Background and Hypothesis: Because prostate cancer is a leading cause of cancer related deaths among men in the United States, novel strategies to prevent this disease are highly desirable. During the funded period of this grant, we demonstrated that cruciferous vegetable constituent phenethyl isothiocyanate (PEITC) suppresses growth of prostate cancer cells in culture and in vivo irrespective of their androgen responsiveness or p53 status. The PEITC-mediated suppression of prostate cancer cell growth correlated with type I apoptotic cell death as well as type II autophagic death. We also found that PEITC is a potent suppressor of angiogenesis in vitro and ex vivo. The present continuation application builds upon these novel observations and proposes experiments that will not only test the efficacy of dietary PEITC administration for prevention of prostate carcinogenesis and metastasis in a transgenic mouse model of prostate cancer (TRAMP) but also fill the gaps in our knowledge concerning mechanism of its anticarcinogenic effects. We hypothesize that PEITC administration will prevent prostate carcinogenesis and metastasis in TRAMP mice by causing apoptotic and autophagic death and suppressing angiogenesis. The mechanistic hypothesis predicts that while ROS generation is a critical event in PEITC-induced apoptosis (and possibly autophagy), induction of autophagy and suppression of angiogenesis is mediated by inhibition of Akt and its downstream effectors.
Specific Aims :
The specific aims of the present renewal application are to: (1) determine the efficacy of dietary PEITC administration for prevention of prostate carcinogenesis in male TRAMP mice and determine markers/molecular regulators of apoptosis, autophagy, and angiogenesis in prostate/tumor tissues harvested from control and PEITC-fed TRAMP mice;(2) determine the role of ROS in apoptosis induction by PEITC using PC-3, LNCaP and PrEC cells as a model;(3) determine the mechanism of PEITC-mediated autophagy using above mentioned cells as a model;and (4) determine the efficacy of dietary PEITC administration for inhibition of angiogenesis in vivo using Matrigel plug assay and elucidate the mechanism of Akt inactivation by PEITC using PC-3 and LNCaP cells as a model. Significance: Positive outcome of the proposed preclinical studies will provide compelling rationale for initiation of clinical trials to determine efficacy of PEITC against human prostate cancer.
Because prostate cancer is one of the most commonly diagnosed malignancies and a leading cause of cancer related deaths among American men, identification and preclinical/clinical evaluation of agents that are relatively safe but can be used to delay onset and/or progression of this disease are highly desirable. Studies conducted during the funded period of this grant indicate that PEITC, a naturally-occurring agent present in many edible cruciferous vegetables, is highly likely to prevent prostate cancer. The present competitive renewal application proposes experiments that will not only directly test efficacy of PEITC for prevention of prostate carcinogenesis in a transgenic mouse model of prostate cancer but also fill the gaps in our understanding on mechanism of its anticarcinogenic effects. Positive outcome of these studies will justify future clinical trials to determine efficacy of PEITC for prevention of prostate cancer in humans.
|Singh, Krishna B; Singh, Shivendra V (2017) Fatty Acid Synthesis Intermediates Represent Novel Noninvasive Biomarkers of Prostate Cancer Chemoprevention by Phenethyl Isothiocyanate. Cancer Prev Res (Phila) 10:279-289|
|Sehrawat, Anuradha; Roy, Ruchi; Pore, Subrata K et al. (2016) Mitochondrial dysfunction in cancer chemoprevention by phytochemicals from dietary and medicinal plants. Semin Cancer Biol :|
|Sakao, Kozue; Vyas, Avani R; Chinni, Sreenivasa R et al. (2015) CXCR4 is a novel target of cancer chemopreventative isothiocyanates in prostate cancer cells. Cancer Prev Res (Phila) 8:365-74|
|Stan, Silvia D; Singh, Shivendra V; Whitcomb, David C et al. (2014) Phenethyl isothiocyanate inhibits proliferation and induces apoptosis in pancreatic cancer cells in vitro and in a MIAPaca2 xenograft animal model. Nutr Cancer 66:747-55|
|Tailor, Dhanir; Hahm, Eun-Ryeong; Kale, Raosaheb K et al. (2014) Sodium butyrate induces DRP1-mediated mitochondrial fusion and apoptosis in human colorectal cancer cells. Mitochondrion 16:55-64|
|Hahm, Eun-Ryeong; Karlsson, A Isabella; Bonner, Michael Y et al. (2014) Honokiol inhibits androgen receptor activity in prostate cancer cells. Prostate 74:408-20|
|Hahm, Eun-Ryeong; Sakao, Kozue; Singh, Shivendra V (2014) Honokiol activates reactive oxygen species-mediated cytoprotective autophagy in human prostate cancer cells. Prostate 74:1209-21|
|Zhu, Jianzhong; Ghosh, Arundhati; Coyle, Elizabeth M et al. (2013) Differential effects of phenethyl isothiocyanate and D,L-sulforaphane on TLR3 signaling. J Immunol 190:4400-7|
|Sakao, Kozue; Hahm, Eun-Ryeong; Singh, Shivendra V (2013) In vitro and in vivo effects of phenethyl isothiocyanate treatment on vimentin protein expression in cancer cells. Nutr Cancer 65 Suppl 1:61-7|
|Kim, Su-Hyeong; Sehrawat, Anuradha; Singh, Shivendra V (2012) Notch2 activation by benzyl isothiocyanate impedes its inhibitory effect on breast cancer cell migration. Breast Cancer Res Treat 134:1067-79|
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