Oral diindolylmethane (DIM): Pilot evaluation of a nonsurgical treatment for cervical dysplasia

Priore, Giuseppe Del; Gudipudi, Deleep Kumar; Montemarano, Nadine; Restivo, Antonella; Malanowska-Stega, Jeanetta; Arslan, Alan A.

doi:10.1016/j.ygyno.2009.10.060

Cited by 64 publications

(50 citation statements)

References 22 publications

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“…The 20-μM dose for BR-DIM used here is above the 2.5-μm therapeutic plasma dose range for treatments of cervical dysplasia [18] and dose range used for anti-cancer treatments that slow growth and can kill prostate cancer cells [96]. However, different diet formulations can increase BR-DIM to 7 μM in plasma, and the anti-cancer uses of BR-DIM have led to new formulations and dietary combinations (e.g., delivery with cod liver oil) that will improve absorption and enable a 20-μM plasma dose.…”

Section: Discussionmentioning

confidence: 96%

“…BR-DIM is a commonly used diet extract of yellow cruciferous vegetables [17]. BR-DIM is used to treat women with reproductive problems such as cervical dysplasia [18] and can affect pregnancy [19]. Consumption of cruciferous vegetables is associated with lower prostate cancer risk [20], and cruciferous diet extract BR-DIM slows growth and causes human prostate cancer cell death, in vitro and in vivo in an AMPK-dependent manner [21].…”

Section: Introductionmentioning

confidence: 99%

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Commonly used fertility drugs, a diet supplement, and stress force AMPK-dependent block of stemness and development in cultured mammalian embryos

Bolnick

Abdulhasan

Kilburn

et al. 2016

J Assist Reprod Genet

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Purpose The purpose of the present study is to test whether metformin, aspirin, or diet supplement (DS) BioResponse-3, 3′-Diindolylmethane (BR-DIM) can induce AMP-activated protein kinase (AMPK)-dependent potency loss in cultured embryos and whether metformin (Met) + Aspirin (Asa) or BR-DIM causes an AMPK-dependent decrease in embryonic development. Methods The methods used were as follows: culture post-thaw mouse zygotes to the two-cell embryo stage and test effects after 1-h AMPK agonists' (e.g., Met, Asa, BR-DIM, control hyperosmotic stress) exposure on AMPK-dependent loss of Oct4 and/or Rex1 nuclear potency factors, confirm AMPK dependence by reversing potency loss in two-cell-stage embryos with AMPK inhibitor compound C (CC), test whether Met + Asa (i.e., co-added) or DS BR-DIM decreases development of two-cell to blastocyst stage in an AMPK-dependent (CCsensitive) manner, and evaluate the level of Rex1 and Oct4 nuclear fluorescence in two-cell-stage embryos and rate of two-cell-stage embryo development to blastocysts. Result(s) Met, Asa, BR-DIM, or hyperosmotic sorbitol stress induces rapid~50-85 % Rex1 and/or Oct4 protein loss in twocell embryos. This loss is~60-90 % reversible by co-culture with AMPK inhibitor CC. Embryo development from twocell to blastocyst stage is decreased in culture with either Met + Asa or BR-DIM, and this is either >90 or~60 % reversible with CC, respectively. Conclusion These experimental designs here showed that Met-, Asa-, BR-DIM-, or sorbitol stress-induced rapid potency loss in two-cell embryos is AMPK dependent as suggested by inhibition of Rex1 and/or Oct4 protein loss with an AMPK inhibitor. The DS BR-DIM or fertility drugs (e.g., Met + Asa)Capsule Drugs metformin and aspirin and diet supplement BR-DIM cause AMPK-dependent potency loss and decrease embryonic development from two-cell to blastocyst stage. Reprod Genet (2016) 33:1027-1039 DOI 10.1007 that are used to enhance maternal metabolism to support fertility can also chronically slow embryo growth and block development in an AMPK-dependent manner.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Commonly used fertility drugs, a diet supplement, and stress force AMPK-dependent block of stemness and development in cultured mammalian embryos

