Foods/Supplements-Vitamins: Cruciferous Phytochemicals - [3] 3,3'-Diindolylmethane [DIM]

[pjoshea13]

DIM (3,3'-Diindolylmethane) is thought to be the most important phytochemical found in broccoli.

[1] Estrogen Metabolism.

Some may think it odd to begin with estrogen. Much of the DIM literature relates to its effect on estrogen metabolism, & this is of major interest to women with hormonal cancer, but why should it concern men with PCa?

I recently posted on the subject of estradiol in PCa. An alarming aspect of prostatic epithelial cells that become cancerous is (a) the disappearance of ERbeta - the protective estrogen receptor; (b) the emergence & upregulatio of ERalpha - the growth promoting estrogen receptor, & (c) the appearance of aromatase, the enzyme that converts testosterone [T] to estradiol [E2].

Men generally experience a small but persistent annual decline in T, beginning in their early 30's. With a decline of 1-2% a year, the aging man has a significantly lower T than at age 21. The result is a loss of muscle mass & an increase in body fat. Visceral fat secretes E2. E2 should be in the 20-30 pg/mL range, but can be much higher in men with low T. The body responds to high E2 by reducing T - the putative source of E2 (via aromatization). & so we get a downward spiral, with an increasingly unfavorable E2:T ratio. Complete with gynecomastia ("swelling of the breast tissue in ... men, caused by an imbalance of the hormones estrogen and testosterone" Mayo Clinic [1a]).

Testosterone is a pussycat compared to estradiol. There are two major hydroxylation metabolic pathways for its elimination: the "2" path (2-Hydroxylation) & the "16alpha" path (16α-Hydroxylation). The latter produces metabolites thare thought to be carcinogenic. The "2" path produces benign, & perhaps even protective, metabolites.

The reason that many women take DIM is that it can shunt E2 down the "2" path. Men with elevated E2 should consider it too. In PCa, we can't readily look inside the cancer cells, but E2 looks to be a legitimate target. I use Arimidex to keep E2 close to 20 pg/mL, & DIM to influence the E2 metabolic pathway.

[1b] (2004 - U.S.)

"Pilot study: effect of 3,3'-diindolylmethane supplements on urinary hormone metabolites in postmenopausal women with a history of early-stage breast cancer."

"In this pilot study, DIM increased the 2-hydroxylation of estrogen urinary metabolites."

There was an "increase of 47% in the 2-OHE1/16alpha-OHE1 ratio from 1.46 to 2.14 ..."

i.e. more "2" & less "16alpha" metabolites.

[1c] (2002 - U.S.)

The introduction in this paper summarizes the estrogen danger:

"Estrogens are known for their proliferative effects on estrogen-sensitive tissues resulting in tumorigenesis. Results of experiments in multiple laboratories over the last 20 years have shown that a large part of the cancer-inducing effect of estrogen involves the formation of agonistic metabolites of estrogen, especially 16-alpha-hydroxyestrone. Other metabolites, such as 2-hydroxyestrone and 2-hydroxyestradiol, offer protection against the estrogen-agonist effects of 16-alpha-hydroxyestrone."

[2] Bio-Response DIM [BR-DIM] [DIM-Plus]

This product is the creation of Dr. Michael Zeligs. It has been used in a number of studies. I have used it for at least ten years. Nalakrats is a big fan.

The product contains 9 IU Vitamin E (as Tocophersolan) per 2 caps. I'm not too keen about that. Also, "Protectamins® Vegetable Blend (spinach powder, broccoli powder, cabbage powder)."

2 caps contain 100 mg BioResponse-DIM® Complex, providing, 25% diindolylmethane [25 mg].

"BR-DIM is a dietary supplement which contains pharmaceutically pure DIM, microdispersed in spray-dried starch particles." ("crystalline DIM is highly insoluble in both water and oil") [2a]

There are 12 PubMed hits for <prostate "br-dim">, 11 of which involve Fazlul H Sarkar. There are also 10 other studies by Sarkar that mention Michael Zeligs as the supplier of the DIM. i.e. most of what we know about BR-DIM & PCa comes out of a single lab.

