xanthohumol and Prostatic-Neoplasms

Fourier Transform Infrared spectroscopy was applied to detect in vitro cell death induced in prostate (PC-3) and breast (T47D) cancer cell lines treated with xanthohumol (XN). After incubation of the cancer cells with XN, specific spectral shifts in the infrared spectra arising from selected cellular components were identified that reflected biochemical changes characteristic for apoptosis and necrosis. Detailed analysis of specific absorbance intensity ratios revealed the compositional changes in the secondary structure of proteins and membrane lipids. In this study, for the first time we examined the changes in these molecular components and linked them to deduce the involvement of molecular mechanisms in the XN-induced death of the selected cancer cells. We showed that XN concentration-dependent changes were attributed to phospholipid ester carbonyl groups, especially in the case of T47D cells, suggesting that XN acts as an inhibitor of cell proliferation. Additionally, we observed distinct changes in the region assigned to the absorption of DNA, which were correlated with a specific marker of cell death and dependent on the XN dose and the type of cancer cells. The microscopic observation and flow cytometry analysis revealed that the decrease in cancer cell viability was mainly related to the induction of necrotic cell death. Moreover, the T47D cells were slightly more sensitive to XN than the PC-3 cells. Considering the results obtained, it can be assumed that apoptosis and necrosis induced by XN may contribute to the anti-proliferative and cytotoxic properties of this flavonoid against cancer cell lines PC-3 and T47D.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Drug Screening Assays, Antitumor; Female; Flavonoids; Humans; Male; Propiophenones; Prostatic Neoplasms; Spectroscopy, Fourier Transform Infrared

Radix Sophorae flavescentis is generally used for the treatment of different stages of prostate cancer in China. It has ideal effects when combined with surgical treatment and chemotherapy. However, its active components are still ambiguous. We devised a comprehensive two-dimensional PC-3 prostate cancer cell membrane chromatography system for screening anti-prostate cancer components in Radix Sophorae flavescentis. Gefitinib and dexamethasone were chosen as positive and negative drugs respectively for validation and optimization the selectivity and suitability of the comprehensive two-dimensional chromatographic system. Five compounds, sophocarpine, matrine, oxymatrine, oxysophocarpine, and xanthohumol were found to have significant retention behaviors on the PC-3 cell membrane chromatography and were unambiguously identified by time-of-flight mass spectrometry. Cell proliferation and apoptosis assays confirmed that all five compounds had anti-prostate cancer effects. Matrine and xanthohumol had good inhibitory effects, with half maximal inhibitory concentration values of 0.893 and 0.137 mg/mL, respectively. Our comprehensive two-dimensional PC-3 prostate cancer cell membrane chromatographic system promotes the efficient recognition and rapid analysis of drug candidates, and it will be practical for the discovery of prostate cancer drugs from complex traditional Chinese medicines.

Topics: Alkaloids; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cell Membrane; China; Chromatography, High Pressure Liquid; Drug Screening Assays, Antitumor; Drugs, Chinese Herbal; Flavonoids; Humans; Male; Matrines; Propiophenones; Prostatic Neoplasms; Quinolizines; Sophora

TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is an endogenous ligand, which plays role in immune surveillance and anti-tumor immunity. It has ability to selectively kill tumor cells showing no toxicity to normal cells. We tested the apoptotic and cytotoxic activities of xanthohumol, a prenylated chalcone found in Humulus lupulus on androgen-sensitive human prostate adenocarcinoma cells (LNCaP) in combination with TRAIL. Cytotoxicity was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide tetrazolium reduction assay (MTT) and lactate dehydrogenase assay (LDH). The expression of death receptors (DR4/TRAIL-R1 and DR5/TRAIL-R2) and apoptosis were detected using flow cytometry. We examined mitochondrial membrane potential (ΔΨm) by DePsipher reagent using fluorescence microscopy. The intracellular expression of proteins was evaluated by Western blotting. Our study showed that xanthohumol enhanced cytotoxic and apoptotic effects of TRAIL. The tested compounds activated caspases-3, -8, -9, Bid, and increased the expression of Bax. They also decreased expression of Bcl-xL and decreased mitochondrial membrane potential, while the expression of death receptors was not changed. The findings suggest that xanthohumol is a compound of potential use in chemoprevention of prostate cancer due to its sensitization of cancer cells to TRAIL-mediated apoptosis.

