Patients with malignant diseases commonly consume poorly characterized medicine or dietary supplements. Extensive use of untested formulations, provide both opportunities and danger. BIRM, an Ecuadorian oral solution, is a dietary supplement developed from the Andean variety of Solanum dulcamara L, which is widely consumed in the Americas for a variety of diseases, including prostate and breast cancers, without any noted toxicity. Initial laboratory studies of BIRM on prostate cancer models showed strong cytotoxic antitumor activity, including induction of apoptosis, cell-cycle arrest, reduction in androgen receptor levels and down-regulation of pro-survival genes. Oral dosing of BIRM in a rat Dunning MAT LyLu model and in human prostate cancer xenografts showed chemopreventive and antimetastatic activities of BIRM. It decreased tumor incidence (75%), tumor growth (50%) and metastasis (63%). These observations provide the basis for further investigation into the use of BIRM as a chemopreventive dietary supplement. The main hypothesis, to be tested in this project, is that BIRM is a non-toxic, chemopreventive, natural product with the potential to retard tumor growth, progression and recurrence. The main objective of this application is to establish the chemopreventive and antimetastatic activity of BIRM in transgenic models of prostate cancer with the goal of establishing its safety and efficacy for use in controlled clinical trials.
In Aim 1, the minimum effective dose, optimum effective dose and maximum tolerated dose of BIRM will be established in the TRAMP (transgenic adenocarcinoma of the mouse prostate) model. In addition, the chemopreventive and antitumor activities of BIRM will be investigated using two distinct transgenic models that develop prostate tumor by either an androgen-independent (GvT-15 model) mechanism or by the conditional knock-out of a tumor suppressor gene (PTEN) in the prostate (PTEN loxp/loxpPBCre-4).
In Aim 2, the molecular mechanism of BIRM induced apoptosis, cell cycle arrest and androgen receptor degradation will be investigated by delineating the alterations in the molecular signatures of respective signaling pathways.
In Aim 3, the efficacy of BIRM either alone, or in combination with standard chemotherapy, will be evaluated for preventing the emergence of hormone-refractory prostate cancer in two human prostate cancer orthotopic xenograft models, LNCaP and LAPC-4, which demonstrate distinct molecular forms of androgen receptor. Relevance: This study will establish safety and toxicity profiles of BIRM and determine whether BIRM, a complex natural product, has 1. a proven chemopreventive efficacy against prostate cancer and 2. if the efficacy of proven cancer therapies are enhanced or significantly compromised by BIRM. This study should also provide a rationale for further development (if any), of this chemopreventive agent, i.e., clinical trials for orostate cancer and other malignant cancers.
|Shamaladevi, Nagarajarao; Araki, Shinako; Lyn, Dominic A et al. (2016) The andean anticancer herbal product BIRM causes destabilization of androgen receptor and induces caspase-8 mediated-apoptosis in prostate cancer. Oncotarget 7:84201-84213|
|Salazar, Nicole; Castellan, Miguel; Shirodkar, Samir S et al. (2013) Chemokines and chemokine receptors as promoters of prostate cancer growth and progression. Crit Rev Eukaryot Gene Expr 23:77-91|
|Shamaladevi, Nagarajarao; Lyn, Dominic A; Shaaban, Khaled A et al. (2013) Ericifolin: a novel antitumor compound from allspice that silences androgen receptor in prostate cancer. Carcinogenesis 34:1822-32|
|Zhang, Lei; Lokeshwar, Bal L (2012) Medicinal properties of the Jamaican pepper plant Pimenta dioica and Allspice. Curr Drug Targets 13:1900-6|
|Singh, Rajendra Kumar; Lokeshwar, Bal L (2011) The IL-8-regulated chemokine receptor CXCR7 stimulates EGFR signaling to promote prostate cancer growth. Cancer Res 71:3268-77|
|Lokeshwar, Bal L (2011) Chemically modified non-antimicrobial tetracyclines are multifunctional drugs against advanced cancers. Pharmacol Res 63:146-50|
|Shamaladevi, Nagarajarao; Lyn, Dominic A; Escudero, Diogo O et al. (2009) CXC receptor-1 silencing inhibits androgen-independent prostate cancer. Cancer Res 69:8265-74|
|Singh, Rajendra K; Lokeshwar, Bal L (2009) Depletion of intrinsic expression of Interleukin-8 in prostate cancer cells causes cell cycle arrest, spontaneous apoptosis and increases the efficacy of chemotherapeutic drugs. Mol Cancer 8:57|