Background: Originating from Africa, India, and the Middle East, frankincense oil has been important both socially and economically as an ingredient in incense and perfumes for thousands of years. Frankincense oil is prepared from aromatic hardened gum resins obtained by tapping Boswellia trees. One of the main components of frankincense oil is boswellic acid, a component known to have anti-neoplastic properties. The goal of this study was to evaluate frankincense oil for its anti-tumor activity and signaling pathways in bladder cancer cells.

We tested the hypothesis that insulin-like growth factor-I (IGF-I) stimulates ovarian androgen production by increasing theca-interstitial cell luteinizing hormone (LH) binding affinity and/or binding capacity. We then investigated the role of transcriptional and translational events in mediating these actions of IGF-I.LH bound to saturable, high affinity binding sites on rat ovarian theca-interstitial cells. Preincubation with LH produced a decrease in LH binding capacity with no effect on LH binding affinity. Treatment with IGF-I, both in the absence and presence of LH, increased LH binding capacity 1.5-to 2-fold with no change in LH binding affinity. Androgen production was increased progressively by LH, suggesting that LH-stimulated steroidogenesis is not tightly coupled to LH receptor downregulation. IGF-I increased androgen synthesis in proportion to its upregulation of LH binding capacity. Transcriptional inhibition with dichlorobenzimidazole riboside inhibited the IGF-I-mediated increase in LH binding capacity but had no effect on androgen production. Translational inhibition with cycloheximide inhibited both the IGF-I-mediated increase in LH binding and stimulation of androgen synthesis.We conclude that IGF-I increases theca-interstitial cell LH binding capacity and reverses the LH-induced downregulation of LH binding sites. The enhancement of LH binding by IGF-I is compatible with transcriptional mediation whereas the effect of IGF-I on androgen synthesis appears to be mediated by a direct effect of the peptide on the translational process(es) involved in steroidogenesis. (J. Clin. Invest. 1990. 86:560-565.)

BackgroundAldo-keto reductase (AKR) 1C family member 3 (AKR1C3), one of four identified human AKR1C enzymes, catalyzes steroid, prostaglandin, and xenobiotic metabolism. In the prostate, AKR1C3 is up-regulated in localized and advanced prostate adenocarcinoma, and is associated with prostate cancer (PCa) aggressiveness. Here we propose a novel pathological function of AKR1C3 in tumor angiogenesis and its potential role in promoting PCa progression.MethodsTo recapitulate elevated AKR1C3 expression in cancerous prostate, the human PCa PC-3 cell line was stably transfected with an AKR1C3 expression construct to establish PC3-AKR1C3 transfectants. Microarray and bioinformatics analysis were performed to identify AKR1C3-mediated pathways of activation and their potential biological consequences in PC-3 cells. Western blot analysis, reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and an in vitro Matrigel angiogenesis assays were applied to validate the pro-angiogenic activity of PC3-AKR1C3 transfectants identified by bioinformatics analysis.ResultsMicroarray and bioinformatics analysis suggested that overexpression of AKR1C3 in PC-3 cells modulates estrogen and androgen metabolism, activates insulin-like growth factor (IGF)-1 and Akt signaling pathways, as well as promotes tumor angiogenesis and aggressiveness. Levels of IGF-1 receptor (IGF-1R) and Akt activation as well as vascular endothelial growth factor (VEGF) expression and secretion were significantly elevated in PC3-AKR1C3 transfectants in comparison to PC3-mock transfectants. PC3-AKR1C3 transfectants also promoted endothelial cell (EC) tube formation on Matrigel as compared to the AKR1C3-negative parental PC-3 cells and PC3-mock transfectants. Pre-treatment of PC3-AKR1C3 transfectants with a selective IGF-1R kinase inhibitor (AG1024) or a non-selective phosphoinositide 3-kinases (PI3K) inhibitor (LY294002) abolished ability of the cells to promote EC tube formation.ConclusionsBioinformatics analysis followed by functional genomics demonstrated that AKR1C3 overexpression promotes angiogenesis and aggressiveness of PC-3 cells. These results also suggest that AKR1C3-mediated tumor angiogenesis is regulated by estrogen and androgen metabolism with subsequent IGF-1R and Akt activation followed by VEGF expression in PCa cells.

The angiogenic potential of a biomaterial is a critical factor for successful graft intake in tissue engineering. We developed a modified, rapid and reproducible chicken embryo chorioallantoic membrane (CAM) assay to evaluate the ability of biomaterials in inducing blood vessel density. Five biomaterials including one-layer porcine small intestinal submucosa (SIS), two-layer SIS, four-layer vacuum pressed (VP) SIS, polyglycolic acid (PGA) and PGA modified with poly(lactic-co-glycolic acid) (PLGA) were analyzed. A circular section (1.2 mm diameter) of each biomaterial was placed near a group of blood vessels in the CAM. Blood vessels around the biomaterials were captured with black and white images at 96 h post implantation; and the images were subjected to densitometry evaluation. One-layer SIS induced a significant increase in blood vessel density as compared to the cellulose nitrate negative control, and had the greatest increase in blood vessel density as compared to four-layer VP SIS, PGA, or PLGA modified PGA. Although two-layer SIS has enhanced physical structure for surgical manipulation, its induction in blood vessel density was significantly lower than the one-layer SIS. Stripping the SIS proteins or incubating one-layer SIS with neutralizing antibodies against basic fibroblast growth factor (bFGF) or vascular endothelial growth factor (VEGF) resulted in decreased angiogenesis. Consistent with results obtained from bladder augmentation animal models, these results confirmed that angiogenic growth factors were present in SIS and affected the angiogenic potential of biomaterials. These data also demonstrated that the CAM assay can be used to ascertain methodically the angiogenic potential of biomaterials.

Human aldo-keto reductase (AKR) 1C3 (type 2 3alpha-hydroxysteroid dehydrogenase/type 5 17beta-hydroxysteroid dehydrogenase) catalyzes androgen, estrogen, and prostaglandin metabolism. AKR1C3 is therefore implicated in regulating ligand access to the androgen receptor, estrogen receptor, and peroxisome proliferator activating receptor gamma in hormone target tissues. Recent reports on close relationships between ARK1C3 and various cancers including breast and prostate cancers implicate the involvement of AKR1C3 in cancer development or progression. We previously described the characterization of an isoform-specific monoclonal antibody against AKR1C3 that does not cross-react with related, >86% sequence identity, human AKR1C1, AKR1C2, or AKR1C4, human aldehyde reductase AKR1A1, or rat 3alpha-hydroxysteroid dehydrogenase (AKR1C9). In this study, a clone of murine monoclonal antibody raised against AKR1C3 was identified and characterized for its recognition of rat homolog. Tissue distribution of human AKR1C3 and its rat homolog in adult genitourinary systems including kidney, bladder, prostate, and testis was studied by IHC. A strong immunoreactivity was detected not only in classically hormone-associated tissues such as prostate and testis but also in non-hormone-associated tissues such as kidney and bladder in humans and rats. The distribution of these two enzymes was comparable but not identical between the two species. These features warrant future studies of AKR1C3 in both hormone- and non-hormone-associated tissues and identification of the rodent homolog for establishing animal models.