Dietary Feeding of Dibenzoylmethane Inhibits Prostate Cancer in Transgenic Adenocarcinoma of the Mouse Prostate Model

Abstract

Dibenzoylmethane (DBM), a minor B-diketone constituent of licorice, has been shown to exhibit antineoplastic effects in prostate cancer cell lines by induction of cell cycle arrest and regulation of androgen receptor expression. In the present study, we investigated the in vitro and in vivo efficacy of DBM using TRAMP-C1 cell lines and TRAMP mice. DBM was found to arrest TRAMP-C1 cells at G 2 -M phase of cell cycle and suppressed phosphorylated retinoblastoma, cyclin D1, and cyclin A. Importantly, DBM was found to be equally effective in suppression of prostate tumor progression in TRAMP mice. At 8 or 12 weeks of age, mice were fed control or 1% DBMsupplemented diets until 24 weeks of age. Our results show that DBM-fed groups had a lower incidence of palpable tumor and high-grade prostatic intraepithelial neoplasia. Subsequent mechanistic studies show that the expression of phosphorylated retinoblastoma, c-myc, cyclin D1, cyclin A, phosphorylated Akt, phosphorylated PDK-1, and phosphorylated S6 was significantly reduced by DBM. Our findings suggest that DBM blocks the growth and progression of prostate cancer in TRAMP mice via modulation of tumor cell cycle regulation and therefore merits its consideration for future clinical intervention of human prostate cancer. [Cancer Res 2009;69(17):7096-102]

Epigenetic Modifications of Nrf2 by 3,3′-diindolylmethane In Vitro in TRAMP C1 Cell Line and In Vivo TRAMP Prostate Tumors

“…Lesions were classified as PIN I, II, III, and IV as described by Park et al, as well as what we have reported previously (5,9,28,29). For ease of classification, PIN I and II were combined as lowgrade PIN (LG-PIN) while PIN III and IV were combined as high-grade PIN (HG-PIN) as we have performed previously (5,9,28,29).…”

“…The sections were stained with hematoxylin and eosin to examine any neoplastic changes and then a histopathologist in a blinded fashion was evaluated to classify prostatic intraepithelial neoplasia (PIN) lesion, as what we have reported previously (5,9,10,28). Lesions were classified as PIN I, II, III, and IV as described by Park et al, as well as what we have reported previously (5,9,28,29). For ease of classification, PIN I and II were combined as lowgrade PIN (LG-PIN) while PIN III and IV were combined as high-grade PIN (HG-PIN) as we have performed previously (5,9,28,29).…”

Frequent Gene Products and Molecular Pathways Altered in Prostate Cancer- and Metastasis-Initiating Cells and Their Progenies and Novel Promising Multitargeted Therapies

“…Numerous preclinical studies aiming to develop novel therapies for preventing or treating PCs have led to the identification of a variety of potential chemopreventive and chemotherapeutic agents, including natural and dietary compounds and pharmacological agents or gene therapies, to eradicate the total tumor cell mass, including PC stem/progenitor cells and their progenies (76,137,(185)(186)(187)(188)(189)(190)(191)(192)(193)(194)(195)(196)(197)(198).…”

“…Some preclinical investigations aiming to develop novel strategies to prevent PC formation or disease progression have aimed to establish the chemopreventive and anticarcinogenic effects induced by diverse dietary compounds using TRAMP and PTEN knockdown transgenic mouse models of PC (137,(187)(188)(189)(190)(191)(192)(193)(194)198). In fact, the TRAMP and PTEN knockdown transgenic mouse models of PC, which are driven by PC stem/progenitor cells endowed with stem cell-like properties, represent useful animal models to estimate the chemopreventive and chemotherapeutic effects induced by the dietary substances on total PC cell mass and their local microenvironment as well as their potential to reverse the treatment resistance (63,97,98,(181)(182)(183)(184)199,200).…”

“…In fact, the TRAMP and PTEN knockdown transgenic mouse models of PC, which are driven by PC stem/progenitor cells endowed with stem cell-like properties, represent useful animal models to estimate the chemopreventive and chemotherapeutic effects induced by the dietary substances on total PC cell mass and their local microenvironment as well as their potential to reverse the treatment resistance (63,97,98,(181)(182)(183)(184)199,200). Of therapeutic interest, it has been shown that different dietary compounds, including curcumin, lycopene, silibinin, feeding of dibenzoylmethane, green tea polyphenols, genistein, α-difluoromethylornithine, toremifene, R-flurbiprofen, celecoxib and sulindax, or their chemical derivatives, significantly decreased the incidence of PIN lesions and PC formation and/or delayed the disease progression in the TRAMP or PTEN knockdown transgenic mouse models of PC (137,(187)(188)(189)(190)(191)(192)(193)(194)198). The anticarcinogenic effects of these dietary agents, alone or in combination, were mediated at least in part through downregulation of diverse growth factor cascades, including EGFR and sonic hedgehog and their downstream signaling elements such as PI3K/Akt and NF-κB in cancer cells (137,(187)(188)(189)(190)(191)(192)(193)(194)198).…”