Topics: Adenocarcinoma; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Flavonoids; Humans; Humulus; Ligands; Male; Plant Extracts; Propiophenones; Prostatic Neoplasms; Receptors, Death Domain; Tumor Necrosis Factor-alpha

Despite recent advances in understanding the biological basis of prostate cancer, management of the disease, especially in the phase resistant to androgen ablation, remains a significant challenge. The long latency and high incidence of prostate carcinogenesis provides the opportunity to intervene with chemoprevention to prevent or eradicate prostate malignancies. In this study, we have used human hormone-resistant prostate cancer cells, DU145 and PC3, as an in vitro model to assess the efficacy of xanthohumol (XN) against cell growth, motility and invasion. We observed that treatment of prostate cancer cells with low micromolar doses of XN inhibits proliferation and modulates focal adhesion kinase (FAK) and AKT phosphorylation leading to reduced cell migration and invasion. Oxidative stress by increased production of reactive oxygen species (ROS) was associated with these effects. Transgenic adenocarcinoma of the mouse prostate (TRAMP) transgenic mice were used as an in vivo model of prostate adenocarcinoma. Oral gavage of XN, three times per week, beginning at 4 wks of age, induced a decrease in the average weight of the urogenital (UG) tract, delayed advanced tumor progression and inhibited the growth of poorly differentiated prostate carcinoma. The ability of XN to inhibit prostate cancer in vitro and in vivo suggests that XN may be a novel agent for the management of prostate cancer.

Topics: Administration, Oral; Androgens; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Transformation, Neoplastic; Disease Progression; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Flavonoids; G1 Phase; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neoplasm Invasiveness; Neoplasm Staging; Propiophenones; Prostatic Neoplasms; Reactive Oxygen Species; Resting Phase, Cell Cycle

Promotion of apoptosis in cancer cells could potentially lead to the regression and improved prognosis of hormone-refractory prostate cancer. Xanthohumol (XN), a prenylated chalcone-derived from hops, has shown strong antitumorigenic activity towards diverse types of cancer cells. In the present study, the growth-inhibitory and apoptosis-inducing activity of XN was tested in hormone-sensitive and hormone-refractory human prostate cancer cells lines. Cell growth/viability assay (MTS) demonstrated that prostate cancer cells are highly sensitive to XN at a concentration range of 20-40 μM. The primary mode of tumor cell destruction was apoptosis as demonstrated by the binding of annexin V-FITC, cleavage of PARP-1, activation of procaspases -3, -8, and -9, mitochondrial depolarization and release of cytochrome c from mitochondria. Induction of apoptosis by XN was associated with the inhibition of prosurvival Akt, NF-κB and mTOR signaling proteins and NF-κB-regulated anti-apoptotic Bcl-2 and survivin. These studies provide a rationale for clinical evaluation of XN for the treatment of hormone-refractory metastatic prostate cancer.

Topics: Antineoplastic Agents; Apoptosis; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Flavonoids; Humans; Humulus; Male; Membrane Potential, Mitochondrial; Phytotherapy; Plant Extracts; Propiophenones; Prostatic Neoplasms; Signal Transduction

Xanthohumol (X), isoxanthohumol (IX), 8-prenylnaringenin (8PN) and 6-prenylnaringenin (6PN), prenylflavonoids from hop (Humulus lupulus L.), were investigated for their cytotoxicity and the mechanism by which they exert cell death when incubated with prostate cancer cell lines PC-3 and DU145. All compounds induced cell death in the absence of caspase-3 activation and typical apoptotic morphological features. The general pan-caspase inhibitor zVAD-fmk could not protect this form of cell death. In addition, the formation of vacuoles was observed in PC-3 cells treated with IX and 6PN, and in DU145 treated with IX, 8PN and 6PN, which could suggest the induction of autophagy and consequent cell death. The results indicate that hop-derived prenylflavanones (IX, 8PN, 6PN), but not prenylchalcones (X) induce a caspase-independent form of cell death, suggested to be autophagy. Therefore, IX, 8PN and 6PN appear to be promising candidates for further investigation in prostate anticancer therapy.