[2a] ( 2010 - U.S. - Phase I study in CRPC men without metastases)

"3, 3'-diindolylmethane (DIM) modulates estrogen metabolism and acts as an anti-androgen which down-regulates the androgen receptor and prostate specific antigen (PSA). We conducted a dose-escalation, phase I study of BioResponse (BR)-DIM with objectives to determine the maximum tolerated dose (MTD), toxicity profile, and phar-macokinetics (PK) of BR-DIM, and to assess its effects on serum PSA and quality of life (QoL)."

"Cohorts of 3-6 patients received escalating doses of twice daily oral BR-DIM providing DIM at 75 mg, then 150 mg, 225 mg, and 300 mg."

"One patient without AH at 225 mg experienced a 50% PSA decline. One patient with BR-DIM dose of 225 mg had PSA stabilization. The other 10 patients had an initial deceleration of their PSA rise (decrease in slope), but eventually progressed based on continual PSA rise or evidence of metastatic disease."

"... the maximum tolerated dose (MTD) was deemed to be 300 mg {6 caps} and the recommended phase II dose ... of BR-DIM was 225 mg twice daily {4-5 caps daily}."

[2b] (2016 - U.S.)

"Castrate-resistant prostate cancer (CRPC) progression after androgen deprivation therapy (ADT) shows up-regulated expression of androgen receptor (AR) splice variants, induced epithelial-to-mesenchymal transition (EMT) phenotypes, and enhanced stem cell characteristics, all of which are associated with resistance to enzalutamide."

"we found that BioRespose 3,3’-Diindolylmethane (BR-DIM) treatment in vitro and in vivo caused down regulation in the expression of wild-type AR, the AR splice variants, Lin28B and EZH2 ..."

"The inhibitory effects of BR-DIM on AR and AR target gene such as prostate-specific antigen (PSA) were also observed in the clinical trial. Our preclinical and clinical studies provide the scientific basis for a “proof-of-concept” clinical trial in CRPC patients treated with enzalutamide in combination with BR-DIM."

[2c] (2016 - U.S. - pre-prostatectomy study.)

"Men with localized prostate cancer were treated with a specially formulated DIM capsule designed for enhanced bioavailability (BR-DIM) at a dose of 225 mg orally twice daily for a minimum of 14 days. DIM levels and AR activity were assessed at the time of prostatectomy. Out of 28 evaluable patients, 26 (93%) had detectable prostatic DIM levels, with a mean concentration of 14.2 ng/gm. The mean DIM plasma level on BR-DIM therapy was 9.0 ng/mL ..."

"After BR-DIM therapy, 96% of patients exhibited exclusion of the AR from the cell nucleus. In contrast, in prostate biopsy samples obtained prior to BR-DIM therapy, no patient exhibited AR nuclear exclusion."

{Proliferation can only occur if AR is able to relocate to the nucleus.}

[2d] (2015 - U.S.)

"Cell migration, clonogenicity, sphere-forming capacity was assessed using PCa cells under all experimental conditions and 3,3'-diindolylmethane (DIM; BR-DIM) treatment. Human PCa samples from BR-DIM untreated or treated patients were also used for assessing the expression of AR3 and stem cell markers."

"Overexpression of AR led to the induction of EMT phenotype, while overexpression of AR3 not only induced EMT but also led to the expression of stem cell signature genes. More importantly, ADT enhanced the expression of AR and AR3 concomitant with up-regulated expression of EMT and stem cell marker genes. Dihydrotestosterone (DHT) treatment decreased the expression of AR and AR3, and reversed the expression of these EMT and stem cell marker genes. BR-DIM administered to PCa patients prior to radical prostatectomy inhibited the expression of cancer stem cell markers consistent with inhibition of self-renewal of PCa cells after BR-DIM treatment."

