Rosemary (Rosmarinus officinalis) Extract Modulates CHOP/GADD153 to Promote Androgen Receptor Degradation and Decreases Xenograft Tumor Growth

Abstract

The Mediterranean diet has long been attributed to preventing or delaying the onset of cardiovascular disease, diabetes and various solid organ cancers. In this particular study, a rosemary extract standardized to carnosic acid was evaluated for its potential in disrupting the endoplasmic reticulum machinery to decrease the viability of prostate cancer cells and promote degradation of the androgen receptor. Two human prostate cancer cell lines, 22Rv1 and LNCaP, and prostate epithelial cells procured from two different patients undergoing radical prostatectomy were treated with standardized rosemary extract and evaluated by flow cytometry, MTT, BrdU, Western blot and fluorescent microscopy. A significant modulation of endoplasmic reticulum stress proteins was observed in cancer cells while normal prostate epithelial cells did not undergo endoplasmic reticulum stress. This biphasic response suggests that standardized rosemary extract may preferentially target cancer cells as opposed to “normal” cells. Furthermore, we observed standardized rosemary extract to decrease androgen receptor expression that appears to be regulated by the expression of CHOP/GADD153. Using a xenograft tumor model we observed standardized rosemary extract when given orally to significantly suppress tumor growth by 46% compared to mice not receiving standardized rosemary extract. In the last several years regulatory governing bodies (e.g. European Union) have approved standardized rosemary extracts as food preservatives. These results are especially significant as it is becoming more likely that individuals will be receiving standardized rosemary extracts that are a part of a natural preservative system in various food preparations. Taken a step further, it is possible that the potential benefits that are often associated with a “Mediterranean Diet” in the future may begin to extend beyond the Mediterranean diet as more of the population is consuming standardized rosemary extracts.

Nano-liquid Chromatography-orbitrap MS-based Quantitative Proteomics Reveals Differences Between the Mechanisms of Action of Carnosic Acid and Carnosol in Colon Cancer Cells

“…In support of the activation of the reactive mode of UPR by CA treatment, several published studies suggest that CA induces ER stress in various cell types (21,24,29,49). Also, it has been shown that the UPR contributes signals to cell death pathways in CA-treated cells as consequence of severe or unresolved ER stress that determine cell fate (21,24), a mechanism that does not occur in the anticipatory UPR (48). It has been suggested that this effect was caused by a redox imbalance because of the elevation of intracellular reactive oxygen species (ROS) levels, a condition that is generally believed to alter ER homeostasis (24).…”

“…In our study, such UPR signaling pattern does not seem compatible with the observed elevated levels of the eleven ATF4-regulated proteins in CA-treated cells. In support of the activation of the reactive mode of UPR by CA treatment, several published studies suggest that CA induces ER stress in various cell types (21,24,29,49). Also, it has been shown that the UPR contributes signals to cell death pathways in CA-treated cells as consequence of severe or unresolved ER stress that determine cell fate (21,24), a mechanism that does not occur in the anticipatory UPR (48).…”

“…Indeed, the wide spectrum of molecular targets of CA and CS in cancer cells has been recently reviewed by Petiwala and Johnson (12). For instance, CS has been shown to target Bcl-2 (13), CREBbinding protein/p300 (14), NF-kB and c-Jun (15), ␤-catenin (16), p21 (9), ERK1/2 (17), Jak2/Src-STAT3 (18), AMPK-mTOR (19), androgen receptor and estrogen receptor ␣ (20,21), among others. In the case of CA, its anticancer activity has also been linked to different molecular targets.…”

Biological activities ofRosmarinus officinalisL. (rosemary) extract as analyzed in microorganisms and cells

“…19 From the oral cavity, P. aeruginosa can be disseminated systemically and cause respiratory infection, particularly in hospitalized and immunosuppressed patients. 20 The action of different types of R. officinalis L. extracts was reported on some tumor cell lines such as the ovarian cancer (SK-OV-3 and HO-8910), hepatocellular carcinoma (Bel-7402), 21 colorectal cancer (SW620 and DLD-1), pancreas cancer (MIA-PaCa-2 and PANC-1), 22 prostate cancer (LNCaP and 22Rv1), 23 colorectal adenocarcinoma (LoVo), hepatocarcinoma (HepG2). On the target lineages in this study, MCF-7 24 and HeLa, 25 the action of R. officinalis L has also been reported; however, in our study, we used three different cell viability tests and glycolic extract.…”

Inhibitory effects of wild dietary plants on lipid peroxidation and on the proliferation of human cancer cells

“…Anticarcinogenic effects of many plants derivatives, by inhibiting cancer cell proliferation in vitro, were assessed in many scientific reports (Galasso et al, 2014;Petiwala et al, 2014;Mastron et al, 2015).…”