Topics: Amino Acid Chloromethyl Ketones; Caspase 3; Caspase Inhibitors; Caspases; Cell Death; Cell Line, Tumor; Cell Survival; Cysteine Proteinase Inhibitors; Dose-Response Relationship, Drug; Flavanones; Flavonoids; Humans; Humulus; Male; Molecular Structure; Plant Extracts; Propiophenones; Prostatic Neoplasms; Xanthones

There is increasing evidence that certain natural compounds found in plants may be useful as cancer chemopreventive or chemotherapeutic agents. Limited in vitro studies indicate that several prenylated flavonoids present in the hop plant (Humulus lupulus) possess anticarcinogenic properties. The purpose of this study was to investigate the anti-tumorigenic effects of xanthohumol (XN), the major prenylflavonoid in hops, on prostate cancer and benign prostate hyperplasia. BPH-1 and PC3 cell lines were used in our study to represent both non-tumorigenic hyperplasia and malignant prostate cancer. In both BPH-1 and PC3 cells, XN and its oxidation product, XAL, decreased cell viability in a dose dependent manner (2.5-20 microM) as determined by MTT assay and caused an increase in the formation of early and late apoptotic cells as determined by Annexin V staining and multicaspase assays. XN and its oxygenated derivative also induced cell cycle changes in both cells lines, seen in an elevated sub G1 peak at 48h treatment. Western blot analysis was performed to confirm the activation of proapoptotic proteins, Bax and p53. XN and its derivative caused decreased activation of NFkappaB. This work suggests that XN and its oxidation product, XAL, may be potentially useful as a chemopreventive agent during prostate hyperplasia and prostate carcinogenesis, acting via induction of apoptosis and down-regulation of NFkappaB activation in BPH-1 cells.

Topics: Apoptosis; Blotting, Western; Cell Cycle; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Epithelial Cells; Flavonoids; Flow Cytometry; Humans; Humulus; Male; Molecular Structure; NF-kappa B; Propiophenones; Prostatic Hyperplasia; Prostatic Neoplasms

Chalcones xanthohumol (X) and desmethylxanthohumol (DMX), present in hops (Humulus lupulus L.), and the corresponding flavanones isoxanthohumol (IX, from X), 8-prenylnaringenin (8-PN, from DMX), and 6-prenylnaringenin (6-PN, from DMX), have been examined in vitro for their anti-proliferative activity on human prostate cancer cells PC-3 and DU145. X proved to be the most active compound in inhibiting the growth of the cell lines with IC50 values of 12.3+/-1.1 microM for DU145 and 13.2+/-1.1 microM for PC-3. 6-PN was the second most active growth inhibitor, particularly in PC-3 cells (IC50 of 18.4+/-1.2 microM). 8-PN, a highly potent phytoestrogen, exhibited pronounced anti-proliferative effects on PC-3 and DU145 (IC50 of 33.5+/-1.0 and 43.1+/-1.2 microM, respectively), and IX gave comparable activities (IC50 of 45.2+/-1.1 microM for PC-3 and 47.4+/-1.1 microM for DU145). DMX was the least active compound. It was evidenced for the first time that this family of prenylated flavonoids from hops effectively inhibits proliferation of prostate cancer cells in vitro.

Topics: Cell Line, Tumor; Cell Proliferation; Flavonoids; Humans; Humulus; Male; Phytotherapy; Propiophenones; Prostatic Neoplasms