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Colorectal Cancer Chemoprevention by S-Allyl Cysteine-Caffeic Acid Hybrids: Pro-apoptotic Effect, Anti-inflammatory, in Vitro/in Silico Antioxidant, Docking and Drug-Likeness Studies
Herrera-Ramirez, A.; Yepes-Pérez, A.F.; Quintero-Saumeth, J.; Moreno-Quintero, G.; Naranjo, T.W.; Cardona-Galeano, W. Colorectal Cancer Chemoprevention by S-Allyl Cysteine–Caffeic Acid Hybrids: In Vitro Biological Activity and In Silico Studies. Sci. Pharm.2022, 90, 40.
Herrera-Ramirez, A.; Yepes-Pérez, A.F.; Quintero-Saumeth, J.; Moreno-Quintero, G.; Naranjo, T.W.; Cardona-Galeano, W. Colorectal Cancer Chemoprevention by S-Allyl Cysteine–Caffeic Acid Hybrids: In Vitro Biological Activity and In Silico Studies. Sci. Pharm. 2022, 90, 40.
Herrera-Ramirez, A.; Yepes-Pérez, A.F.; Quintero-Saumeth, J.; Moreno-Quintero, G.; Naranjo, T.W.; Cardona-Galeano, W. Colorectal Cancer Chemoprevention by S-Allyl Cysteine–Caffeic Acid Hybrids: In Vitro Biological Activity and In Silico Studies. Sci. Pharm.2022, 90, 40.
Herrera-Ramirez, A.; Yepes-Pérez, A.F.; Quintero-Saumeth, J.; Moreno-Quintero, G.; Naranjo, T.W.; Cardona-Galeano, W. Colorectal Cancer Chemoprevention by S-Allyl Cysteine–Caffeic Acid Hybrids: In Vitro Biological Activity and In Silico Studies. Sci. Pharm. 2022, 90, 40.
Abstract
Conventional chemotherapy for colorectal cancer (CRC) gives only a small increase in patient survival, since it is often diagnosed in late stages, when tumor has disseminated to other organs. Besides, it is common to observe that malignant cells acquire tumor escape mechanisms which leads to therapy resistance. Considering these facts, the discovery of new molecules with therapeutic potential has become an invaluable tool in chemoprevention. In this context, we previously evaluated two hybrids (SAC-CAFA-MET and SAC-CAFA-PENT) which exhibited selective cytotoxicity against SW480, with better results than the conventional chemotherapeutic agent (5-fluorouracil; 5-FU). Here, we investigated a little deeper in the possible mechanism of these molecules to identify potential therapeutic alternatives for the treatment of CRC. Both compounds induced cell damage and reduced ROS formation. Further evaluations showed that SAC-CAFA-MET induces cell death independent from caspases and p53, but probably mediated by the negative regulation of the proapoptotic Bcl-2. In addition, the lack of activation of caspase 8 and the positive regulation of caspase 3 induced by SAC-CAFA-PENT suggest this compound acts through an apoptotic mechanism, probably initiated by intrinsic pathway. Besides, the down regulation of IL-6 by SAC-CAFA-PENT suggests it also induces a significant anti-inflammatory process. In addition, docking studies would suggest caspase-3 modulation as the primary mechanism by which hybrids elicits apoptosis in human colorectal adenocarcinoma SW480. Meanwhile, DFT calculations suggest that hybrids would produce effects in modulation of ROS in SW480 cells via hydrogen atom transfer pathway (HAT). Finally, both, SAC-CAFA-MET and SAC-CAFA-PENT displayed a favorable pharmacokinetic profile. The current work highlights the potential of the lead compounds SAC-CAFA-MET and SAC-CAFA-PENT as potential agents for colorectal cancer chemoprevention.
Chemistry and Materials Science, Medicinal Chemistry
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