Phase Ib placebo-controlled, tissue biomarker trial of diindolylmethane (BR-DIMNG) in patients with prostate cancer who are undergoing prostatectomy

Abstract

Epidemiologic, preclinical, and early phase I studies of the cruciferous vegetable bioactive metabolite, 3,3'-diindolylmethane (DIM), support its potential prostate cancer chemopreventive ability. We performed a multicenter, double-blind, placebo-controlled trial of DIM in patients diagnosed with prostate cancer and scheduled for radical prostatectomy. A total of 45 patients with organ-confined prostate cancer were randomized to 21-28 days of an absorption-enhanced formulation of DIM (BR-DIM) at doses of 100 or 200 mg per os twice daily or to placebo twice daily. Prostate tissue levels of DIM were the primary endpoint, with selected secondary biomarker endpoints including blood levels of DIM, total prostate-specific antigen, testosterone, and the insulin-like growth factor-1: insulin-like growth factor binding protein-3 ratio and the urinary 2-hydroxyestrone/16-hydroxyestrone ratio, obtained at baseline, at day 15, and before surgery, as well as tissue expression of androgen receptor, prostate-specific antigen, Ki67, caspase 3 with cytochrome p450 mRNA expression and genotyping (polymorphisms). DIM was well tolerated with excellent study compliance and relatively rapid accrual of all 45 patients within 1 year. DIM levels were detected in only seven of 28 prostate tissue specimens. There was a statistically significant difference in the change in the urinary 2-hydroxyestrone/16-hydroxyestrone ratio from baseline until before surgery between the placebo and 400 mg DIM groups, with otherwise statistically nonsignificant changes in plasma biomarker expression. The administration of BR-DIM to prostate cancer patients before prostatectomy yields detectable plasma levels but without consistent or significant tissue accumulation or biomarker modulation. This study demonstrates the feasibility of biologic evaluation of relatively nontoxic preventive agents in the preprostatectomy setting with the potential for rapid accrual.

Bioactive natural products for chemoprevention and treatment of castration-resistant prostate cancer

“…Chemical modification of orally delivered natural products has shown improved efficacy in curcumin and other bioactive natural products [108, 110]. Similar studies in DIM have also shown improved bioavailability in an absorption enhanced form of DIM (BR-DIMNG) which has the potential for oral administration [111]. While numerous synthetic compounds have been tested in clinical trials for treatment of PCa in general, only a few natural products have been investigated in the clinic [42, 107, 108, 111].…”

DNA-Methyltransferase 1 Induces Dedifferentiation of Pancreatic Cancer Cells through Silencing of Krüppel-Like Factor 4 Expression

“…Mounting evidence showed that 3,3’-diindolylmethane (DIM), the major bioactive metabolite of nutritional component indole-3-carbinol found relatively high in cruciferous vegetables, is a promising cancer preventative and anti-tumor agent in various cancers including breast, prostate, and cervical cancers (25, 26), and several clinical trials have been approved in healthy subjects or patients with premalignant or malignant lesion ( see clinical trials: NCT01391689, NCT01022333, NCT02197000, NCT01726127, NCT00392652, NCT00784394 ) (27, 28). Available preliminary data indicate that supplementation with I3C or the related dimer 3,3’-diindolylmethane (DIM) may have beneficial effects in treating conditions related to human papilloma virus infection, such as cervical intraepithelial neoplasia and recurrent respiratory papillomatosis (25, 29, 30). However, whether DIM has antitumor effect in pancreatic cancer and if so, the exact molecular mechanisms behind remain poorly understood.…”

The Role of Brassica Bioactives on Human Health: Are We Studying It the Right Way?

“…Within the short-term studies (Table S1), we found two documents on prostate [39] and melanoma [40], three papers on respiratory pathologies [41][42][43], and one on type 2 diabetes [44]. The main limitation observed in these studies is the length or duration of the study, of 1 month or less, because the validity of the data in terms of changes in bioavailability of the intake of compounds could be acceptable, but for the evaluation of data from tissues, the time of exposition is too low.…”

“…The main limitation observed in these studies is the length or duration of the study, of 1 month or less, because the validity of the data in terms of changes in bioavailability of the intake of compounds could be acceptable, but for the evaluation of data from tissues, the time of exposition is too low. In the article of Gee et al [39], a Phase Ib study, studied the concentration of DIM in prostate tissue after its administration in three groups: 200 mg, 400 mg, or placebo. They found a positive increase of DIM in plasma, but not concomitant or related with the presence of DIM in the prostate tissues, and the initial hypothesis was not corroborated.…”