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Background: The Purple mangosteen (Garcinia mangostana) has a long history of usage as a medicinal plant in Southeast Asia. Many studies have shown that the chemical constituents of Garcinia mangostana, mainly xanthone derivatives, have a variety of health-promoting properties including antioxidant, anti-inflammatory, antitumoral, antiallergic, antibacterial and antiviral activities. In this study, we evaluated the anticancer effects of gartanin, one of the major xanthones from the mangosteen fruit, in human prostate cancer cells. Next, we investigated the possible mechanisms involved in its anticancer effects. Methods: Two human prostate cancer cell lines, 22Rv1 and LNCaP, were treated with gartanin. Cell apoptosis, viability, proliferation, androgen receptor, prostate specific antigen (PSA), endoplasmic reticulum (ER) stress were evaluated by TdT-mediated dUTP Nick-End Labeling (TUNEL), 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), BrdU, Western blot, RT-PCR, androgen receptor competitor assay, siRNA transfection, ELISA and fluorescent microscopy. Results: Gartanin decreased viability and inhibited proliferation of prostate cancer cells in a dose-dependent manner. Gartanin induced apoptosis as evidenced by TUNEL staining, increased caspase-3 and Bax/Bcl-2 ratio. As a valuable target of prostate cancer, androgen receptor (AR) expression was significantly inhibited by gartanin. Further, gartanin was shown to be an effective AR antagonist, similar to flutamide. Gartanin decreased PSA, a prostate cancer risk factor regulated by the AR signaling pathway. Gartanin increased ER stress proteins and chaperones, such as phosphorylated PERK, CHOP, IRE1 and Bip. Gartanin also induced spliced XBP-1 mRNA, which is an ER stress marker. CHOP knockdown partly inhibited gartanin-induced apoptosis in LNCaP cells, as evidenced by cleaved caspase-3 decrease. Interestingly, CHOP knockdown showed evidence of restoring AR expression in gartanin treated cells. Conclusions: Our study demonstrated that gartanin inhibited proliferation and induced apoptosis on prostate cancer cells in vitro. It achieves its anticancer effects partly through inhibiting AR and promoting ER stress. The ability of gartanin to inhibit prostate cancer cells suggests further research is needed to evaluate gartanin as a novel agent for the management of prostate cancer. Citation Format: Gongbo Li, Sakina Petiwala, Jeremy Johnson. Gartanin from the mangosteen fruit modulates androgen receptor and ER stress proteins in prostate cancer cells leading to apoptosis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4110. doi:10.1158/1538-7445.AM2014-4110

Background: The Mediterranean herb rosemary has been used for culinary purposes and for their medicinal properties for millennia. Rosemary and its polyphenolic diterpenes (carnosol and carnosic acid) are known to possess anti-oxidant activity that may be beneficial for cancer control. Colorectal cancer is the second leading cause of death from cancer in the United States. Nutrition, particularly intake of vegetables and certain plant components, has been reported to have a major role in colon cancer risk reduction. In our current study, we investigated the anticancer effects of rosemary extract and its two main active ingredients carnosol and carnosic acid on colon cancer cell lines to understand the mechanism. Next, we evaluated the anti-cancer activity of rosemary extract in a nude mice model. Methods: Two human colon cancer cell lines, HCT116 and SW480, were treated with rosemary extract, carnosol or carnosic acid. MTT, TUNEL and ELISA were used to evaluate cell viability and apoptosis. Western blot and immunofluorescence were used to detect proteins involved in apoptosis. We also evaluated the anti-cancer activity of rosemary extract in nude mouse inoculated with HCT116 cells. Results: Rosemary extract, carnosol and carnosic acid, increased apoptosis, decreased viability in colon cancer cell lines. Rosemary extract, carnosol and carnosic acid significantly upregulated the expression of Nrf2 and ERK. Rosemary extract also effectively suppressed tumor growth in a xenograft tumor model without affecting body weight. Conclusions: Rosemary extract inhibits colon cancer cell growth in a xenograft mouse model without observable toxicity. Furthermore, rosemary extract, carnosol and carnosic acid induce the expression of Nrf2 and ERK pathways in colon cancer cells, suggesting further research is needed to evaluate its potential as an anti-cancer and/or chemoprevention agent. Citation Format: Miao Yan, Gongbo Li, Sakina M. Patiwala, Emily Householter, Jeremy J. Johnson. Anti-cancer activity of rosemary extract in colon cancer cells: Involvement of Nrf2 and ERK pathways. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4122. doi:10.1158/1538-7445.AM2014-4122

