noscapine and Prostatic-Neoplasms

Bitter taste receptors (Tas2Rs) are a subfamily of G-protein coupled receptors expressed not only in the oral cavity but also in several extra-oral tissues and disease states. Several natural bitter compounds from plants, such as bitter melon extract and noscapine, have displayed anti-cancer effects against various cancer types. In this study, we examined the prevalence of Tas2R subtype expression in several epithelial ovarian or prostate cancer cell lines, and the functionality of Tas2R14 was determined. qPCR analysis of five TAS2Rs demonstrated that mRNA expression often varies greatly in cancer cells in comparison to normal tissue. Using receptor-specific siRNAs, we also demonstrated that noscapine stimulation of ovarian cancer cells increased apoptosis in ovarian cancer cells in a receptor-dependent, but ROS-independent manner. This study furthers our understanding of the function of Tas2Rs in ovarian cancer by demonstrating that their activation has an impact on cell survival.

Topics: Apoptosis; Cell Line, Tumor; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Noscapine; Ovarian Neoplasms; Prostatic Neoplasms; Receptors, G-Protein-Coupled

We have previously shown that a novel microtubule-modulating noscapinoid, EM011 (9-Br-Nos), displays potent anticancer activity by inhibition of cellular proliferation and induction of apoptosis in prostate cancer cells and preclinical mice models. However, physicochemical and cellular barriers encumber the development of viable formulations for future clinical translation. To circumvent these limitations, we have synthesized EM011-cyclodextrin inclusion complexes to improve solubility and enhance therapeutic index of EM011. Phase solubility analysis indicated that EM011 formed a 1:1 stoichiometric complex with β-CD and methyl-β-CD, with a stability constant (K(c)) of 2.42 × 10(-3) M and 4.85 × 10(-3) M, respectively. Fourier transform infrared spectroscopy suggested the penetrance of either a O-CH(2) or OCH(3)-C(6)H(4)-OCH(3) moiety of EM011 in the β-CD or methyl-β-CD cavity. In addition, multifarious techniques, namely, differential scanning calorimetry, powder X-ray diffraction, scanning electron microscopy, NMR spectroscopy, and computational studies validated the cage complex of EM011 with β-CD and methyl-β-CD. Moreover, rotating frame overhauser enhancement spectroscopy showed that the H(a) proton of the OCH(3)-C(6)H(4)-OCH(3) moiety was in close proximity with H3 proton of the β-CD or methyl-β-CD cavity. Furthermore, we found that the solubility of EM011 in phosphate buffer saline (pH 7.4) was enhanced by ~11 fold and ~21 fold upon complexation with β-CD and methyl-β-CD, respectively. The enhanced dissolution of the drug CD-complexes in aqueous phase remarkably decreased their IC(50) to 28.5 μM (9-Br-Nos-β-CD) and 12.5 μM (9-Br-Nos-methyl-β-CD) in PC-3 cells compared to free EM011 (~200 μM). This is the first report to demonstrate the novel construction of cylcodextrin-based nanosupramolecular vehicles for enhanced delivery of EM011 that warrants in vivo evaluation for the superior management of prostate cancer.

Topics: Calorimetry, Differential Scanning; Cell Line, Tumor; Cell Survival; Cyclodextrins; Dioxoles; Humans; Isoquinolines; Magnetic Resonance Spectroscopy; Male; Noscapine; Prostatic Neoplasms; Solubility; Spectroscopy, Fourier Transform Infrared; X-Ray Diffraction

The tubulin-binding anticancer activity of noscapine, an orally available plant-derived anti-tussive alkaloid, has been recently identified. Noscapine inhibits tumor growth in nude mice bearing human xenografts of hematopoietic, breast, lung, ovarian, brain and prostate origin. Despite its nontoxic attributes, significant elimination of the disease has not been achieved, perhaps since the bioavailability of noscapine to tumors saturates at an oral dose of 300 mg/kg body weight. To enable the selective and specific delivery of noscapine to prostate cancer cells, we have engineered a multifunctional nanoscale delivery vehicle that takes advantage of urokinase plasminogen activator receptor (uPAR) overexpression in prostate cancer compared to normal prostate epithelia and can be tracked by magnetic resonance imaging (MRI) and near-infrared (NIR) imaging. Specifically, we employed the human-type 135 amino-acid amino-terminal fragment (hATF) of urokinase plasminogen activator (uPA), a high-affinity natural ligand for uPAR. Noscapine (Nos) was efficiently adsorbed onto the amphiphilic polymer coating of uPAR-targeted nanoparticles (NPs). Nos-loaded NPs were uniformly compact-sized, stable at physiological pH and efficiently released the drug at pH 4 to 5 within a span of 4h. Our results demonstrate that these uPAR-targeted NPs were capable of binding to the receptor and were internalized by PC-3 cells. uPAR-targeted Nos-loaded NPs enhanced intracellular noscapine accumulation as evident by the ~6-fold stronger inhibitory effect on PC-3 growth compared to free noscapine. In addition, Nos-loaded iron oxide NPs maintained their T2 MRI contrast effect upon internalization into tumor cells owing to their significant susceptibility effect in cells. Thus, our data provide compelling evidence that these optically and magnetic resonance imaging (MRI)-trackable uPAR-targeted NPs may offer a great potential for image-directed targeted delivery of noscapine for the management of prostate cancer.

Topics: Antineoplastic Agents; Antitussive Agents; Cell Line; Cell Line, Tumor; Cell Survival; Drug Delivery Systems; Gene Expression Regulation, Neoplastic; Humans; Magnetic Resonance Imaging; Male; Nanoparticles; Noscapine; Prostate; Prostatic Neoplasms; Receptors, Urokinase Plasminogen Activator

Noscapine has demonstrated potent antitumour activity and minimum toxicity in cancer models. Recently, noscapine has been shown to limit tumour growth and lymphatic metastasis of PC3 human prostate cancer mice. The prophylactic effects of noscapine are not known.. Nude mice received oral noscapine (300 mg/kg per day; 'treatment'; n=10) or diluent ('control'; n=10) for 56 days, beginning 7 days after inoculation with PC3 human prostate cancer cells; or noscapine for 70 days, beginning 7 days before inoculation ('pretreatment'; n=10).. Mean total tumour volumes were 1731.6+/-602.0 mm(3) in the control group, 644.3+/-545.1 mm(3) in the noscapine pretreatment group and 910.9+/-501.1 mm(3) in the noscapine treatment group (p<0.001 pretreatment vs. control, p<0.05 pretreatment vs. control, p<0.001 pretreatment vs. treatment group), with no evidence of toxicity. Noscapine pretreatment and treatment also reduced tumour weight, the incidence of metastasis and primary tumour inhibition rate.. Pretreatment with oral noscapine limited tumour growth and lymphatic metastasis of PC3 human prostate cancer in this mouse model and conferred a significant additional benefit over noscapine treatment in final tumour volume.

Topics: Animals; Antitussive Agents; Cell Line, Tumor; Disease Models, Animal; Disease Progression; Humans; Lymphatic Metastasis; Male; Mice; Mice, Nude; Noscapine; Prostatic Neoplasms; Xenograft Model Antitumor Assays