Characterization of Precursor-Dependent Steroidogenesis in Human Prostate Cancer Models.

Castration-resistant prostate tumors acquire the independent capacity to generate androgens by upregulating steroidogenic enzymes or using steroid precursors produced by the adrenal glands for continued growth and sustainability. The formation of steroids was measured by liquid chromatography-mass spectrometry in LNCaP and 22Rv1 prostate cancer cells, and in human prostate tissues, following incubation with steroid precursors (22-OH-cholesterol, pregnenolone, 17-OH-pregnenolone, progesterone, 17-OH-progesterone). Pregnenolone, progesterone, 17-OH-pregnenolone, and 17-OH-progesterone increased C21 steroid (5-pregnan-3,20-dione, 5-pregnan-3,17-diol-20-one, 5-pregnan-3-ol-20-one) formation in the backdoor pathway, and demonstrated a trend of stimulating dihydroepiandrosterone or its precursors in the backdoor pathway in LNCaP and 22Rv1 cells. The precursors differentially affected steroidogenic enzyme messenger RNA (mRNA) expressions in the cell lines. The steroidogenesis following incubation of human prostate tissue with 17-OH-pregnenolone and progesterone produced trends similar to those observed in cell lines. Interestingly, the formation of C21 steroids from classical pathway was not stimulated but backdoor pathway steroids (e.g., 5-pregnan-3,20-dione, 5-pregnan-3-ol-20-one) were elevated following incubations with prostate tissues. Overall, C21 steroids were predominantly formed in the classical as well as backdoor pathways, and steroid precursors induced a diversion of steroidogenesis to the backdoor pathway in both cell lines and human prostate tissue, and influenced adaptive steroidogenesis to form C21 steroids.

Pomegranate extracts impact the androgen biosynthesis pathways in prostate cancer models in vitro and in vivo.

Castration-resistant prostate cancer (CRPC) remains largely dependent on androgen receptor (AR). Residual tissue androgens are consistently detected within CRPC tumors and play a critical role in facilitating AR-mediated signaling pathways which lead to disease progression. Testosterone and dihydrotestosterone (DHT) are the major androgens detected in tumors. They are produced through three biosynthesis pathways: Δ(4), Δ(5), and backdoor pathways. Both androgens bind to and stimulate AR activation. The current study investigates the effects of pomegranate extracts (POM) and their ability to inhibit androgen biosynthesis using PCa cell lines (22RV1 and LNCaP) in vitro as well as the PTEN knockout mouse model representing prostate cancer. Steroids were extracted using ethyl acetate or solid phase extraction, and then analyzed by UPLC/MS/MS. The results showed that POM (0-12µg/mL) reduced the production of testosterone, DHT, DHEA, androstenedione, androsterone, and pregnenolone in both cell lines. In addition our in vivo data supports this observation with a reduction in serum steroids determined after 20 weeks of POM treatment (0.17 g/L in drinking water). In accordance with these results, Western blotting of cell lysates and tPSA analysis determined that PSA was significantly decreased by the treatment of POM. Interestingly, AKR1C3 and AR levels were shown to be increased in both cell lines, perhaps as a negative feedback effect in response to steroid inhibition. Overall, these results provide mechanistic evidence to support the rationale for recent clinical reports describing efficacy of POM in CRPC patients.

The structure and absolute configuration of Shuangkangsu: a novel natural cyclic peroxide from Lonicera japonica (Thunb.).

A novel cyclic peroxide, shuangkangsu (1), has been obtained from the water extract of the buds of Lonicera japonica (Thunb.). The structure was elucidated as 5,8-divinyl-1,4-dihydro-1,4-di-O-beta-d-glucopyranosyl-2,3-dioxane (1) on the basis of the spectral data. Its absolute stereochemistry was determined to be (1S, 4S) by comparison of its CD curves with those of its optically pure analogs 2 and 3, which were synthesized from the phthalaldehyde. The absolute configurations of 2 and 3 were determined to be (1R, 4R) and (1S, 4S) by X-ray analysis and CD spectra, respectively. Compound 1 showed significant antiviral activities against influenza virus in chicken embryo and respiratory syncytial virus in cells.

A new compound from Geum rivale L.

A new compound, 1-O-methyl-6-O-caffeoyl-beta-D-glucopyranose (1), has been isolated from the aerial part of G. rivale, together with five known compounds, cecropiacic acid (2), niga-ichgoside (3), gallic acid (4), 1-o-protocatechuoylglucose (5), and sucrose (6). Their structures were elucidated by spectral methods and chemical reactions.

Chemical constituents of Ganoderma applanatum of British Columbia forests.

A new compound, ganoderma aldehyde (1),was isolated from the fruiting body of Ganoderma applanatum. Its structure was elucidated on the basis of one-dimensional and two-dimensional NMR as well as MS spectroscopic analysis.