Resveratrol-induced potentiation of the antitumor effects of oxaliplatin is accompanied by an altered cytokine profile of human monocyte-derived macrophages.

The objective of this study was to investigate, whether the naturally occurring polyphenol resveratrol (Res) enhances the anti-tumor activities of the chemotherapeutic agent oxaliplatin (Ox) in a cell culture model of colorectal cancer, also with regard to a possible inflammatory response and cytotoxic side-effects. Res and Ox in combination synergistically inhibit cell growth of Caco-2 cells, which seems to be due to the induction of different modes of cell death and further leads to an altered cytokine profile of cocultured macrophages. Moreover, combinatorial treatment does not affect non-transformed cells as severe cytotoxicity is not detected in human foreskin fibroblasts and platelets.

Selective glucocorticoid receptor agonists for the treatment of inflammatory bowel disease: studies in mice with acute trinitrobenzene sulfonic acid colitis.

Despite being a mainstay of inflammatory bowel disease (IBD) therapy, glucocorticoids (GCs) still carry significant risks with respect to unwanted side effects. Alternative drugs with a more favorable risk/benefit ratio than common GCs are thus highly desirable for the management of IBD. New and supposedly selective glucocorticoid receptor (GR) agonists (SEGRAs), with dissociated properties, have been described as promising candidates for circumventing therapeutic problems while still displaying full beneficial anti-inflammatory potency. Here, we report on compound A [CpdA; (2-((4-acetophenyl)-2-chloro-N-methyl)ethylammonium-chloride)] and N-(4-methyl-1-oxo-1H-2,3-benzoxazine-6-yl)-4-(2,3-dihydrobenzofuran-7-yl)-2-hydroxy-2-(trifluoromethyl)-4-methylpentanamide (ZK216348), two GR agonists for the treatment of experimental colitis. Their therapeutic and anti-inflammatory effects were tested in the acute trinitrobenzene sulfonic acid-mediated colitis model in mice against dexamethasone (Dex). In addition to their influence on immunological pathways, a set of possible side effects, including impact on glucose homeostasis, steroid resistance, and induction of apoptosis, was surveyed. Our results showed that, comparable with Dex, treatment with CpdA and ZK216348 reduced the severity of wasting disease, macroscopic and microscopic damage, and colonic inflammation. However, both SEGRAs exhibited no GC-associated diabetogenic effects, hypothalamic pituitary adrenal axis suppression, or development of glucocorticoid resistance. In addition, CpdA and ZK216348 showed fewer transactivating properties and successfully dampened T helper 1 immune response. Unlike ZK216348, the therapeutic benefit of CpdA was lost at higher doses because of toxic apoptotic effects. In conclusion, both SEGRAs acted as potent anti-inflammatory agents with a significantly improved profile compared with classic GCs. Although CpdA revealed a narrow therapeutic window, both GR agonists might be seen as a starting point for a future IBD treatment option.

Phytochemicals resveratrol and sulforaphane as potential agents for enhancing the anti-tumor activities of conventional cancer therapies.

Even though conventional cancer therapies, comprising surgery and chemo- and radiotherapy, play an important role in the treatment of most solid tumours, successful therapeutic outcome is often limited due to high toxicity and related side-effects, as well as the development of multi-drug resistances. Therefore, there is need for new therapeutic strategies not only to obtain higher treatment efficacy, but also for the reduction of toxicity and adverse effects. Emerging evidence suggests that natural compounds with distinct anticarcinogenic activity may be considered as potential agents for enhancing the therapeutic effects of common cancer treatments. By using the examples of resveratrol and sulforaphane this review will summarize the findings of recent investigations focusing this topic so far and the current knowledge of the molecular mechanisms by which these selected phytochemicals may potentiate the anti-tumor effects of different cancer therapies.

Sulforaphane potentiates oxaliplatin-induced cell growth inhibition in colorectal cancer cells via induction of different modes of cell death.

The objective of this study was to investigate, whether the plant-derived isothiocyanate Sulforaphane (SFN) enhances the antitumor activities of the chemotherapeutic agent oxaliplatin (Ox) in a cell culture model of colorectal cancer. Caco-2 cells were cultured under standard conditions and treated with increasing concentrations of SFN [1-20 µM] and/or Ox [100 nM-10 µM]. For co-incubation, cells were pre-treated with SFN for 24 h. Cell growth was determined by BrdU incorporation. Drug interactions were assessed using the combination-index method (CI) (Cl < 1 indicates synergism). Apoptotic events were characterized by different ELISA techniques. Protein levels were examined by Western blot analysis. Annexin V- and propidium iodide (PI) staining followed by FACS analysis was used to differentiate between apoptotic and necrotic events. SFN and Ox alone inhibited cell growth of Caco-2 cells in a dose-dependent manner, an effect, which could be synergistically enhanced, when cells were incubated with the combination of both agents. Co-treated cells further displayed distinctive morphological changes that occurred during the apoptotic process, such as cell surface exposure of phosphatidylserine, membrane blebbing as well as the occurence of cytoplasmic histone-associated DNA fragments. Further observations thereby pointed toward simultaneous activation of both extrinsic and intrinsic apoptotic pathways. With increasing concentrations and treatment duration, a shift from apoptotic to necrotic cell death could be observed. In conclusion, the data suggest that the isothiocyanate SFN sensitizes colon cancer cells to Ox-induced cell growth inhibition via induction of different modes of cell death.

Isothiocyanate sulforaphane inhibits protooncogenic ornithine decarboxylase activity in colorectal cancer cells via induction of the TGF-ß/Smad signaling pathway.

SCOPE: The objective of this study was to elucidate molecular mechanisms behind the antitumor activities of the isothiocyanate sulforaphane (SFN) in colorectal cancer cells. METHODS AND RESULTS: Cell growth was determined by BrdU incorporation and crystal violet staining. Protein levels were examined by Western blot analysis. Ornithine decarboxylase (ODC) activity was assayed radiometrically. Reverse transcriptase-PCR was used for measuring mRNA expression. For reporter gene assays plasmids were transfected into cells via lipofection and luciferase activity was measured luminometrically. Acetyl-histone H3 and H4 chromatin immunoprecipitation (ChIP) assays were performed followed by PCR with TGF-ß-receptor II promoter specific primers. We could show that SFN-mediated cell growth inhibition closely correlates with a dose-dependent reduction of protein expression and enzymatic activity of ODC. This effect seems to be due to reduced protein levels and transactivation activity of transcription factor c-myc, a direct regulator of ODC expression, as a consequence of SFN-induced TGF-ß/Smad signaling. The coherency of these results was further confirmed by using TGF-ß receptor kinase inhibitor SB431542, which largely abolishes inhibitory effects of SFN on both, ODC activity and cell growth. CONCLUSION: Since elevated ODC enzyme activity is associated with enhanced tumor development, SFN may be a dietary phytochemical with potential to prevent carcinogenesis.