Novel Polymethoxylated Chalcones as Potential Compounds Against KRAS-Mutant Colorectal Cancers.
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.
['Mahmoud|Alaa|A|', 'Elkhalifa|Dana|D|', 'Alali|Feras|F|', 'Al Moustafa|Ala-Eddin|AE|', 'Khalil|Ashraf|A|']
D017209:Apoptosis D045744:Cell Line, Tumor D002465:Cell Movement D049109:Cell Proliferation D047188:Chalcones D015179:Colorectal Neoplasms D058750:Epithelial-Mesenchymal Transition D006801:Humans D016283:Proto-Oncogene Proteins p21(ras)
Chalcone colorectal cancer analogs KRAS mutation epithelial-mesenchymal transition (EMT) metastasis.