Interesting that DHT decreased AR3 - aka AR-V7. An indication that BAT therapy might turn back the clock.

Also of interest: "... results suggest that AR3 but not AR is involved in the regulation of stem cell marker gene expression ..."

[2e] (2012 - U.S.)

(Note that a major action of Metformin is AMPK activation.)

"Accumulating evidence suggests that AMP-activated protein kinase (AMPK) plays an essential role in cellular energy homeostasis and tumor development and that targeting AMPK may be a promising therapeutic option for cancer treatment in the clinic."

"Our results showed, for the first time, that B-DIM could activate the AMPK signaling pathway, associated with suppression of the mammalian target of rapamycin (mTOR), down-regulation of androgen receptor (AR) expression, and induction of apoptosis in both androgen-sensitive LNCaP and androgen-insensitive C4-2B prostate cancer cells. B-DIM also activates AMPK and down-regulates AR in androgen-independent C4-2B prostate tumor xenografts in SCID mice."

[2f] (2012 - U.S.)

{PCa achieves much of the changes required for its survival, not by gene mutation but by epigenetic silencing. These are reversible changes.}

"These results suggest, for the first time, epigenetic silencing of miR-34a in PCa, which could be reversed by BR-DIM treatment and, thus BR-DIM could be useful for the inactivation of AR in the treatment of PCa."

[2g] (2011 - U.S.)

"B-DIM Impairs Radiation-Induced Survival Pathways Independently of Androgen Receptor Expression and Augments Radiation Efficacy in Prostate Cancer"

[2h] (2009 - U.S.)

"3,3′-Diindolylmethane Enhances Taxotere-Induced Apoptosis in Hormone-Refractory Prostate Cancer Cells through Survivin Down-regulation"

[2i] (2009 - U.S.)

"Inactivation of uPA and its receptor uPAR by 3, 3'-Diindolylmethane (DIM) leads to the inhibition of Prostate Cancer Cell growth and migration"

[2j] (2009 - U.S.)

"We believe that our results show for the first time the cell cycle-dependent effects of B-DIM on proliferation and apoptosis of synchronized prostate cancer cells progressing from G(1) to S phase. B-DIM inhibited this progression by induction of p27(Kip1) and down-regulation of AR. We also show for the first time that B-DIM inhibits proteasome activity in S phase, leading to the inactivation of NF-kappaB signaling and induction of apoptosis in LNCaP and C4-2B cells."

[3] Non-BR-DIM studies.

Out of kindness to my readers, I'm disinclined to include them. More of the same.

-Patrick

[1a] mayoclinic.org/diseases-con...

[1b] ncbi.nlm.nih.gov/pubmed/156...

[1c] ncbi.nlm.nih.gov/pubmed/119...

[2a] ncbi.nlm.nih.gov/pmc/articl...

[2b] ncbi.nlm.nih.gov/pmc/articl...

[2c] ncbi.nlm.nih.gov/pmc/articl...

[2d] ncbi.nlm.nih.gov/pmc/articl...

[2e] ncbi.nlm.nih.gov/pmc/articl...

[2f] ncbi.nlm.nih.gov/pmc/articl...

[2g] ncbi.nlm.nih.gov/pmc/articl...

[2h] cancerres.aacrjournals.org/...

[2i] ncbi.nlm.nih.gov/pmc/articl...

[2j] ncbi.nlm.nih.gov/pubmed/190...

[AlanMeyer]

Patrick,

I am quite confused about the role of estradiol (one form of estrogen, a "female" hormone) in prostate cancer. You've cited a lot of literature indicating, if I understand it, that estradiol stimulates the growth of PCa. However I have also read that estradiol has been used to treat PCa. I seem to recall that Dr. Snuffy Myers sometimes gave it to men who had a very good and long lasting response to ADT, but were sick of the side effects and wanted to try something else.

Is there a contradiction between these two theories? Do you think one is right and one is wrong? Or is each one right under different circumstances? Or am I terminally confused here?

Thanks.

