psoralidin and Prostatic-Neoplasms

Cadmium, an established carcinogen, is a risk factor for prostate cancer. Induction of autophagy is a prerequisite for cadmium-induced transformation and metastasis. The ability of Psoralidin (Pso), a non-toxic, orally bioavailable compound to inhibit cadmium-induced autophagy to prevent prostate cancer was investigated.. Psoralidin was studied using cadmium-transformed prostate epithelial cells (CTPE), which exhibit high proliferative, invasive and colony forming abilities. Gene and protein expression were evaluated by qPCR, western blot, immunohistochemistry and immunofluorescence. Xenograft models were used to study the chemopreventive effects in vivo.. Cadmium-transformed prostate epithelial cells were treated with Pso resulting in growth inhibition, without causing toxicity to normal prostate epithelial cells (RWPE-1). Psoralidin-treatment of CTPE cells inhibited the expression of Placenta Specific 8, a lysosomal protein essential for autophagosome and autolysosome fusion, which resulted in growth inhibition. Additionally, Pso treatment caused decreased expression of pro-survival signalling proteins, NFκB and Bcl2, and increased expression of apoptotic genes. In vivo, Pso effectively suppressed CTPE xenografts growth, without any observable toxicity. Tumours from Pso-treated animals showed decreased autophagic morphology, mesenchymal markers expression and increased epithelial protein expression.. These results confirm that inhibition of autophagy by Pso plays an important role in the chemoprevention of cadmium-induced prostate carcinogenesis.

Topics: Animals; Apoptosis; Autophagosomes; Autophagy; Benzofurans; Blotting, Western; Cadmium; Carcinogenesis; Cell Proliferation; Cells, Cultured; Coumarins; Fluorescent Antibody Technique; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Lysosomes; Male; Mice, Nude; Neoplasm Transplantation; NF-kappa B; Polymerase Chain Reaction; Prostate; Prostatic Neoplasms; Proteins; Proto-Oncogene Proteins c-bcl-2

Oxidative stress is one causative factor of the pathogenesis and aggressiveness of most of the cancer types, including prostate cancer (CaP). A moderate increase in reactive oxygen species (ROS) induces cell proliferation whereas excessive amounts of ROS promote apoptosis. In this study, we explored the pro-oxidant property of 3,9-dihydroxy-2-prenylcoumestan (psoralidin [pso]), a dietary agent, on CaP (PC-3 and C4-2B) cells. Pso greatly induced ROS generation (more than 20-fold) that resulted in the growth inhibition of CaP cells. Overexpression of anti-oxidant enzymes superoxide dismutase 1 (SOD1), SOD2, and catalase, or pretreatment with the pharmacological inhibitor N-acetylcysteine (NAC) significantly attenuated both pso-mediated ROS generation and pso-mediated growth inhibition in CaP cells. Furthermore, pso administration significantly inhibited the migratory and invasive property of CaP cells by decreasing the transcription of β-catenin, and slug, which promote epithelial-mesenchymal transition (EMT), and by concurrently inducing E-cadherin expression in CaP cells. Pso-induced ROS generation in CaP cells resulted in loss of mitochondrial membrane potential, cytochrome-c release, and activation of caspase-3 and -9 and poly (ADP-ribose) polymerase (PARP), which led to apoptosis. On the other hand, overexpression of anti-oxidants rescued pso-mediated effects on CaP cells. These findings suggest that increasing the threshold of intracellular ROS could prevent or treat CaP growth and metastasis.

Topics: Acetylcysteine; Antioxidants; Apoptosis; Benzofurans; beta Catenin; Cadherins; Caspase 3; Caspase 9; Catalase; Cell Line, Tumor; Cell Movement; Cell Proliferation; Coumarins; Cytochromes c; Enzyme Activation; Epithelial-Mesenchymal Transition; Humans; Male; Membrane Potential, Mitochondrial; Neoplasm Invasiveness; Oxidative Stress; Poly(ADP-ribose) Polymerases; Prostatic Neoplasms; Reactive Oxygen Species; Snail Family Transcription Factors; Superoxide Dismutase; Superoxide Dismutase-1; Transcription Factors; Transcription, Genetic

Numerous compounds detected in medical plants and dietary components or supplements possess chemopreventive, antitumor and immunomodulatory properties. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an important endogenous anticancer factor that induces apoptosis selectively in cancer cells. However, some tumor cells are resistant to TRAIL-mediated apoptosis. Naturally occurring agents could sensitize TRAIL-resistant cancer cells and augment their apoptotic activity.We examined the cytotoxic and apoptotic effects of neobavaisoflavone and psoralidin in combination with TRAIL on LNCaP prostate cancer cells. The cytotoxicity was evaluated by MTT and LDH assays. The apoptosis was detected using Annexin V-FITC by flow cytometry and fluorescence microscopy. The LNCaP cells were shown to be resistant to TRAIL-induced apoptosis. Our study demonstrated that neobavaisoflavone and psoralidin sensitized TRAIL-resistant cells and markedly augmented TRAIL-mediated apoptosis and cytotoxicity in prostate cancer cells. Cotreatment of LNCaP cells with 100 ng/ml TRAIL and 50 μM neobavaisoflavone or 50 μM psoralidin increased the percentage of the apoptotic cells to 77.5±0.5% or 64.4±0.5%, respectively. The data indicate the potential role of the bioactive compounds isolated from the medicinal plant Psoralea corylifolia (neobavaisoflavone and psoralidin) in prostate cancer chemoprevention through enhancement of TRAIL-mediated apoptosis.

