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AuthorMahmoud, Alaa
AuthorElkhalifa, Dana
AuthorAlali, Feras
AuthorAl Moustafa, Ala-Eddin
AuthorKhalil, Ashraf
Available date2023-01-23T05:30:13Z
Publication Date2020
Publication NameCurrent Pharmaceutical Design
ResourceScopus
URIhttp://dx.doi.org/10.2174/1381612826666200206095400
URIhttp://hdl.handle.net/10576/38686
AbstractBackground/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.
SponsorThis 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.
Languageen
PublisherBentham Science Publishers
SubjectChalcone
analogs
epithelial-mesenchymal transition (EMT)
metastasis
colorectal cancer
KRAS mutation
TitleNovel polymethoxylated chalcones as potential compounds against kras-mutant colorectal cancers
TypeArticle
Pagination1622-1633
Issue Number14
Volume Number26
dc.accessType Abstract Only


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