Background: Prostate cancer is one of the most prevalent forms of cancer among men, especially in the United States. Epidemiological studies have shown that consumption of natural dietary phytochemicals helps in prevention of many types of cancers. One such dietary phytochemical, rosemary (Rosmarinus officinalis), widely used in Mediterranean cuisine is well known for its antitumor activities. However, not much is known about the effect of rosemary on pathogenesis of prostate cancer. Androgens play a critical role in progression of prostate cancer and hence androgen receptor has been a target for prostate cancer treatment since a long time. Herein we have examined the effect of rosemary on prostate cancer progression. Specifically we have examined how rosemary promotes endoplasmic reticulum (ER) stress and modulates the activity and expression of androgen receptor (AR). Materials and Methods: Prostate cancer cell lines, 22Rv1 and LNCaP cells, were used for all experiments. Cell proliferation and cell viability were studied using BrdU and MTT assay respectively. Western blotting, ELISA and siRNA were used to determine the association between ER stress and AR degradation. Results: Rosemary inhibited growth and decreased the cell viability of 22Rv1 and LNCaP cells in a dose-dependent manner. The anti-proliferative effect was associated with apoptosis as evidenced by a significant increase in levels of cleaved caspase-3 protein and TUNEL assay. Moreover, upon treatment with rosemary we saw a dose-dependent decrease in expression of AR in 22Rv1 and LNCaP cells along with decreased PSA levels in LNCaP cells. Rosemary induced apoptosis was associated with ER stress as evidenced by up-regulation of ER stress proteins PERK, IRE1, BiP, CHOP, XBP-1 and caspase- 4. ER stress proteins are known to play an important role in folding of misfolded proteins and degrading continuously misfolded proteins. We therefore explored the relationship between ER stress and AR degradation. Interestingly, we observed that AR degradation was dependent on ER stress proteins BiP and CHOP. Conclusion: Rosemary induces ER stress-mediated apoptotic cell death in prostate cancer cell lines, 22Rv1and LNCaP cells, leading to disruption of AR expression. Our data suggests that this Mediterranean dietary phytochemical possess strong anticancer activity and should be evaluated further as potential chemopreventive and/or chemotherapeutic agent for controlling prostate cancer. Citation Format: Sakina M. Petiwala, Saba Berhe, Gongbo Li, Angela G. Puthenveetil, Larisa Nonn, Jeremy J. Johnson. The Mediterranean herb rosemary modulates ER stress proteins to promote androgen receptor degradation in prostate cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1255. doi:10.1158/1538-7445.AM2014-1255

Background: It is well-established that during endoplasmic reticulum (ER) stress cells utilize several cell signal pathways collectively named “unfolded protein reaction (UPR)” to re-establish homeostasis and promote cell survival. The upregulation of UPR proteins to an extent is thought to be a growth advantage for cancer cells. However, chronic ER stress or prolonged UPR will lead to apoptosis. Alpha-mangostin, a xanthone from mangosteen fruit, has been reported to effectively induce prostate cancer cell apoptosis in vitro and suppress xenograft tumor growth. Thus, we investigated the alteration of ER stress-related proteins in mangosteen fruit extract (MFE)- or α-Mangostin-treated prostate cancer cells as well as its correlation with apoptosis. Methods: Two human prostate cancer cell lines, 22Rv1 and LNCaP, and a prostate epithelial cell line were treated with MFE or α-mangostin. Flow cytometry, MTT and BrdU were used to evaluate cell apoptosis, viability and proliferation. Western blot and fluorescent microscopy were used to detect proteins involved in apoptosis or ER stress. We also evaluated the anti-cancer activity of MFE and α-mangostin in nude mice inoculated with 22Rv1 cells. In addition, pharmacokinetics data of α-mangostin was collected on wild type C57BL6 mice for toxicity concern. Results: MFE increased apoptosis, decreased viability and inhibited proliferation in prostate cancer cell lines. Both MFE and α-mangostin significantly upregulated the expression of ER stress proteins, such as PERK, CHOP and IRE1α. Both MFE and α-mangostin also effectively suppressed tumor growth in a xenograft tumor model without affecting body weight. Interestingly, CHOP knockdown enhanced apoptosis in α-mangostin-treated prostate cancer cells; both MFE and α-mangostin decreased PERK expression and did not induce ER stress in prostate epithelial cells (PrECs) from prostate cancer patients. Conclusions: Both MFE and α-mangostin selectively promote ER stress in prostate cancer cells and inhibit prostate cancer cell growth in a xenograft mouse model without observable toxicity, suggesting further research is needed to evaluate its potential as an anti-cancer agent. Citation Format: Gongbo Li, Sakina Petiwala, Dana Pierce, Jeremy Johnson. Selective modulation of CHOP/GADD153 in prostate cancer cells by alpha-mangostin promotes cell death. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3676. doi:10.1158/1538-7445.AM2013-3676