Bolnick

Abdulhasan

Kilburn

et al. 2016

J Assist Reprod Genet

View full text Add to dashboard Cite

show abstract

“…DIM is a major indole compound present in cruciferous vegetables and consumed on a daily basis (Grose and Bjeldanes, 1992). DIM is well tolerated not only by healthy volunteers but also by patients with cervical cancer (Reed et al, 2008;Del Priore et al, 2010). In addition, DIM alone demonstrated significant clinical improvement in patients with cervical intraepithelial neoplasia (Del Priore et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…DIM is well tolerated not only by healthy volunteers but also by patients with cervical cancer (Reed et al, 2008;Del Priore et al, 2010). In addition, DIM alone demonstrated significant clinical improvement in patients with cervical intraepithelial neoplasia (Del Priore et al, 2010). Several pharmacokinetic studies on DIM stated that up to 300 mg of a single dose of DIM can be tolerated by humans (Reed et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

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Blocking Epidermal Growth Factor Receptor Activation by 3,3′-Diindolylmethane Suppresses Ovarian Tumor Growth In Vitro and In Vivo

Kandala¹,

Wright²,

Srivastava

2012

The Journal of Pharmacology and Experimental Therapeutics

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Genetic alterations, including the overexpression of epidermal growth factor receptor (EGFR) (in approximately 70% of ovarian tumors), play a crucial role in the signal transduction pathways that regulate key cellular functions, such as cell survival and proliferation, and are responsible for compromising traditional chemotherapy. 3,3Ј-Diindolylmethane (DIM) is an indole compound present in Brassica vegetables. In our previous studies, we demonstrated that BR-DIM, a formulated version of DIM, suppressed the growth of ovarian cancer cells by causing cell cycle arrest and apoptosis. In the present study, we delineated the mechanism by which DIM suppressed the growth of SKOV-3, OVCAR-3, and TOV-21G human ovarian cancer cells. DIM treatment caused significant down-regulation of the constitutive EGFR protein level as well as phosphorylation of EGFR at Tyr1068, Tyr992, Tyr845, and Tyr1173 in various ovarian cancer cells. To determine whether DIM suppressed the activation of EGFR by activating phosphorylation, cells were treated with epidermal growth factor. Epidermal growth factor treatment significantly blocked the DIM-mediated inhibition of EGFR activation and apoptosis in both SKOV-3 and OVCAR-3 cells. In addition, DIM treatment drastically reduced the phosphorylation of mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated kinase (ERK), which are downstream to EGFR, without affecting their protein levels. DIM treatment also inhibited the kinase activity of ERK, as observed by the down-regulation of phospho-E twenty-six like transcription factor 1 (p-ELK1) in all three ovarian cancer cell lines. DIM significantly suppressed the growth of ovarian tumors in vivo. Tumor growth suppressive effects of DIM in SKOV-3 tumor xenografts were associated with reduced phosphorylation of EGFR, MEK, and ERK. These results indicate that DIM induces apoptosis in ovarian cancer cells by inhibiting the EGFR-ERK pathway in vitro and in vivo.

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Clinical Efficacy Trials With Natural Products and Herbal Medicines

Nance

2015

Phytotherapies

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Oral diindolylmethane (DIM): Pilot evaluation of a nonsurgical treatment for cervical dysplasia

Cited by 64 publications

References 22 publications

Commonly used fertility drugs, a diet supplement, and stress force AMPK-dependent block of stemness and development in cultured mammalian embryos

Commonly used fertility drugs, a diet supplement, and stress force AMPK-dependent block of stemness and development in cultured mammalian embryos

Blocking Epidermal Growth Factor Receptor Activation by 3,3′-Diindolylmethane Suppresses Ovarian Tumor Growth In Vitro and In Vivo

Clinical Efficacy Trials With Natural Products and Herbal Medicines

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