wogonin and Prostatic-Neoplasms

Prostate cancer (PCa) cells exploit cellular metabolic reprogramming as their survival advantage, especially aberrant lipid signaling and metabolism. Although recent studies deemed that PCa tends to rely on lipid fuel in comparison with aerobic glycolysis, the relationship between lipid metabolism and cancer growth remains unknown. We demonstrated that wogonin, a naturally occurring mono-flavonoid, could induce apoptosis of PCa cells in vivo and in vitro. Mechanistically, 100 μM wogonin significantly increased the expression of proteins related to the fatty acid synthesis and accumulation as a result of stimulation of AKT phosphorylation and nuclear accumulation of sterol regulatory element-binding protein 1 (SREBP1). The wogonin-induced up-regulation of fatty acid synthase (FASN) promoted fatty acid synthesis and storage, while increased oxidation in mitochondria driven by carnitine palmitoyl-transferase 1A (CPT1A) resulted in the loss of mitochondrial membrane potential and reactive oxygen species (ROS) accumulation, ultimately inducing apoptosis in DU145 and 22Rv1 cells. In vivo, 100 mg/kg of wogonin (i.v.) significantly repressed tumor growth without any obvious toxicity in the PCa xenograft model. In short, we proved that wogonin regulated the fatty acid metabolism and induced apoptosis by activating the AKT-SREBP1-FASN signaling network in human PCa cells, and it exhibited potent anti-tumor effects both in vivo and vitro. Thus it might be a promising candidate for the development of anti-cancer drugs.

Topics: Antineoplastic Agents; Apoptosis; Carnitine O-Acetyltransferase; Cell Line, Tumor; Fatty Acid Synthase, Type I; Fatty Acids; Flavanones; Humans; Lipid Metabolism; Male; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Sterol Regulatory Element Binding Protein 1

Prostate cancer (PCa) is a malignant tumor for which there are no effective treatment strategies. In this study, we developed a targeted strategy for prostate-specific membrane-antigen (PSMA)-positive PCa in vitro based on 2-(3-((S)-5-amino-1-carboxypentyl)ureido) pentanedioic acid (ACUPA) modified polyethylene glycol (PEG)-Cholesterol micelles containing wogonin (WOG), which was named ACUPA-M-WOG. ACUPA-M-WOG was conventionally prepared using a self-assembling method, which produced stable particle size and ζ potential. Moreover, ACUPA-M-WOG showed good drug encapsulating capacity and drug release profiles. Fluorescence activated cell sorting (FACS) results suggested that ACUPA modified PEG-Cholesterol micelles could effectively enhance the drug uptake on PSMA(+) PCa cells, and the cytotoxicity of ACUPA-M-WOG was stronger than other controls according to in vitro cellular proliferation and apoptosis assays, separately through methyl thiazolyl tetrazolium (MTT) and Annexin V/Propidium Iodide (PI) staining. Finally, the molecular mechanisms of ACUPA-M-WOG's effects on human PSMA(+) PCa were investigated, and were mainly the intrinsic or extrinsic apoptosis signaling pathways. The Western blot results suggested that ACUPA-M-WOG could enhance the WOG-induced apoptosis, which was mainly via the intrinsic signaling pathway rather than the extrinsic signaling pathway. In conclusion, ACUPA-M-WOG was successfully developed for WOG-selective delivery to PSMA(+) PCa cells and had stronger inhibition than free drugs, which might make it an effective strategy for PSMA(+) PCa.

Topics: Antigens, Surface; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cholesterol; Flavanones; Gene Expression Regulation, Neoplastic; Glutamate Carboxypeptidase II; Humans; Male; Micelles; Molecular Targeted Therapy; Pentanoic Acids; Polyethylene Glycols; Prostatic Neoplasms; Signal Transduction

