genistin and Lung-Neoplasms

Here, we attempted to identify novel target genes of genistein in human A549 cells. Using analysis of proteins related to cell cycle and apoptotic pathways, we confirmed an elevated level of p53 accompanying p21 Waf1/Cip1 protein in genistein-treated or genistin-treated A549 and WI-38 cells, but not in HeLa cells. In addition, a p53-upregulated modulator of apoptosis (Puma) protein accumulated significantly in genistein-treated A549 and WI-38 cells, but not in genistin-treated or beta-estradiol-treated cells, though the growth of any ingredient-treated cells was severely inhibited. Intriguingly, the caspase-3 activity of genistein-treated A549 cells, in which Puma or p53 expression was knocked-down by RNA interference (RNAi), remained unaltered compared to that in cells transfected with irrelevant RNAi. These results raise a concern that molecular targets identified by powerful omic approaches may not necessarily represent key molecules responsible for given cellular phenotypes and thus must be verified by conclusive assays.

Topics: Antineoplastic Agents; Apoptosis Regulatory Proteins; Bromodeoxyuridine; Caspase 3; Cell Division; Cell Line; Cell Line, Tumor; Genistein; HeLa Cells; Humans; Isoflavones; Lung Neoplasms; Proto-Oncogene Proteins; RNA Interference; RNA, Small Interfering; Tetrazolium Salts

Systematic analysis of the influence of diet on the initiation and progression of prostate cancer is often difficult in human populations, for which dietary variables overlap a diversity of genetic backgrounds and social behaviors. Animal models that emulate human prostate cancer allow experimental analysis of the mechanisms of action of nutritional agents that show anti-prostate cancer activity.. We have used an orthotopic implant model to characterize the in vivo response of androgen-sensitive LNCaP prostate tumors to three well-characterized soy dietary supplements: isoflavone depleted soy protein, soy phytochemical concentrate (SPC), and genistin.. In male SCID mice orthotopically implanted with the androgen-sensitive human prostate cell line LNCaP, dietary supplements of soy protein, genistin, and SPC reduced primary tumor weight by 42% (P = 0.07), 57% (P < 0.05) and 70% (P < 0.005), respectively. All three soy supplements significantly increased tumor apoptosis and decrease microvessel density, with no significant change in tumor proliferation. Each supplement produced a distinct serum androgen response, with genistin producing the greatest decrease in total serum testosterone and dihydrotestosterone (DHT) (P < 0.05) and the greatest increase in testosterone to DHT ratio (P < 0.05) and soy protein the greatest decrease in bioactive androgen (P < 0.05). Only SPC significantly inhibited metastases to lymph nodes and lungs, and only SPC produced a significant increase in tumor p53 expression.. Taken together, these data suggest that the anti-prostate cancer activity of dietary soy protein, soy phytochemicals, and genistin use different molecular pathways. In addition, we have demonstrated that this animal model can be used in the design of dietary strategies for prostate cancer prevention and therapy.

Topics: Animals; Apoptosis; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Dihydrotestosterone; Glycine max; Humans; Isoflavones; Lung Neoplasms; Lymph Nodes; Male; Mice; Mice, SCID; Neoplasms, Hormone-Dependent; Neovascularization, Pathologic; Plant Extracts; Prostatic Neoplasms; Random Allocation; Receptors, Androgen; Soybean Proteins; Specific Pathogen-Free Organisms; Testosterone; Tumor Cells, Cultured; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

The multidrug resistance protein (MRP) is an ATP-dependent transport protein for organic anions, as well as neutral or positively charged anticancer agents. In this study we report that dinitrophenyl-S-glutathione increases ATPase activity in plasma membrane vesicles prepared from the MRP-overexpressing cell line GLC4/ADR. This ATPase stimulation parallels the uptake of DNP-SG in these vesicles. We also show that the (iso)flavonoids genistein, kaempferol and flavopiridol stimulate the ATPase activity of GLC4/ADR membranes, whereas genistin has no effect. The present data are consistent with the hypothesis that certain (iso)flavonoids affect MRP-mediated transport of anticancer drugs by a direct interaction with MRP.

Topics: Adenosine Triphosphatases; ATP-Binding Cassette Transporters; Carcinoma, Small Cell; Cell Membrane; Drug Resistance, Multiple; Flavonoids; Genistein; Glutathione; Humans; Isoflavones; Kaempferols; Lung Neoplasms; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Piperidines; Quercetin; Tumor Cells, Cultured