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Novel Polymethoxylated Chalcones as Potential Compounds Against KRAS-Mutant Colorectal Cancers
Alaa Mahmoud1, Dana Elkhalifa1, Feras Alali1
1College of Pharmacy, QU Health, Qatar University, Doha, Qatar.
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.
Insights
Novel chalcone analogs show promise in targeting KRAS-mutant colorectal cancers (CRC). Compounds 3 and 14 effectively reduced cancer cell viability, induced apoptosis, and inhibited metastasis, offering potential new treatments for this aggressive cancer.
Area of Science:
- Oncology
- Medicinal Chemistry
Background:
- KRAS-mutant colorectal cancer (CRC) presents a poor prognosis with limited effective therapeutic options.
- Targeting KRAS mutations in CRC is a critical unmet medical need.
Purpose of the Study:
- To design and synthesize novel chalcone analogs as potential therapeutics for KRAS-mutant CRC.
- To investigate the in vitro effects of these compounds on cancer cell behavior.
Main Methods:
- Synthesis and characterization of fourteen chalcone analogs.
- In vitro testing against KRAS-mutant CRC cell lines (HCT-116, LoVo) and normal colon cells.
- Evaluation of cell viability, apoptosis, cell cycle, migration, colony formation, EMT, and angiogenesis.
Main Results:
- Compounds 3 and 14 demonstrated potent and selective cytotoxicity against KRAS-mutant CRC cells.
- These compounds induced apoptosis, inhibited cell migration and colony formation, and reversed epithelial-mesenchymal transition (EMT).
- Compounds 3 and 14 also significantly inhibited angiogenesis.
Conclusions:
- Chalcone analogs 3 and 14 are identified as promising leads for KRAS-mutant CRC.
- Further in vitro and in vivo studies are warranted to validate their therapeutic potential.