Topics: Apoptosis; Benzofurans; Cell Line, Tumor; Coumarins; Flow Cytometry; Humans; Isoflavones; Male; Microscopy, Fluorescence; Prostatic Neoplasms; Psoralea; TNF-Related Apoptosis-Inducing Ligand

The tumor necrosis factor (TNF) receptor super family comprises of members that induce two distinct signaling cascades, leading to either cell survival or apoptosis. However, in prostate cancer (PCa), TNF-mediated prosurvival signaling is the predominant pathway that leads to cell survival and resistance to therapy. Although inhibition of TNF signaling by pharmacological agents or monoclonal antibodies has gained importance in the field of cancer therapy, toxicity to normal cells has impaired their extensive use for cancer treatment. We previously identified a natural, nontoxic compound psoralidin that inhibited viability and induced apoptosis in androgen independent prostate cancer (AIPC) cells. Thus, the goal of our study is to investigate whether psoralidin inhibits TNF-mediated prosurvival signaling in AIPC cells. Our results suggest that psoralidin inhibits constitutive and TNF-induced expression of TNF-alpha and its downstream prosurvival signaling molecules such as NF-kappaB and Bcl-2 in AIPC cells. On the other hand, psoralidin simultaneously induces the death receptor (DR)-mediated apoptotic signaling eventually causing the activation of caspase cascade and resultant induction of apoptosis. Oral administration of psoralidin inhibits expression of TNF-alpha and NF-kappaB/p65 in tumor sections, resulting in tumor regression in PC-3 xenografts. Our results suggest that psoralidin inhibits TNF-mediated survival signaling in AIPC and thus is a potent therapeutic agent for prostate cancer.

Topics: Androgens; Animals; Apoptosis; Benzofurans; Caspases; Cell Line, Tumor; Cell Survival; Coumarins; Down-Regulation; Drug Resistance, Neoplasm; Humans; Male; Mice; NF-kappa B; Prostatic Neoplasms; Receptors, Death Domain; Recombinant Proteins; Signal Transduction; Transcription Factor RelA; Tumor Necrosis Factor-alpha; Xenograft Model Antitumor Assays

Epidermal growth factor receptor (EGFR) activation is an important event that regulates mitogenic signaling, such as the Raf, mitogen-activated protein kinase (MAPK), and extracellular signal-regulated kinase 1/2 cascades. EGFR activation has been implicated in the transition of prostate cancer from androgen dependence to independence. Therefore, inhibition of EGFR may effectively suppress prostate cancer growth and progression. The goal of this study was to determine whether the natural compound psoralidin alters EGFR-mediated signaling resulting in the inhibition of prostate cancer growth. Results suggest that inhibition of EGFR alone (by serum deprivation) fails to induce stress-mediated protein kinases (SAPK), namely, Jun NH(2)-terminal kinase/c-Jun signaling, in androgen-independent prostate cancer (AIPC) cells. Treatment with psoralidin, however, inhibited both constitutive and EGF-induced EGFR activation and simultaneously triggered SAPK signaling, resulting in the induction of apoptosis in AIPC cells. In addition, psoralidin downregulated EGFR-regulated MAPK signaling and inhibited cell proliferation in AIPC cells. Oral administration of psoralidin effectively suppressed PC-3 xenograft tumors in nude mice. Compared with control tumors, inhibition of pEGFR expression and an increase in the phosphorylation, activation, and nuclear translocation of c-Jun were observed in psoralidin-treated tumor sections. Our studies suggest that psoralidin may be a potent therapeutic agent that modulates EGFR-mediated key epigenetic events in AIPC.

Topics: Animals; Apoptosis; Benzofurans; Cell Line, Tumor; Coumarins; Down-Regulation; Enzyme Activation; ErbB Receptors; Humans; Immunohistochemistry; JNK Mitogen-Activated Protein Kinases; Male; MAP Kinase Signaling System; Mice; Phosphorylation; Prostatic Neoplasms; Transfection; Transplantation, Heterologous

The protein kinase Akt plays an important role in cell proliferation and survival in many cancers, including prostate cancer. Due to its kinase activity, it serves as a molecular conduit for inhibiting apoptosis and promoting angiogenesis in most cell types. In most of the prostate tumors, Akt signaling is constitutively activated due to the deletion or mutation of the tumor suppressor PTEN, which negatively regulates phosphatidylinositol 3-kinase through lipid phosphatase activity. Recently, we identified a natural compound, psoralidin, which inhibits Akt phosphorylation, and its consequent activation in androgen-independent prostate cancer (AIPC) cells. Furthermore, ectopic expression of Akt renders AIPC cells resistant to chemotherapy; however, psoralidin overcomes Akt-mediated resistance and induces apoptosis in AIPC cells. While dissecting the molecular events, both upstream and downstream of Akt, we found that psoralidin inhibits phosphatidylinositol 3-kinase activation and transcriptionally represses the activation of nuclear factor-kappaB and its target genes (Bcl-2, Survivin, and Bcl-xL, etc.), which results in the inhibition of cell viability and induction of apoptosis in PC-3 and DU-145 cells. Interestingly, psoralidin selectively targets cancer cells without causing any toxicity to normal prostate epithelial cells. In vivo xenograft assays substantiate these in vitro findings and show that psoralidin inhibits prostate tumor growth in nude mice. Our findings are of therapeutic significance in the management of prostate cancer patients with advanced or metastatic disease, as they provide new directions for the development of a phytochemical-based platform for prevention and treatment strategies for AIPC.

Topics: Animals; Benzofurans; Cell Line, Tumor; Cell Proliferation; Coumarins; Drug Screening Assays, Antitumor; Humans; Male; Mice; Mice, Nude; Neoplasm Transplantation; Phosphatidylinositol 3-Kinases; Plant Preparations; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Signal Transduction