Anti-Inflammatory and Pro-apoptotic Effects of Curcumin and Resveratrol on the Human Lung Fibroblast Cell Line MRC-5 Burkhard Kloesch1*, Elisabeth Dietersdorfer1, Silvia Loebsch1 and Guenter Steiner1,2
1Ludwig Boltzmann Institute for Rheumatology and Balneology, Cluster Rheumatology, Balneology and Rehabilitation, Vienna, Austria 2Division of Rheumatology, Department of Internal Medicine III, Medical University Vienna, Austria
Abstract Background: The naturally occuring polyphenols curcumin and resveratrol are considered to be powerful antioxidants and anti-inflammatory compounds and both inhibit the proliferation of different types of cancer cells. In the present study, we investigated possible anti-inflammatory and pro-apoptotic effects of curcumin and resveratrol on the human lung fibroblast cell line MRC-5.
Methods: MRC-5 cells were stimulated for 6 h with interleukin (IL)-1β or phorbol 12- myristate 13-acetate (PMA) in the absence or presence of different concentrations of curcumin or resveratrol. The release of interleukin (IL)-6 was quantified by enzyme-linked immunosorbent assay (ELISA). The modulation in phosphorylation of the transcription factor nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) such as p38 and ERK1/2 were analyzed by Western blot. Cytotoxic and pro-apoptotic effects of curcumin and resveratrol were monitored by the measurement of lactate dehydrogenase (LDH) activity and by Annexin-V/7-AAD staining.
Results: Both curcumin and resveratrol effectively attenuated IL-1β and PMA-induced IL-6 expression in MRC-5 cells. Furthermore, curcumin treatment induced apoptosis via caspase-3 signaling and caused endoplasmic reticulum (ER) stress. Salubrinal, an inhibitor of serine/threonine phosphatase PP1, and antioxidants such as N-acetyl-cysteine (NAC), reduced glutathione (GSH) and sodium hydrogen sulfide (NaHS) diminished the cytotoxic effects of curcumin on MRC-5 cells. In contrast to curcumin, resveratrol had no negative effects on cell viability
Resveratrol Reduces TNF-α-induced U373MG Human Glioma Cell Invasion through Regulating NF-κB Activation and uPA/uPAR Expression
Abstract Background: High invasiveness of glioma cells is one of the reasons that patients with malignant glioma have a poor prognosis. Resveratrol, a plant compound abundant in the peel of grapes, has been suggested as a potential cancer chemopreventive agent. Therefore, we investigated the effect of resveratrol on glioma cell invasion.
Materials and Methods: The effect of resveratrol on U373MG human glioma cell invasion was assessed by Matrigel assay and methylthiazoltetrazolium assay. Western blotting and reverse transcription-polymerase chain reaction were performed to elucidate the action mechanism of resveratrol.
Results: Resveratrol reduced tumor necrosis factor (TNF)-α-induced U373MG human glioma cell invasion. In addition, resveratrol repressed nuclear factor kappa B (NF-κB) activation and down-regulated mRNA expression of urokinase plasminogen activator (uPA) and its receptor in TNF-α-treated glioma cells.
Conclusion: These findings suggest that resveratrol could prevent glioma cell invasion via inhibiting proteolysis of extracellular matrix.
Synergistic Effects of Combined Phytochemicals and Skin Cancer Prevention in SENCAR Mice Magdalena C. Kowalczyk, Piotr Kowalczyk, Olga Tolstykh, et al.
Abstract The purpose of our study was to determine the inhibitory effect of combined phytochemicals on chemically induced murine skin tumorigenesis. Our hypothesis was that concurrent topical and dietary treatment with selected compounds would lead to more efficient prevention of skin cancer. We tested ellagic acid and calcium D-glucarate as components of diets, while resveratrol was applied topically; grape seed extract was applied topically or in the diet. The 4-week inflammatory-hyperplasia assay based on the 7,12-dimethylbenz[a]anthracene (DMBA)–induced skin carcinogenesis model in SENCAR mice was used. We have found that all the selected combinations caused a marked decrease of epidermal thickness compared with the DMBA-treated group and also with groups treated with a single compound and DMBA. All combinations of resveratrol with other compounds showed a synergistic effect on hyperplasia and Ha-ras mutations. Skin tissue of mice receiving the combinations showed decreased cell proliferation and Bcl2 expression; decreased p21, a regulator of cell cycle; and decreased marker of inflammation cyclooxygenase-2. All the selected combinations diminished the DMBA-induced mRNA expression of the CYP1B1 level, and also caused a marked decrease of proto-oncogenes c-jun and c-fos, components of transcription factor activator protein. In conclusion, all combinations showed either additive or synergistic effects and their joint actions allowed for decreasing the doses of the compounds. Especially, resveratrol combinations with ellagic acid, grape seed extract, and other phytochemicals are very potent inhibitors of skin tumorgenesis, based on the suppression of epidermal hyperplasia as well as on the modulation of intermediate biomarkers of cell proliferation, cell survival, inflammation, oncogene mutation, and apoptosis.
Cancer Prevention and Treatment with Resveratrol: From Rodent Studies to Clinical Trials
Resveratrol (3,4′,5-trihydroxy-trans-stilbene) is a dietary polyphenol derived from grapes, berries, peanuts, and other plant sources. During the last decade, resveratrol has been shown to possess a fascinating spectrum of pharmacologic properties. Multiple biochemical and molecular actions seem to contribute to resveratrol effects against precancerous or cancer cells. Resveratrol affects all three discrete stages of carcinogenesis (initiation, promotion, and progression) by modulating signal transduction pathways that control cell division and growth, apoptosis, inflammation, angiogenesis, and metastasis. The anticancer property of resveratrol has been supported by its ability to inhibit proliferation of a wide variety of human tumor cells in vitro. These in vitro data have led to numerous preclinical animal studies to evaluate the potential of this drug for cancer chemoprevention and chemotherapy. This review provides concise, comprehensive data from preclinical in vivo studies in various rodent models of human cancers, highlighting the related mechanisms of action. Bioavailability, pharmacokinetic, and potential toxicity studies of resveratrol in humans and ongoing interventional clinical trials are also presented. The conclusion describes directions for future resveratrol research to establish its activity and utility as a human cancer preventive and therapeutic drug.