The Effect of Difluoromethylornithine on Decreasing Prostate Size and Polyamines in Men: Results of a Year-Long Phase IIb Randomized Placebo-Controlled Chemoprevention Trial

Simoneau, Anne R.; Gerner, Eugene W.; Nagle, Ray B.; Ziogas, Argyrios; Fujikawa-Brooks, Sharon; Yerushalmi, Hagit; Ahlering, Thomas E.; Lieberman, Ronald; McLaren, Christine E.; Anton‐Culver, Hoda; Meyskens, Frank L.

doi:10.1158/1055-9965.epi-07-0658

Cited by 73 publications

(65 citation statements)

References 41 publications

(43 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We showed that treatment of RWPE1-ODC cells with DFMO reduced the proliferation activity to levels similar to those seen in RWPE1 parental cells. Although a phase 2 clinical trial of DFMO with patients with a family history of prostate cancer but no previous personal history of prostate cancer has been reported, 55 no trials have included patients with a diagnosis of HGPIN and no evidence of prostate cancer. Different chemopreventive clinical trials have been developed to control progression of HGPIN to prostate cancer using selenium, soy, vitamin E, 56,57 toremifene, 58 or green tea extract, 59,60 with different success rates.…”

Section: Discussionmentioning

confidence: 99%

Ornithine Decarboxylase Is Sufficient for Prostate Tumorigenesis via Androgen Receptor Signaling

Shukla–Dave

Castillo-Martín

Chen

et al. 2016

The American Journal of Pathology

View full text Add to dashboard Cite

Increased polyamine synthesis is known to play an important role in prostate cancer. We aimed to explore its functional significance in prostate tumor initiation and its link to androgen receptor (AR) signaling. For this purpose, we generated a new cell line derived from normal epithelial prostate cells (RWPE-1) with overexpression of ornithine decarboxylase (ODC) and used it for in vitro and in vivo experiments. We then comprehensively analyzed the expression of the main metabolic enzymes of the polyamine pathway and spermine abundance in 120 well-characterized cases of human prostate cancer and high-grade prostate intraepithelial neoplasia (HGPIN). Herein, we show that the ODCoverexpressing prostate cells underwent malignant transformation, revealing that ODC is sufficient for de novo tumor initiation in 94% of injected mice. This oncogenic capacity was acquired through alteration of critical signaling networks, including AR, EIF2, and mTOR/MAPK. RNA silencing experiments revealed the link between AR signaling and polyamine metabolism. Human prostate cancers consistently demonstrated up-regulation of the main polyamine enzymes analyzed (ODC, polyamine oxidase, and spermine synthase) and reduction of spermine. This phenotype was also dominant in HGPIN, rendering it a new biomarker of malignant transformation. In summary, we report that ODC plays a key role in prostate tumorigenesis and that the polyamine pathway is altered as early as HGPIN. (Am J Pathol 2016, 186: 3131e3145; http://dx

show abstract

Section: Discussionmentioning

confidence: 99%

Ornithine Decarboxylase Is Sufficient for Prostate Tumorigenesis via Androgen Receptor Signaling

Shukla–Dave

Castillo-Martín

Chen

et al. 2016

The American Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…• Clinical ototoxicities: no difference between arms, but subclinical changes documented by audiometry in the AA/AG group (Zell et al 2010) a Summarized from Simoneau (2001Simoneau ( , 2008 range of preclinical studies are examining the role of natural compounds in prostate cancer prevention (Horie 2012;Ozten-Kandas ß and Bosland 2011;Cimino et al 2012;Thapa and Ghosh 2012), but to date the results have been unconvincing and clinical trials have not been forthcoming (Horie 2012).…”

Section: The Futurementioning

confidence: 99%

“…Until recently selection of at-risk patients were driven by clinical parameters, Gleason scores, and prostate-specific antigen (PSA) levels. We began our studies of prostate cancer chemoprevention in 1995 and have reported results from a 1-month phase IIa trial in 2001 and a 12-month phase IIb trial in 2008 (Simoneau et al 2001(Simoneau et al , 2008.…”