The initial response rates of advanced-stage epithelial ovarian cancer to the chemotherapeutic agents carboplatin and paclitaxel are high. However, once drug resistance develops, further chemotherapy is less effective. The objective of this study is to investigate the anti-proliferative activity of the phyto-active chemicals (PACs) oridonin and wogonin in chemo-resistant epithelial ovarian cancer cells. Primary cell cultures from the ascitic fluid of three patients at diagnosis, two patients chemo-resistant to carboplatin and paclitaxel, and one patient treated with letrozole for breast cancer were studied and compared to the ovarian cancer cell lines A2780 and PTX10, by cell viability assay (MTS). Effects on cell cycle modulation and apoptosis were examined by flow cytometry and Western blot analysis (WB). WB was further conducted to investigate protein expressions altered by PACs. The results show that IC(50) of the primary cultures ranged from 0.6 to 5.4 μg/ml for oridonin and 0.3-12.7 μg/ml for wogonin. The paclitaxel-resistant cell line PTX10 was more sensitive to each of the PACs than the chemo-sensitive cell line A2780. Of particular interest is that in combination, the two PACs were synergistic in their cytotoxicity to five of six of the primary cultures and to both the cell lines (combination indices of 0.39-0.95). The inhibition is attributable to apoptosis and cell cycle modulation induced by the PACs as demonstrated in A2780 and PTX10. Up-regulation of the functional p53 protein in A2780 and down-regulation of Akt protein in PTX10 have in part contributed to the apoptosis. These findings suggest that oridonin and wogonin may have activity in ovarian cancer following its development of resistance to carboplatin and paclitaxel.

Topics: Aged; Antigens, Neoplasm; Ascites; Biomarkers, Tumor; Cell Adhesion Molecules; Cell Cycle; Cell Death; Cell Line, Tumor; Cell Proliferation; Cell Shape; Cell Survival; Diterpenes, Kaurane; Drug Screening Assays, Antitumor; Drug Therapy, Combination; Epithelial Cell Adhesion Molecule; Epithelial Cells; Female; Flavanones; Humans; Inhibitory Concentration 50; Male; Middle Aged; Neoplasm Proteins; Neoplasm Staging; Neoplastic Stem Cells; Ovarian Neoplasms; Prostatic Neoplasms; Staining and Labeling

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers apoptotic death in a variety of cancer cells without marked toxicity to most normal cells. We previously reported that wogonin, a potent anticancer agent from a Chinese herb, up-regulates p53 in prostate cancer cells. In this study, the effects of combinations of TRAIL and wogonin on a human prostate cancer cell line LNCaP, resistant to TRAIL, was evaluated for evidence of synergy in triggering apoptosis.. Western blot assay and the 'comet' assay were used to study the underlying mechanisms of cell death and search for any mechanisms of enhancement of TRAIL-induced apoptosis in the presence of wogonin.. During combined treatment with wogonin and TRAIL, cytotoxicity, poly(ADP-ribose) polymerase cleavage and caspase activation were associated with up-regulation of p53 through DNA damage and reactive oxygen species (ROS) generation. N-acetylcysteine (NAC), an antioxidant, inhibited ROS generation and synergistic interaction between TRAIL and wogonin. Experimental results in human colon cancer HCT116 cells demonstrated that p53-dependent Puma up-regulation played an important role; deficiency in either p53 or Puma prevented wogonin-enhanced TRAIL-induced apoptosis.. The present studies suggest that wogonin enhances TRAIL-induced cytotoxicity through up-regulation of p53 and Puma, mediated by ROS.

Topics: Antineoplastic Agents; Antioxidants; Apoptosis; Apoptosis Regulatory Proteins; bcl-2-Associated X Protein; Caspases; Cell Line, Tumor; DNA Damage; Drug Synergism; Enzyme Activation; Flavanones; Gene Knockdown Techniques; Histones; Humans; Male; Phosphorylation; Prostatic Neoplasms; Proto-Oncogene Proteins; Reactive Oxygen Species; Recombinant Proteins; RNA, Small Interfering; TNF-Related Apoptosis-Inducing Ligand; Tumor Suppressor Protein p53; Up-Regulation

The androgen receptor (AR) signaling pathway continues to be active in hormone resistant prostate cancer (HRPC) and can inappropriately activate transcription. Consequently the AR is a therapeutic target for HRPC. We reported that PC-SPES is active against HRPC, partly due to its actions in down-regulating AR protein expression and modulating cell cycle. Further investigation has identified five active anticancer compounds. This study describes the effects of three of these compounds (oridonin, isoliquiritigenin and wogonin) on cell proliferation, cell apoptosis, cell cycle parameters, AR and PSA protein expression. In each case, these compounds have independent activities which may partly contribute to the biological activity of PC-SPES.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Chalcones; Diterpenes; Diterpenes, Kaurane; Flavanones; Gene Expression Regulation, Neoplastic; Humans; Male; Plant Extracts; Prostate-Specific Antigen; Prostatic Neoplasms; Receptors, Androgen