Novel polymethoxylated chalcones as potential compounds against kras-mutant colorectal cancers
Author | Mahmoud, Alaa |
Author | Elkhalifa, Dana |
Author | Alali, Feras |
Author | Al Moustafa, Ala-Eddin |
Author | Khalil, Ashraf |
Available date | 2023-01-23T05:30:13Z |
Publication Date | 2020 |
Publication Name | Current Pharmaceutical Design |
Resource | Scopus |
Abstract | Background/Objective: KRAS-mutant colorectal cancers (CRC) are tumors that are associated with poor prognosis. However, no effective treatments are available to target them. Therefore, we designed and synthesized novel chalcone analogs, small organic molecules, to investigate their effects on KRAS-mutant CRC cells. Methods: Fourteen new chalcone analogs were synthesized, optimized, characterized, and tested against two KRAS-mutant CRC cell lines (HCT-116 and LoVo), one p-53 and BRAF mutant CRC cell line (HT-29) and one normal immortalized colon cells (NCE-1 E6/E7). Effects on cell viability, apoptosis, cell cycle, migration, colony formation, EMT, and angiogenesis were investigated. Results: Compounds 3 and 14 were the most effective. Compound 3 showed potent activity against HCT-116 and LoVo cell lines (GI50 of 6.10 μM and 7.00 μM, respectively). While compound 14 showed GI50 of 8.60 μM and 8.80 μM on HCT-116 and LoVo cell lines, respectively. Both compounds were approximately 2-3 times more selective toward cancer cells rather than normal colon cells. Compound 3 was effective in inducing apoptosis in HCT-116 cells via Bax upregulation and Bcl-2 downregulation. Invasion and metastasis of KRAS-mutant cells were modulated by compounds 3 and 14 through significant inhibition of cell migration and the prevention of colony formation. In addition, they reversed EMT by downregulation of EMT markers (vimentin, fascin, and β- catenin) and upregulation of cell-cell adhesion marker, E-cadherin. Furthermore, compounds 3 and 14 had significantly inhibited angiogenesis in ovo. Conclusion: Compounds 3 and 14 represent potent and selective leads for KRAS-mutant CRC cells, thus, further in vitro and in vivo studies are necessary to confirm their effect on KRAS-mutant CRCs. |
Sponsor | This research work was supported by Grants no. QUST-1-CPH-2018-19, QUST-1-CPH-2019-2 and Grant no. GCC-2017-002 from Qatar University. The NMR and the elemental analyses were accomplished in the Central Laboratories Unit, Qatar University. |
Language | en |
Publisher | Bentham Science Publishers |
Subject | 1 [4 (methylsulfonyl)phenyl] 3 (2,4,6 trimethoxyphenyl)prop 2 en 1 one; 1 [4 (methylthio)phenyl] 3 (2,4,6 trimethoxyphenyl)prop 2 en 1 one; 1 [4 (methylthio)phenyl] 3 [3 (trifluoromethyl)phenyl]prop 2 en 1 one; 3 (2 methoxyphenyl) 1 [4 (methylsulfonyl)phenyl]prop 2 en 1 one; 3 (2,5 dimethoxyphenyl) 1 [4 (methylsulfonyl)phenyl]prop 2 en 1 one; 3 (6 bromobenzo[d][1,3]dioxol 5 yl) 1 [4 (methylsulfonyl)phenyl]prop 2 en 1 one; 3 (6 bromobenzo[d][1,3]dioxol 5 yl) 1 [4 (methylthio)phenyl]prop 2 en 1 one; 3 (6 bromobenzo[d][1,3]dioxol 5 yl) 1 [4 (piperazin 1 yl)phenyl]prop 2 en 1 one; 3 (benzo[b]thiophen 2 yl) 1 (3 methoxyphenyl)prop 2 en 1 one; 3 (benzo[b]thiophen 2 yl) 1 (3,4,5 trimethoxyphenyl)prop 2 en 1 one; 3 (benzo[b]thiophen 2 yl) 1 (benzo[d][1,3]dioxol 5 yl)prop 2 en 1 one; 3 (benzo[b]thiophen 2 yl) 1 [4 (methylsulfonyl)phenyl]prop 2 en 1 one; 3 (benzo[b]thiophen 2 yl) 1 [4 (methylthio)phenyl]prop 2 en 1 one; 3 [2 fluoro 4 (trifluoromethyl)phenyl] 1 [4 (methylthio)phenyl]prop 2 en 1 one; antineoplastic agent; B Raf kinase; beta catenin; chalcone derivative; fascin; paclitaxel; protein Bax; protein bcl 2; unclassified drug; uvomorulin; vimentin; chalcone derivative; KRAS protein, human; protein p21; antiangiogenic activity; antineoplastic activity; apoptosis; Article; BRAF gene; cancer inhibition; cell adhesion; cell cycle; cell viability; colony formation; colorectal cancer; controlled study; down regulation; drug design; drug effect; drug efficacy; drug potency; drug potentiation; drug screening; drug selectivity; drug synthesis; epithelial mesenchymal transition; gene mutation; GI50; HCT 116 cell line; HT-29 cell line; immortalized cell line; in vitro study; in vivo study; LoVo cell line; metastasis; migration inhibition; oncogene K ras; priority journal; proapoptotic activity; process optimization; tumor invasion; tumor suppressor gene; tumor vascularization; upregulation; cell motion; cell proliferation; chemistry; colorectal tumor; genetics; human; tumor cell line; Apoptosis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chalcones; Colorectal Neoplasms; Epithelial-Mesenchymal Transition; Humans; Proto-Oncogene Proteins p21(ras) Biomarkers COVID-19 MiRNA SARS-CoV-2 SnoRNA |
Type | Article |
Pagination | 1622-1633 |
Issue Number | 14 |
Volume Number | 26 |
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