دورية أكاديمية
Assessing the Antiproliferative Potential of a Novel Combretastatin A4 Derivative via Modulating Apoptosis, MAPK/ERK and PI3K/AKT Pathways in Human Breast Cancer Cells.
| العنوان: | Assessing the Antiproliferative Potential of a Novel Combretastatin A4 Derivative via Modulating Apoptosis, MAPK/ERK and PI3K/AKT Pathways in Human Breast Cancer Cells. |
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| المؤلفون: | Nazmy MH; Department of Biochemistry, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt., Abu-Baih DH; Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Deraya University, 61111 Minia, Egypt., Elrehany MA; Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Deraya University, 61111 Minia, Egypt., Mustafa M; Department of Medicinal Chemistry, Faculty of Pharmacy, Deraya University, 61111 Minia, Egypt.; IBMM, CNRS, ENSCM, Université de Montpellier, 34095 Montpellier, France., Aly OM; Medicinal Chemistry Department, Faculty of Pharmacy, Port said University, 42526 Port said, Egypt., El-Sheikh AAK; Basic Health Sciences Department, College of Medicine, Princess Nourah bint Abdulrahman University, 11671 Riyadh, Saudi Arabia., Fathy M; Department of Biochemistry, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt.; Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 930-0194 Toyama, Japan. |
| المصدر: | Frontiers in bioscience (Landmark edition) [Front Biosci (Landmark Ed)] 2023 Aug 28; Vol. 28 (8), pp. 185. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: IMR Press Country of Publication: Singapore NLM ID: 101612996 Publication Model: Print Cited Medium: Internet ISSN: 2768-6698 (Electronic) Linking ISSN: 27686698 NLM ISO Abbreviation: Front Biosci (Landmark Ed) Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2022- : Singapore : IMR Press Original Publication: Searington, NY : Frontiers in Bioscience |
| مواضيع طبية MeSH: | Breast Neoplasms*/drug therapy , Breast Neoplasms*/genetics, Humans ; Female ; Phosphatidylinositol 3-Kinases ; Proto-Oncogene Proteins c-akt ; bcl-2-Associated X Protein/genetics ; Apoptosis |
| مستخلص: | Background: Breast cancer is the most predominant tumor in women. Even though current medications for distinct breast cancer subtypes are available, the non-specificity of chemotherapeutics and chemoresistance imposes major obstacles in breast cancer treatment. Although combretastatin A-4 (CA-4) has been well-reported to have potential anticancer activity, in vivo studies of CA-4 reveal a decrease in its activity. In this respect, a series of CA-4 analogues have been designed, from which one analog [(1-(3-chloro-4-fluorophenyl)-N-(2methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-1H-1,2,4-triazole-3-carboxamide, C25H22ClFN4O5] showed drastic cytotoxicity against breast cancer cells. Therefore, this research focused on investigating the in vitro molecular mechanism underlying the cytotoxicity of the CA-4 analogue, particularly the MAPK/ERK as well as PI3K/AKT pathways as attractive therapeutic targets in breast cancer. Methods: The cell viability of MCF-7, MDA-MB231, and MDA-MB453 was assessed after treatment with the CA-4 analogue, and apoptosis was analyzed via Annexin V-FITC/PI dual staining. MAPK/ERK and PI3K/AKT were thoroughly assessed using western blotting. Real-time PCR was used to estimate apoptosis-related markers, including the P53 , Bcl-2-associated X protein ( Bax ), and B-cell lymphoma 2 ( Bcl2 ) genes. Results: The CA-4 analogue reduced the survival of all cancerous cells in a concentration-dependent manner and induced apoptosis through the mitochondrial pathway (39.89 ± 1.5%, 32.82 ± 0.6%, and 23.77 ± 1.1% in MCF-7, MDA-MB231, and MDA-MB453 cells), respectively. The analogue also attenuated the expression of pMEK1/2/t-MEK1/2, p-ERK1/2/t-ERK1/2, p-PI3K/t-PI3K, and p-AKT/t-AKT proteins in all three cancer cell lines in a time-dependent manner. Furthermore, the CA-4 analogue upregulated the expression of the P53 gene and dramatically increased the ratio of Bax/Bcl2 genes. Conclusions: The enhanced cytotoxicity can be attributed to substituting the hydroxyl group in CA-4 with chlorine in the meta-position of ring B, substituting the para-methoxy group in CA-4 with fluorine in the analogue, and lastly, introducing an extension to the compound's structure (ring C). Therefore, CA-4 analogue can attenuate the proliferation of human breast cancer cells by inducing apoptosis and simultaneously suppressing the MAPK/ERK and PI3K/AKT pathways. Competing Interests: The authors declare no conflict of interest. (© 2023 The Author(s). Published by IMR Press.) |
| فهرسة مساهمة: | Keywords: MAPK/ERK; PI3K/AKT; anticancer; apoptosis; breast cancer; combretastatin A-4 |
| المشرفين على المادة: | I5590ES2QZ (fosbretabulin) EC 2.7.1.- (Phosphatidylinositol 3-Kinases) EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) 0 (bcl-2-Associated X Protein) 7O62J06F18 (combretastatin) |
| تواريخ الأحداث: | Date Created: 20230904 Date Completed: 20230905 Latest Revision: 20230914 |
| رمز التحديث: | 20230914 |
| DOI: | 10.31083/j.fbl2808185 |
| PMID: | 37664933 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2768-6698 |
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| DOI: | 10.31083/j.fbl2808185 |