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Different hybrids based on curcumin and resveratrol were previously synthesized and characterized by spectroscopic techniques. The most active molecules (3a, 3e, 3i, and 3k) were evaluated in vitro as an approach to determine the possible mechanism of action of the hybrids. The results indicated that the evaluated curcumin/resveratrol hybrids induce mitochondrial instability in SW620 and SW480 cells. Moreover, these molecules caused a loss in membrane integrity, suggesting an apoptotic process mediated by caspases after the treatment with compounds 3i (SW480) and 3k (SW620). In addition, the results suggest that the mechanism of action of the hybrids could be independent of the p53 status. Furthermore, hybrids 3e and 3i caused G0/G1 phase arrest, which highlights the potential of these molecules not only as cytotoxic but also as cytostatic compounds. Hybrids 3e and 3i caused a negative modulation of the matrix metalloproteinase 7 (MMP7) on SW480 cells. These curcumin resveratrol hybrids could be potential candidates for further investigations in the search for potential chemopreventive agents, even in those cases with resistance to conventional chemotherapy because of the lack of p53 expression or function. Molecular docking simulations showed that compounds 3e, 3i, and 3k bind efficiently to proapoptotic human caspases 3/7 proteins, as well as human MMP-7 and p53, which, in turn, could explain at the molecular level the in vitro cytotoxic effect of these compounds in SW480 and SW620 colon cancer cell lines.

Himatanthus sucuuba, also known as “Bellaco caspi”, is a medicinal plant whose latex, stem bark, and leaves possess phenolic acids, lupeol, β-dihydro-plumbericinic acid, plumericin, and plumeride, among other components. Some of these have been linked to such biological activities as antiulcer, anti-inflammatory, and wound healing. The aim of this study was to determine the phytochemical compounds of H. sucuuba latex, as well as its in vitro cytotoxicity and wound healing effect in mice. Latex was collected in the province of Iquitos, Peru. Phytochemical analysis was carried out with UPLC-ESI-MS/MS. The cytotoxicity was evaluated on two colon tumor cell lines (SW480 and SW620) and non-malignant cells (human keratinocytes, HaCaT, and Chinese hamster ovary, CHO-K1). The mice were distributed into two groups, as follows: Group I—control (n = 10; without treatment); II—(n = 10) H. sucuuba latex; wounds were induced with a scalpel in the dorsal–cervical area and treatments were applied topically twice a day on the incision for 10 days. Molecular docking was carried out on the glycogen synthase kinase 3β protein. Twenty-four chemical compounds were determined, mainly flavonoid-type compounds. Latex did not have a cytotoxic effect on tumor cells with IC50 values of more than 500 µg/mL. The latex had a regenerative effect on wounds in mice. Acacetin-7-O-neohesperidoside had the best docking score of −9.9 kcal/mol. In conclusion, H. sucuuba latex had a wound healing effect in mice, as confirmed by histological study. However, a non-cytotoxic effect was observed on colon tumor cells SW480 and SW620.

We synthesized twelve hybrids based on curcumin and resveratrol, and their structures were elucidated by spectroscopic analysis. The chemopreventive potential of these compounds was evaluated against SW480 human colon adenocarcinoma cells, its metastatic derivative SW620, along with the non-malignant CHO-K1 cell line. Among the tested compounds, hybrids 3e and 3i (for SW480) and 3a, 3e and 3k (for SW620) displayed the best cytotoxic activity with IC50 values ranging from 11.52 ± 2.78 to 29.33 ± 4.73 µM for both cell lines, with selectivity indices (SI) higher than 1, after 48 h of treatment. Selectivity indices were even higher than those reported for the reference drug, 5-fluorouracil (SI = 0.96), the starting compound resveratrol (SI = 0.45) and the equimolar mixture of curcumin plus resveratrol (SI = 0.77). The previous hybrids showed good antiproliferative activity.

Colorectal cancer (CRC) is the third most common cancer diagnosed worldwide and is the second leading cause of cancer-related death due to an insufficiency prognosis and is generally diagnosed in the last step of development. The Peruvian flora has a wide variety of medicinal plants with therapeutic potential in several diseases. Dodonaea viscosa Jacq. is a plant used to treat inflammatory process as well as gastrointestinal diseases. The aim of this study was to examine the cytotoxic, antiproliferative, and cell death-inducing effects of D. viscosa on colorectal cancer cells (SW480 and SW620). The hydroethanolic extract was obtained by maceration at 70% ethanol, the phytochemical constituents were identified by LC-ESI-MS. D. viscosa revealed 57 compounds some of them are: isorhamnetin, kaempferol, quercetin, methyl dodovisate B, hardwickiic acid, viscosol, and dodonic acid. Regarding the antitumoral activity, D. viscosa induced cytotoxic and antiproliferative activity in both SW480 and SW620 cancer cells, accompanied with, important changes in mitochondrial membrane potential, formation of the Sub G0/G1 population and increasing levels of apoptotic biomarkers (caspase 3 and the tumor suppressor protein p53) in the metastatic derivative cell line (SW620), suggesting an intrinsic apoptotic process after the treatment with the hydroethanolic extract of D. viscosa.

