Colorectal Cancer Chemoprevention by S-Allyl Cysteine–Caffeic Acid Hybrids: In Vitro Biological Activity and In Silico Studies

Abstract

Conventional chemotherapy for colorectal cancer (CRC) gives only a small increase in patient survival, since it is often diagnosed at late stages, when the tumor has disseminated to other organs. Moreover, it is common to observe that malignant cells may acquire resistance to conventional chemotherapies through different mechanisms, including reducing drug activation or accumulation (by enhancing efflux), inducing alterations in molecular targets, and inhibiting the DNA damage response, among other strategies. 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) that exhibited selective cytotoxicity against SW480 cells, with better results than the conventional chemotherapeutic agent (5-fluorouracil; 5-FU). Here, we investigated the possible mechanisms of these molecules in greater depth, to identify whether they could be valuable therapeutic scaffolds in the search for new molecules with chemopreventive potential for the treatment of CRC. Both compounds reduced ROS formation, which could be related to antioxidant effects. Further evaluations showed that SAC-CAFA-MET induces cell death independent of caspases and the tumor-suppressor protein p53, but probably mediated by the negative regulation of the pro-apoptotic Bcl-2. In addition, the lack of activation of caspase-8 and the positive regulation of caspase-3 induced by SAC-CAFA-PENT suggest that this compound acts through an apoptotic mechanism, probably initiated by intrinsic pathways. Furthermore, the downregulation of IL-6 by SAC-CAFA-PENT suggests that it also induces a significant anti-inflammatory process. In addition, docking studies would suggest caspase-3 modulation as the primary mechanism by which SAC-CAFA-PENT elicits apoptosis in SW480human colorectal adenocarcinoma cells. Meanwhile, density functional theory (DFT) calculations suggest that both hybrids would produce effects in the modulation of ROS in SW480 cells via the hydrogen atom transfer (HAT) pathway. The present work notes that SAC-CAFA-MET and SAC-CAFA-PENT could be potential candidates for further investigations in the search for potential chemopreventive agents.

Synthesis and Chemopreventive Potential of 5-FU/Genistein Hybrids on Colorectal Cancer Cells

“…For biological evaluations, cells were cultured in Dulbecco’s Modified Eagle Medium, supplemented with 10% heat-inactivated (56 °C) horse serum, 1% penicillin/streptomycin and 1% non-essential amino acids (Gibco Invitrogen, Carlsbad, CA, USA). During the treatments, the serum was reduced to 3%, and the medium was supplemented with insulin (10 mg/mL) transferrin (5 mg/mL) and selenium (5 ng/mL) (ITS-defined medium; Gibco, Invitrogen, Carlsbad, USA) [ 51 , 52 ]. To avoid Mycoplasma spp.…”

New Hybrid Scaffolds Based on 5-FU/Curcumin: Synthesis, Cytotoxic, Antiproliferative and Pro-Apoptotic Effect

“…The cells were then lysed with a cell lysis buffer and centrifuged to obtain the supernatant, which was used to determine the biomarkers of interest by enzyme-linked immunosorbent assays. These ELISA kits were provided by Elabscience Biotechnology Co., Houston, TX, USA [26].…”

Resveratrol/Hydrazone Hybrids: Synthesis and Chemopreventive Activity against Colorectal Cancer Cells

“…N -((E)-2,4-dihydroxy-6-((E)-4-hydroxystyryl)benzylidene)-3-methoxybenzohydrazide (6a): Yield 55%; Yellow solid. Mp 248-250 • C. 1 C) horse serum (10%), non-essential amino acids (1%) and antibiotics (penicillin/streptomycin, 1%) (Gibco Invitrogen, Carlsbad, CA, USA) was used to maintain the cells, reducing the horse serum to 3%, and, adding insulin (10 mg/mL), transferrin (5 mg/mL) and selenium (5 ng/mL) (ITSdefined medium; Gibco, Invitrogen, Carlsbad, CA, USA) for all the experiments [38,39].…”