stilbenes and pifithrin

Resveratrol, a natural product, has been revealed to exert antitumor effects in multiple types of tumors. However, the antitumor effects of resveratrol on hepatocellular carcinoma (HCC) and its potential underlying mechanisms have not yet been elucidated. The present study demonstrated that resveratrol inhibited viability, proliferation, invasion and migration of HCC cells significantly in a time‑ and dose‑dependent manner, indicating that resveratrol exerted antitumor effects in HCC. Furthermore, relative expression of autophagy‑related proteins Beclin1 and LC3 II/I ratio was increased while p62 expression was decreased by resveratrol treatment dose‑dependently. The LC3+ puncta formation, which represented autophagosome formation was also markedly dose‑dependently upregulated by resveratrol treatment, suggesting that resveratrol induced autophagy in HCC cells. In addition, treatment with autophagy inhibitor 3‑methyladenine (3‑MA) counteracted the inhibitory effect of resveratrol on HCC cell proliferation, invasion and migration, indicating that suppressing autophagy may hamper the antitumor effect of resveratrol in HCC. It was revealed that resveratrol upregulated the expression of p53 while decreasing the ratio of phosphorylated protein kinase B (p‑Akt)/Akt in HCC cells. Treatment with p53 inhibitor pifithrin‑α and Akt activator insulin‑like growth factor‑1 decreased the expression of Beclin1 while significantly promoting cell proliferation, invasion and migration compared with the resveratrol treatment group. Taken together, the results of the present study revealed that resveratrol inhibited the proliferation and mobility of HCC cells through inducing autophagy via activating p53 and inhibiting phosphoinositide 3‑kinase/Akt. Enhancing autophagy can augment the antitumor effects of resveratrol in HCC. Therefore, combining resveratrol with an autophagy inducer may be a viable option for treating HCC.

Topics: Adenine; Antineoplastic Agents, Phytogenic; Apoptosis; Autophagy; Benzothiazoles; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Cell Proliferation; Dose-Response Relationship, Drug; Humans; Liver Neoplasms; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Resveratrol; Signal Transduction; Stilbenes; Toluene; Tumor Suppressor Protein p53; Up-Regulation

Treatment with resveratrol at concentrations greater than 0.5 μmol/L resulted in the arrest of mouse embryo development at the two-cell stage. Resveratrol-induced cytotoxicity was investigated in embryos by evaluating morphologic features by using the bromodeoxyuridine assay and acridine orange and ethidium bromide double staining. Resveratrol was found to significantly increase the expressions of p53, p21, Atf3, smac/Diablo, Bax, Bak1, Bok, and Noxa mRNA in the embryos, whereas Cullin 3 and Cdk1 expressions were decreased. Furthermore, active p53 positive signal in embryos arrested at the two-cell stage was localized in the nucleus, whereas no active p53 signal was observed in control embryos. Pretreatment with pifithrin-α, a p53 inhibitor, downregulated active p53 in two-cell embryo nuclei and ameliorated approximately 50% of the embryonic developmental defect caused by resveratrol. The findings of the present study, therefore, suggest that pifithrin-α could be used as an effective cytoprotective agent against a reproductive toxin such as resveratrol.

Topics: Animals; Benzothiazoles; Blastocyst; Cytoprotection; Embryo, Mammalian; Enzyme Inhibitors; Gene Expression Regulation, Developmental; Mice; Resveratrol; Stilbenes; Toluene; Tumor Suppressor Protein p53

This paper is to report the study of resveratrol-induced apoptosis and its mechanisms in MCF-7 cells. MTT assay was performed to assess the cytotoxicity of resveratrol on MCF-7 cells. Hoechst 33258 staining was used to observe cellular morphologic changes in apoptosis. Apoptosis was measured by flow cytometric analysis and the protein expression was examined by Western blotting analysis. The results indicated that resveratrol could inhibit MCF-7 cell growth in a time- and concentration-dependent manner. Remarkable morphologic changes in the cells after 60 micromol L(-1) resveratrol treatment, including cell nuclear shrinkage, DNA condensation and apoptotic bodies, were observed by Hoechst 33258 staining. Resveratrol could induce apoptosis and activate p38 and p53 in a time dependent manner in MCF-7 cells. In addition, the cell growth inhibitory ratio and the apoptotic ratio of resveratrol-treated group decreased markedly by the p38 MAPK inhibitor SB203580 or p53 inhibitor pifithrin-alpha. Further experiments confirmed that resveratrol-induced p53 activation was reduced by SB203580 whereas the activation of p38 was not affected by pifithrin-alpha. In conclusion, resveratrol induced apoptosis in MCF-7 cells could be through activating p38-p53 signal pathway.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Benzothiazoles; Cell Proliferation; Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; Imidazoles; MCF-7 Cells; p38 Mitogen-Activated Protein Kinases; Pyridines; Resveratrol; Signal Transduction; Stilbenes; Toluene; Tumor Suppressor Protein p53

The molecular basis for the sensitivity of tumor cells to chemopreventive natural food compounds and commonly used chemotherapeutic agents is not well understood, not least because studies are frequently confounded by the diversity among cell lines or rely on experimental protein overexpression. Here we investigated the effects of n-butyrate, a cancer-preventive short-chain fatty acid produced by anaerobic bacteria in the gastrointestinal tract, on the human wild-type p53 and p21 expressing HCT116 colon carcinoma cell line and on HCT116 cells with either p53 or p21 alleles inactivated by homologous recombination. The effects of n-butyrate were then compared with those elicited by cytotoxic drugs and the natural chemopreventive phytoalexin of wine and grapes, resveratrol. We document that physiological concentrations of n-butyrate stimulate p21 expression and induce apoptosis independently of p53, and that the absence of p21 increases apoptosis drastically. The apoptosis is mediated through the mitochondria and is accompanied by mitochondrial proliferation and membrane potential changes. Adriamycin, etoposide, cisplatinum, colcemid and resveratrol induce distinct cellular responses; however, absence of p21 favors apoptosis-induction by adriamycin, etoposide and colcemid. Thus, control of p21 expression may support chemoprevention and certain tumor therapies.

Topics: Adenocarcinoma; Alleles; Amino Acid Chloromethyl Ketones; Anticarcinogenic Agents; Antineoplastic Agents; Apoptosis; Benzothiazoles; Butyrates; Cisplatin; Colonic Neoplasms; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Cysteine Proteinase Inhibitors; Demecolcine; Doxorubicin; Drug Resistance, Neoplasm; Etoposide; Fluorouracil; Gene Expression Regulation, Neoplastic; Genes, p53; Humans; Intracellular Membranes; Membrane Potentials; Mitochondria; Neoplasm Proteins; Recombination, Genetic; Resveratrol; Stilbenes; Thiazoles; Toluene; Tumor Cells, Cultured; Tumor Suppressor Protein p53