Prostate cancer (PCA) is the most frequently diagnosed invasive malignancy in the United States men and is the second leading cause of cancer-related deaths after lung (1). Chemoprevention of PCA has been suggested as a novel and rationale approach to control the growth, malignant progression and metastasis to secondary sites (2-4). In this regard, silibinin, isolated from the seeds of milk thistle (Silybum marianum), has shown promising anti-cancer effects in a number of cell culture and in vivo preclinical models of PCA (4- 9). Silibinin is already consumed extensively in the United States and world-wide as a dietary supplement, and used in clinic as a hepatoprotective agent (10-12). This compound has not shown any toxicity in animal studies as well as in humans (11,12), and recently entered pilot phase II clinical trial in PCA patients after completing a successful phase I clinical trial (13). During the funding period of the current grant, in addition to several other major findings, for the first time we identified that oral silibinin inhibits tumor angiogenesis and epithelial-mesenchymal transition (EMT) as well as distant metastasis in transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse model (Cancer Res. August 15, 2008) (14). The present continuation grant builds upon these highly novel observations, and proposes the studies to further establish the efficacy and define the mechanisms for antiangiogenic, antiinvasive and antimetastatic effects of silibinin. We hypothesize that silibinin modulates tumor and tumor microenvironment interaction, and inhibits the processes involved in PCA progression including hypoxia and the hypoxia-driven angiogenesis, invasion, migration and metastasis to distant sites. Together, by targeting these inter-related events, silibinin affords prevention, growth control and therapy of PCA. To test this hypothesis, detailed pre- clinical tumor studies and in depth molecular studies utilizing tumor tissues (and cell culture, where needed) will be performed with silibinin.
The specific aims of this competing renewal application are to: 1) examine and define the effect of silibinin on proliferation, metabolism, hypoxia and angiogenesis in PCA;2) examine and define the inhibitory effect of silibinin on EMT as well as invasive and migratory potential of PCA cells;and 3) identify the anti-metastatic efficacy of silibinin, and define its influence on tumor microenvironment at distant metastatic site. We anticipate that positive outcomes from the proposed studies together with earlier work will further reveal the mechanism-based cancer preventive and therapeutic efficacy of silibinin against PCA. The novelty of the proposed work lies in the fact that for the first time we would be studying in-depth the tumor microenvironment as a target of silibinin to inhibit tumor growth, progression and metastasis, as a strategy for controlling human PCA.
Project Narrative Prostate cancer is second leading cause of cancer-related deaths in United States, and thus is an important public health issue. Use of chemopreventive agents seems to be more effective approach for the control of prostate cancer as it has long latent period of development;sometimes over decade from precursor lesions to full blown disease. Current grant proposal focuses on the development of one such agent, namely silibinin, which is already consumed extensively in the United States and world-wide as a dietary supplement and used in the clinic as a hepatoprotective agent. This compound has not shown any toxicity in animal studies as well as in humans. The outcomes of our proposed research will provide a mechanism-based agent for the prevention and therapeutic intervention of prostate cancer in humans.
|Deep, Gagan; Kumar, Rahul; Nambiar, Dhanya K et al. (2017) Silibinin inhibits hypoxia-induced HIF-1?-mediated signaling, angiogenesis and lipogenesis in prostate cancer cells: In vitro evidence and in vivo functional imaging and metabolomics. Mol Carcinog 56:833-848|
|Ting, Harold; Deep, Gagan; Kumar, Sushil et al. (2016) Beneficial effects of the naturally occurring flavonoid silibinin on the prostate cancer microenvironment: role of monocyte chemotactic protein-1 and immune cell recruitment. Carcinogenesis 37:589-599|
|Deep, Gagan; Kumar, Rahul; Jain, Anil K et al. (2016) Graviola inhibits hypoxia-induced NADPH oxidase activity in prostate cancer cells reducing their proliferation and clonogenicity. Sci Rep 6:23135|
|Qin, Jiang-Jiang; Wang, Wei; Sarkar, Sushanta et al. (2016) Inulanolide A as a new dual inhibitor of NFAT1-MDM2 pathway for breast cancer therapy. Oncotarget 7:32566-78|
|Qin, Jiang-Jiang; Sarkar, Sushanta; Voruganti, Sukesh et al. (2016) Identification of lineariifolianoid A as a novel dual NFAT1 and MDM2 inhibitor for human cancer therapy. J Biomed Res 30:322-33|
|Kaur, Amninder; Raja, Huzefa A; Swenson, Dale C et al. (2016) Talarolutins A-D: Meroterpenoids from an endophytic fungal isolate of Talaromyces minioluteus. Phytochemistry 126:4-10|
|Kaur, Amninder; Raja, Huzefa A; Deep, Gagan et al. (2016) Pannorin B, a new naphthopyrone from an endophytic fungal isolate of Penicillium sp. Magn Reson Chem 54:164-7|
|Kavitha, Chandagirikoppal V; Jain, Anil K; Agarwal, Chapla et al. (2015) Asiatic acid induces endoplasmic reticulum stress and apoptotic death in glioblastoma multiforme cells both in vitro and in vivo. Mol Carcinog 54:1417-29|
|Nambiar, Dhanya K; Rajamani, Paulraj; Deep, Gagan et al. (2015) Silibinin Preferentially Radiosensitizes Prostate Cancer by Inhibiting DNA Repair Signaling. Mol Cancer Ther 14:2722-34|
|Ramteke, Anand; Ting, Harold; Agarwal, Chapla et al. (2015) Exosomes secreted under hypoxia enhance invasiveness and stemness of prostate cancer cells by targeting adherens junction molecules. Mol Carcinog 54:554-65|
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