Alan

[pjoshea13 in reply to AlanMeyer]

Hi Alan,

There is no contradiction. At supra-high levels, estradiol [E2] suppresses androgen. E2 cannot promote growth in the absence of T/DHT.

The other situation wher E2 is safe is during ADT in those whose E2 has dropped below 12 pg/mL. We seem to need that amount for bone health.

In all other situations, E2 should not go above 30 pg/mL.

For those not on ADT, I believe that T should be much higher than 350 ng/dL (the hypogonadal cutoff). T >450 ng/dL (with E2 <30) seems to get us out of the estrogen dominance zone. I feel that this is very important for those on active surveillance & during the off-phase of IADT.

The numbers above are mine, drawn from a mishmash of studies.

-Patrick

[BigRich]

Patrick,

The Patch medication goes directly into the blood stream; unlike the old DES was administered, which lowers the risk of cardiovasular evnts. However, some noted doctors will not use them for they feel compared to drugs such as Lupron the Patch has greater cardiovasular risks. This is regarding Alan's comments on estradiol.

Rich

[pjoshea13]

Rich,

Lupron & estradiol both cause castrate T. There are known morbidity issues when T is absent.

I think it careless of doctors not to monitor E2 in Lupron patients. A low-dose E2 patch can correct a dangerous deficiency. The possibility of Lupron causing E2 insufficiency is not a case for preferring E2 over Lupron.

The big question is whether mega-dose E2 adds morbidity to that already caused by castration. The PATCH trial is presumably going to answer that.

Ideally, PATCH would use low-dose E2 when necessary, so as to give a fair comparison.

-Patrick

[Spaceman210]

Thanks Patrick - question regarding this sentence, if you know: "The inhibitory effects of BR-DIM on AR and AR target gene such as prostate-specific antigen (PSA) were also observed in the clinical trial."

Does this mean it can "artificially" suppress PSA ( i.e. of the sort that should be avoided in supplements when being evaluated for radiation therapy)?

Regards,

Jeff

[pjoshea13 in reply to Spaceman210]

Jeff,

Every now & then, someone warns of things that inhibit PSA but not PCa.

To my knowledge there is only one situation where that applies: where PSA is elevated because of BPH AND PCa. Treat the BPH & PSA will go down.

Regardless, a drop in PSA means less androgen receptor [AR] activity. We only produce PSA when AR is activated & moves to the nucleus of the cell. So, when PSA is entirely due to cancer, I view a drop caused by therapy as always being a good sign.

Over time, some cancer cells begin to produce less PSA, but that's a different matter.

-Patrick

[Spaceman210 in reply to pjoshea13]

Thanks a lot for helping me understand more, Patrick!

Jeff

[Hidden]

Hello! What are you thoughts about broccoli sprouts home grown vs DIM capsules? Do you also grow broccoli sprouts and which brand DIM do you take?

[Spaceman210]

Patrick,

If DIM has all these AR reduction attributes why has there not been more traction or higher-level studies on it validating its usefulness? I have also discussed with R.O.'s and seen an American Cancer Society post somewhere cautioning about herbals reducing PSA as an indicator but not the cancer itself.

Jeff

[pjoshea13 in reply to Spaceman210]

Jeff,

My reason for using DIM not long after diagnosis was that it leads to more favorable estrogen metabolism. The effect on AR was secondary. In fact, at the beginning I was not that concerned about AR, since it is rarely mutated until ADT.

These days, I am very interested in nuclear exclusion of AR. I use melatonin particularly for this, but I think that the 2016 pre-prostatectomy study offers compelling evidence of proof-of-concept:

ncbi.nlm.nih.gov/pmc/articl...

I never bought into the idea that one could reduce PCa cell PSA without reducing the growth rate.

Most men as they get older have some degree of BPH. I never did, so my PSA was only 0.8 when a nodule was discovered. Men who effectively control BPH have fewer biopsies & an increased risk of PCa detection at a later stage. But that's the only situation where reducing PSA might have negative repercussions IMO.

-Patrick