Selenium (Se) has been thought to hold great promise as a cancer chemopreventive agent. However, the negative efficacy outcomes of recently concluded human trials in North America with seleno-methionine (SeMet) for prostate cancer (PCa) prevention (SELECT, HGPIN trials) have caused many to conclude that there is no hope for using Se to prevent cancer. We, however, beg to disagree with such a mainstream opinion. A costly lesson from these well-executed clinical studies is that whatever preclinical efficacy data that existed at the time the decision was made to conduct these trials DID NOT support the choice of SeMet for human efficacy validation, NOR did cell culture-based studies. In contrast, many pre-clinical studies from our group and others have shown inhibition of the genesis of cancers of the prostate and other organ sites by supra-nutritional intake of other Se forms, especially methylseleninic acid (MSeA) and Se- methylselenocysteine (MSeC), the presumed precursors of in vivo active anti-cancer methylselenol pool. Our recent data with a proteomic approach question the validity of the methylselenol paradigm and suggest unique potential molecular targets for MSeA vs. MSeC with little overlap. Our latest data with organ specific Pten- knockout (KO) driven prostate carcinogenesis suggest a super-activation of p53-p21-senescence pathway by MSeA to suppress neoplastic prostatic lesion growth in a preclinical mouse model, heralding in a new prevention paradigm through inducing irreversible terminal arrest of early lesion cells in vivo. Our central hypothesis is that MSeA/C will prevent prostate carcinogenesis in preclinical rodent models each by regulating distinct sets of molecular targets and signaling pathways (e.g., p53-p21-senescence;p53- apoptosis;suppressor/oncoprotein balances). We propose testing this hypothesis with 3 Specific Aims: 1. To contrast the in vivo preventive efficacy of MSeA/C with (the lack thereof) SeMet against epithelial adeno- carcinogenesis in the prostate specific Pten-KO mice and to critically assess the contribution of the p53-p21 senescence pathway to their efficacy using Pten and p53 double KO mice. 2. To contrast the in vivo preventive efficacy of MSeA/C with the lack thereof by SeMet against chemically-induced, androgen-promoted prostate carcinogenesis in rats and to determine whether p53-p21 senescence activation is involved. 3. To identify proteomic signatures and molecular targets in the prostate gland and prostate carcinomas from studies of Aims 1 and 2 of MSeA and MSeC in addition to the p53-p21-senescene pathway and validate identified key targets. The results are expected to provide solid in vivo efficacy data for MSeA/C from multiple preclinical models of prostate carcinogenesis representing diverse human PCa etiologies and different mammalian species (mice and rats). Positive efficacies in multiple models increase the translatability for human application. The results may help to resurrect and advance the field of Se-prostate cancer chemoprevention research, redefining and changing mechanism paradigms of active Se form(s), cellular processes and molecular targets.
Prostate cancer (PCa) is the most commonly diagnosed cancer in American men and is the second leading cause of male cancer death (American Cancer Society Statistics 2012). Treatment options for advanced PCa, including androgen-ablation therapy, radiation and surgery, do not offer a cure but delay the inevitable recurrence of the lethal advanced hormone-refractory disease. Chemotherapy using the cytotoxic drug docetaxel, and the FDA-approved novel taxane drug Cabazitaxel, and a Cyp17 inhibitor drug against androgen synthesis Zytiga (abiraterone acetate) for recurrent CRPCa in patients who fail docetaxel regimen only adds an expected prolongation of survival of 2-4 months. All these treatments have significant side effects that negatively affect the quality of life of the patients and the new drugs are prohibitive expensive. Chemoprevention is key to winning the war on cancer by blocking, inhibiting, and reversing genetic and epigenetic oncogenic events in early stages of carcinogenesis. Selenium (Se) has been thought to hold great promise as a chemopreventive agent. However, the negative efficacy outcomes of recently concluded human trials with seleno-methionine (inactive form compared to Se forms to be evaluated in this proposal) have caused many to conclude that there is no hope for using other or any Se forms to prevent PCa. Our proposal, if successfully accomplished, will fundamentally redefine and even change the mechanism paradigms and provide solid rationale for choice of active and safe Se form for human translations, and resurrect and advance the field of Se-(prostate) cancer chemoprevention research.
|Zhang, Yong; Dong, Yinhui; Melkus, Michael W et al. (2018) Role of P53-Senescence Induction in Suppression of LNCaP Prostate Cancer Growth by Cardiotonic Compound Bufalin. Mol Cancer Ther 17:2341-2352|
|Wang, Lei; Wang, Ji; Xiong, Hua et al. (2016) Co-targeting hexokinase 2-mediated Warburg effect and ULK1-dependent autophagy suppresses tumor growth of PTEN- and TP53-deficiency-driven castration-resistant prostate cancer. EBioMedicine 7:50-61|
|Wang, Lei; Guo, Xiaolan; Wang, Ji et al. (2016) Methylseleninic Acid Superactivates p53-Senescence Cancer Progression Barrier in Prostate Lesions of Pten-Knockout Mouse. Cancer Prev Res (Phila) 9:35-42|
|Lü, Junxuan; Zhang, Jinhui; Jiang, Cheng et al. (2016) Cancer chemoprevention research with selenium in the post-SELECT era: Promises and challenges. Nutr Cancer 68:1-17|
|Bosland, Maarten C (2015) How to Rationally Identify Promising Cancer Chemoprevention Agents? J Natl Cancer Inst 107:djv288|
|Wang, Lei; Xiong, Hua; Wu, Fengxia et al. (2014) Hexokinase 2-mediated Warburg effect is required for PTEN- and p53-deficiency-driven prostate cancer growth. Cell Rep 8:1461-74|