Proteins, Physical and Theoretical Chemistry, Dinaciclib, Kinase activity, PI3K/AKT/mTOR pathway, 030304 developmental biology, Aged, business.industry, Phospholipase C gamma, Organic Chemistry, Cyclin-dependent kinase 2, Cyclin-Dependent Kinase 2, Vascular Endothelial Growth Factor Receptor-2, VEGFR-2, Focal Adhesion Kinase 2, chemistry, Focal Adhesion Kinase 1, Cancer cell, biology.protein, Cancer research, luminal-A breast cancer, business, Tamoxifen |
| الوصف: | The hormonal luminal-A is the most pre-dominant sub type of breast cancer (BC), and it is associated with a high level of cyclin D1 in Saudi patients. Tamoxifen is the golden therapy for hormonal BC, but resistance of cancer cells to tamoxifen contributes to the recurrence of BC due to many reasons, including high levels of AIB1 and cyclin D1. Overcoming drug resistance could be achieved by exploring alternative targetable therapeutic pathways and new drugs or combinations. The objective of this study was to determine the differentially enriched pathways in 12 samples of Saudi women diagnosed with luminal-A using the PamChip peptide microarray-based kinase activity profiling, and to compare the activity of HAA2020 and dinaciclib with tamoxifen in singles and combinations in the MCF7 luminal-A cell line. Our results of network and pathway analysis of the 12 samples highlighted the importance of VEGFR and CDKs in promoting luminal-A breast cancer. The activation of VEGF signaling via VEGFR-2 leads to activation of PI3K/AKT kinases and an increase of cell survival, and leads to activation of Hsp90, which induces the phosphorylation of FAK1, resulting in cytoskeleton remodeling. PLC-gamma 1 is also activated, leading to FAK-2 and PKC activation. Notably, the G1/S cell cycle phases and phosphorylation processes contribute to the top seven tumorigenesis processes in the 12 samples. Further, the MTT combination of HAA2020 and dinaciclib showed the best combination index (CI), was more clonogenic against MCF7 cells compared to the other combinations, and it also showed the best selectivity index (SI) in normal MRC5 cells. Interestingly, HAA2020 and dinaciclib showed a synergistic apoptotic and G1 cell cycle effect in MCF7 cells, which was supported by their synergistic CDK2, cyclin D1, and PCNA inhibition activities. Additionally, the combination showed VEGFR-2 and Hsp90 inhibition activities in MCF7 cells. The results show the significance of targeting VEGFR-2 and cyclin D1 in Saudi luminal-A breast cancer patients, and the effect of combining HAA2020 and dinaciclib on those targets in the MCF7 model. It also warrants further preclinical and in vivo investigations for the combination of HAA2020 and dinaciclib as a possible future second-line treatment for luminal-A breast cancers. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 1420-3049 |
| DOI: | 10.3390/molecules25204606 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e32cc0819b70b9392948725ef2611ee6Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....e32cc0819b70b9392948725ef2611ee6 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14203049 |
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| DOI: | 10.3390/molecules25204606 |