A series of 5-FU-Curcumin hybrids were synthesized, and their structures were elucidated by spectroscopic analysis. The synthesized hybrid compounds were evaluated in different colorectal cancer cell lines (SW480 and SW620) and in non-malignant cells (HaCaT and CHO-K1), to determine their chemopreventive potential. Hybrids 6a and 6d presented the best IC50 value against the SW480 cell line with results of 17.37 ± 1.16 µM and 2.43 ± 0.33 µM, respectively. Similarly, compounds 6d and 6e presented IC50 results of 7.51 ± 1.47 µM and 14.52 ± 1.31 µM, respectively, against the SW620 cell line. These compounds were more cytotoxic and selective than curcumin alone, the reference drug 5-fluorouracil (5-FU), and the equimolar mixture of curcumin and 5-FU. In addition, hybrids 6a and 6d (in SW480) and compounds 6d and 6e (in SW620) induced cell cycle arrest in S-phase, and, compounds 6d and 6e caused a significant increase in the sub-G0/G1 phase population in both cell lines. Hybrid 6e was also observed to induce apoptosis of SW620 cells with a respective increase in executioner caspases 3 and 7. Taken together, these results suggest that the hybrids could actively act on a colorectal cancer model, making them a privileged scaffold that could be used in future research.

A series of resveratrol/hydrazone hybrids were obtained and elucidated by spectroscopic analysis. All compounds were evaluated against colorectal cancer cells (SW480 and Sw620) and nonmalignant cell lines (HaCaT and CHO-K1) to establish the selectivity index. Among the hybrids evaluated, compounds 6e and 7 displayed the highest cytotoxic activity with IC50 values of = 6.5 ± 1.9 µM and 19.0 ± 1.4 µM, respectively, on SW480 cells. In addition, hybrid 7 also exhibited activity on SW620 cells with an IC50 value of 38.41 ± 3.3 µM. Both compounds were even more toxic against these malignant cells in comparison to the nonmalignant ones, as evidenced by higher selectivity indices 48 h after treatment. These compounds displayed better activity and selectivity than parental compounds (PIH and Resveratrol) and the reference drug (5-FU). In addition, it was observed that both compounds caused antiproliferative activity probably exerted by cell cycle arrest at the G2/M or G0/G1 phases, with the formation of cells in the subG0/G1 phase. Furthermore, it was noticed that compound 7 induced mitochondrial depolarization in SW480 cells and positive staining for propidium iodide in both cancer cell lines, suggesting cell membrane damage involving either apoptosis or other processes of death.

A series of 5-FU-Genistein hybrids were synthesized and their structures were elucidated by spectroscopic analysis. The chemopreventive potential of these compounds was evaluated in human colon adenocarcinoma cells (SW480 and SW620) and non-malignant cell lines (HaCaT and CHO-K1). Hybrid 4a displayed cytotoxicity against SW480 and SW620 cells with IC50 values of 62.73 ± 7.26 µM and 50.58 ± 1.33 µM, respectively; compound 4g induced cytotoxicity in SW620 cells with an IC50 value of 36.84 ± 0.71 µM. These compounds were even more selective than genistein alone, the reference drug (5-FU) and the equimolar mixture of genistein plus 5-FU. In addition, hybrids 4a and 4g induced time- and concentration-dependent antiproliferative activity and cell cycle arrest at the S-phase and G2/M. It was also observed that hybrid 4a induced apoptosis in SW620 cells probably triggered by the extrinsic pathway in response to the activation of p53, as evidenced by the increase in the levels of caspases 3/8 and the tumor suppressor protein (Tp53). Molecular docking studies suggest that the most active compound 4a would bind efficiently to proapoptotic human caspases 3/8 and human Tp53, which in turn could provide valuable information on the biochemical mechanism for the in vitro cytotoxic response of this compound in SW620 colon carcinoma cell lines. On the other hand, molecular dynamics (MD) studies provided strong evidence of the conformational stability of the complex between caspase-3 and hybrid 4a obtained throughout 100 ns all-atom MD simulation. Molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) analyses of the complex with caspase-3 showed that the interaction between the ligand and the target protein is stable. Altogether, the results suggest that the active hybrids, mainly compound 4a, might act by modulating caspase-3 activity in a colorectal cancer model, making it a privileged scaffold that could be used in future investigations.

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.