Section: Introductionmentioning

confidence: 99%

Chemoprevention of Prostate Cancer with the Polyamine Synthesis Inhibitor Difluoromethylornithine

Meyskens

Simoneau

Gerner

2014

Prostate Cancer Prevention

Self Cite

View full text Add to dashboard Cite

In vitro and in vivo preclinical results suggest that inhibition of polyamine synthesis inhibits the progression of prostate cancer. These findings has led to two clinical trials in patients at risk for invasive prostate cancer with difluoromethylornithine which specifically and irreversibly inhibits ornithine decarboxylase which catalyses the conversion of ornithine to putrescine the rate limiting step in polyamines synthesis. We have conducted a phase IIa one month and placebo randomized phase IIb 12 months trials in patients at increased risk for invasive prostate cancer. Favorable reduction in prostate polyamine levels and prostate volume was documented with no difference in clinical hearing changes. Patients with Gleason's VI lesions in a surveillance cohort would be appropriate candidates for a definitive risk reduction trial although the unavailability of validated biomarkers for invasive progression would require a large and lengthy study.

show abstract

“…It has been shown that DFMO acts as an antitumoral agent by decreasing Put and Spd levels, which causes cell cycle arrest in cells. DFMO also inhibits the metastatic potential in various cancer cells (13)(14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of ornithine decarboxylase alters the roscovitine-induced mitochondrial-mediated apoptosis in MCF-7 breast cancer cells

et al. 2012

View full text Add to dashboard Cite

Abstract. Polyamines (PAs) are small aliphatic amines that play a major role in multicellular functions. The PA levels are controlled by ornithine decarboxylase (ODC), the rate limiting enzyme of PA biosynthesis. α-difluoromethylornithine (DFMO) is the ODC inhibitor, which has been shown to act as an antiproliferative agent in human cancer cells by irreversibly inhibiting ODC, which is overexpressed in breast cancer cells. Roscovitine (ROSC; CYC202), a selective cyclin-dependent kinase inhibitor, induces cell cycle arrest and concomitantly apoptosis in tumor cells. In this study, we aimed to investigate the possible role of PAs in ROSC-induced apoptosis in estrogen-dependent MCF-7 breast cancer cells. Cell viability was assessed following the exposure of MCF-7 cells to DFMO and/or ROSC by MTT cell viability assay. To evaluate the druginduced apoptotic events, DNA fragmentation by Cell Death ELISA assay and 4,6-diamidino-2-phenylindole staining, were utilized. The disruption of mitochondrial membrane potential, caspase-9 and PARP cleavage was also determined in order to investigate the role of mitochondrial-mediated apoptosis. The modulation of Bcl-2 family members was also evaluated using the immunoblotting technique. Drug-induced reactive oxygen species was determined by a fluorometer following 2' ,7'-dichlorofluorescein diacetate staining. We found that ROSC induced apoptosis in a dose-and caspase-dependent manner. The ODC specific inhibitor, DFMO, altered the apoptotic effects of ROSC by increasing the generation of reactive oxygen species, decreasing the PA intracellular pool and modulating pro-apoptotic and anti-apoptotic Bcl-2 family members. All these findings suggest that ODC may be a critical target for evaluating the PA metabolic pathway as a therapeutic target in ROSC-induced mitochondrial-mediated apoptotis in estrogendependent MCF-7 breast cancer cells.

show abstract

The Effect of Difluoromethylornithine on Decreasing Prostate Size and Polyamines in Men: Results of a Year-Long Phase IIb Randomized Placebo-Controlled Chemoprevention Trial

Cited by 73 publications

References 41 publications

Ornithine Decarboxylase Is Sufficient for Prostate Tumorigenesis via Androgen Receptor Signaling

Ornithine Decarboxylase Is Sufficient for Prostate Tumorigenesis via Androgen Receptor Signaling

Chemoprevention of Prostate Cancer with the Polyamine Synthesis Inhibitor Difluoromethylornithine

Inhibition of ornithine decarboxylase alters the roscovitine-induced mitochondrial-mediated apoptosis in MCF-7 breast cancer cells

Contact Info

Product

Resources

About