Background: Prostate cancer is one of the most prevalent forms of cancer among men, especially in the United States. Previously, we have shown that carnosol, a dietary diterpene from rosemary (Rosmarinus officinalis), has a unique function in that it is a dual disruptor of androgen and estrogen receptor alpha. Herein, we examined how carnosol and another dietary diterpene from rosemary, carnosic acid, promote endoplasmic reticulum (ER) stress and modulate the activity and expression of androgen receptor (AR). Materials and Methods: Experiments were performed using the prostate cancer cell lines 22Rv1 and LNCaP cells. Cell proliferation and cell viability were studied using BrdU and MTT assay respectively. Western blotting, ELISA and siRNA were used to evaluate the relationship between ER stress and androgen receptor degradation. Results: Both, carnosic acid and carnosol, inhibited growth and decreased the cell viability of 22Rv1 and LNCaP cells in a dose-dependent manner. The anti-proliferative effect was associated with apoptosis as evidenced by a significant increase in levels of cleaved caspase-3 protein. Interestingly, these diterpenes modulated proteins associated with ER stress including BiP, IRE1 and CHOP. Furthermore, we saw a dose-dependent decrease in expression of AR in 22Rv1 and LNCaP cells when treated with either carnosol or carnosic acid. The proteasome has been shown to be regulated by multiple proteins including proteins associated with ER stress. The AR expression increased in presence of proteasome inhibitor, MG-132, suggesting that decrease in AR expression was due to proteasomal degradation. Carnosic acid and carnosol, also showed a decrease in expression of prostate-specific antigen (PSA) levels in a dose-dependent manner. Conclusion: Both, carnosic acid and carnosol, induce ER stress-mediated apoptotic cell death in prostate cancer cell lines, 22Rv1and LNCaP cells, leading to disruption of AR expression. Our data suggests that these natural diterpenes possess strong anticancer activity and should be evaluated further as potential chemopreventive and/or chemotherapeutic agents for controlling prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2573. doi:1538-7445.AM2012-2573

Background: The mangosteen fruit (Garcinia mangostana) is native to Southeast Asia and has been reported to contain a variety of health promoting properties that include antioxidant, anti-inflammatory, anti-microbial and anti-diabetic activities. The principle constituents isolated from the mangosteen fruit are the xanthones with over 50 unique entities isolated to date. Prostate cancer (PCa) is the second most common cancer-related death in adult males and is ideal for evaluating promising cancer preventive agents because it develops at old age and is usually asymptomatic until advanced. This suggests that even a slight delay in the diagnosis of prostate cancer could have a profound public health impact. In our current study, we investigated the anticancer effects of a highly characterized mangosteen fruit extract on PCa cell lines to understand the mechanism of endoplasmic reticulum stress. Next, we evaluated the anticancer activity of mangosteen fruit extract in an athymic nude mouse model. Methods: Two human prostate cancer cell lines, 22Rv1 and LNCaP, were treated with a standardized mangosteen fruit extract. Flow cytometry, MTT, BrdU, and siRNA were used to evaluate cell apoptosis, cell viability and cell proliferation. Whole cell lysates were used to detect protein expression changes of androgen receptor (AR), pro-apoptotic protein Bax and other proteins involved in cell cycle or ER stress following treatment with mangosteen fruit extract. Next, we evaluated mangosteen fruit extract for anti-cancer activity in Athymic (nu/nu) nude mice inoculated with 22Rv1 cells. These mice received either mangosteen fruit extract or vehicle. In addition, a pharmacokinetics assay of mangosteen fruit extract, complete blood count (CBC), and serum biochemistry were performed on wild type C57BL6 mice for possible toxicity. Results: Our results demonstrate that mangosteen fruit extract effectively induced apoptosis, decreased cell viability and inhibited cell proliferation in multiple prostate cancer cell lines. Mangosteen fruit extract treatment induced a dose-dependent AR down-regulation and Bax up-regulation, induced G1 cell cycle arrest, and significantly increased the expression of ER stress proteins, such as PERK, CHOP and IRE1 in PCa cells. In addition, mangosteen fruit extract treatment significantly suppressed tumor growth in a xenograft tumor model and did not alter body weight, complete blood count or serum biochemistry in normal mice. Conclusion: Our results demonstrate that mangosteen fruit extract upregulated the ER stress proteins CHOP, PERK and IRE1. Mangosteen fruit extract treatment effectively suppressed PCa cell growth in a xenograft mouse model without obvious toxicity, suggesting further research is needed to determine its potential as a cancer preventive and/or therapeutic agent. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2574. doi:1538-7445.AM2012-2574