3,3′-Diindolylmethane stimulates murine immune function in vitro and in vivo

Xue, Ling; Pestka, James J.; Li, Maoxiang; Firestone, Gary L.; Bjeldanes, Leonard F.

doi:10.1016/j.jnutbio.2007.05.004

Cited by 37 publications

(25 citation statements)

References 73 publications

(68 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our study identified a further important mode of action for the intriguing dietary component DIM that induces mitochondria-dependent PCD, because the effects seen from treatment with DIM are a consequence of its inhibition of the mitochondrial F0F1-ATP synthase in protozoan parasite L. donovani. The upstream events of generation of ROS are different from those in other mechanistic pathways induced by DIM in different cell lines (Xue et al, 2008). Mitochondrial membrane depolarization and ROS formation play significant roles in modulating the response of the parasite to DIM.…”

Section: Discussionmentioning

confidence: 93%

Mitochondria-Dependent Reactive Oxygen Species-Mediated Programmed Cell Death Induced by 3,3′-Diindolylmethane through Inhibition of F0F1-ATP Synthase in Unicellular Protozoan ParasiteLeishmania donovani

Ganguly²,

et al. 2008

View full text Add to dashboard Cite

Mitochondria are the principal site for the generation of cellular ATP by oxidative phosphorylation. F0F1-ATP synthase, a complex V of the electron transport chain, is an important constituent of mitochondria-dependent signaling pathways involved in apoptosis. In the present study, we have shown for the first time that 3,3Ј-diindolylmethane (DIM), a DNA topoisomerase I poison, inhibits mitochondrial F0F1-ATP synthase of Leishmania donovani and induces programmed cell death (PCD), which is a novel insight into the mechanism in protozoan parasites. DIM-induced inhibition of F0F1-ATP synthase activity causes depletion of mitochondrial ATP levels and significant stimulation of mitochondrial reactive oxygen species (ROS) production, followed by depolarization of mitochondrial membrane potential (⌬⌿ m ). Because ⌬⌿ m is the driving force for mitochondrial ATP synthesis, loss of ⌬⌿ m results in depletion of cellular ATP level. The loss of ⌬⌿ m causes the cellular ROS generation and in turn leads to the oxidative DNA lesions followed by DNA fragmentation. In contrast, loss of ⌬⌿ m leads to release of cytochrome c into the cytosol and subsequently activates the caspase-like proteases, which lead to oligonucleosomal DNA cleavage. We have also shown that mitochondrial DNA-depleted cells are insensitive to DIM to induce PCD. Therefore, mitochondria are necessary for cytotoxicity of DIM in kinetoplastid parasites. Taken together, our study indicates for the first time that DIM-induced mitochondrial dysfunction by inhibition of F0F1-ATP synthase activity leads to PCD in Leishmania spp. parasites, which could be exploited to develop newer potential therapeutic targets.Apoptosis, a form of programmed cell death (PCD), is a genetically regulated active physiological process of cell suicide that causes cell deletion without inflammation, scarring, or release of cellular contents. Mitochondria of living cells play a pivotal role in controlling life and death (Green and Reed, 1998). Mitochondria are an important cellular source for the generation of reactive oxygen species (ROS) inside the cells (Halliwell and Gutteridge, 1990). Maintenance of proper mitochondrial transmembrane potential (⌬⌿ m ) is essential for the survival of the cell because it derives the synthesis of ATP and maintains oxidative phosphorylation (Gottlieb, 2001).3,3Ј-Diindolylmethane (DIM) is a major acid condensation product of indole-3-carbinol, a natural compound found in vegetables of the genus Brassica. It has an anticarcinogenic effect and inhibits the growth of human cancer cells. DIM-

show abstract

Section: Discussionmentioning

confidence: 93%

Mitochondria-Dependent Reactive Oxygen Species-Mediated Programmed Cell Death Induced by 3,3′-Diindolylmethane through Inhibition of F0F1-ATP Synthase in Unicellular Protozoan ParasiteLeishmania donovani

Ganguly²,

et al. 2008

View full text Add to dashboard Cite

show abstract

“…DIM is in clinical trials as a treatment for numerous forms of cancer because of its safety at high doses and its promising anti-tumor effect in vitro and in vivo (26,27). It is also being investigated as a potential treatment for a variety of viral and antibiotic-resistant bacterial infections, because of its immunomodulatory effects (28,29). The reported cellular effects of DIM are numerous (30), including cell cycle regulation, apoptosis induction, nuclear receptor-mediated gene transcriptional changes, induction of various drug-metabolizing cytochrome P450 enzymes, estrogen metabolism changes resulting in an increase in anticarcinogenic 2-hydroxylation of estrogen, inhibition of mitochondrial H ϩ -ATP synthase resulting in induction of p21…”

mentioning

confidence: 99%

Lipid G Protein-coupled Receptor Ligand Identification Using β-Arrestin PathHunter™ Assay

Yin¹,

Chu²,

et al. 2009

Journal of Biological Chemistry

296

329

View full text Add to dashboard Cite

A growing number of orphan G-protein-coupled receptors (GPCRs) have been reported to be activated by lipid ligands, such as lysophosphatidic acid, sphingosine 1-phosphate (S1P), and cannabinoids, for which there are already well established receptors. These new ligand claims are controversial due to either lack of independent confirmations or conflicting reports. We used the ␤-arrestin PathHunter TM assay system, a newly developed, generic GPCR assay format that measures ␤-arrestin binding to GPCRs, to evaluate lipid receptor and ligand pairing. This assay eliminates interference from endogenous receptors on the parental cells because it measures a signal that is specifically generated by the tagged receptor and is immediately downstream of receptor activation. We screened a large number of newly "deorphaned" receptors (GPR23, GPR92, GPR55, G2A, GPR18, GPR3, GPR6, GPR12, and GPR63) and control receptors against a collection of ϳ400 lipid molecules to try to identify the receptor ligand in an unbiased fashion. GPR92 was confirmed to be a lysophosphatidic acid receptor with weaker responses to farnesyl pyrophosphate and geranylgeranyl diphosphate. The putative cannabinoid receptor GPR55 responded strongly to AM251, rimonabant, and lysophosphatidylinositol but only very weakly to endocannabinoids. G2A receptor was confirmed to be an oxidized free fatty acid receptor. In addition, we discovered that 3,3-diindolylmethane, a dietary molecule from cruciferous vegetables, which has known anti-cancer properties, to be a CB 2 receptor partial agonist, with binding affinity around 1 M. The anti-inflammatory effect of 3,3-diindolylmethane in RAW264.7 cells was shown to be partially mediated by CB 2 .

show abstract

“…Chemistry DIM (1), its derivatives (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), and isomers of DIM [2,2Ј-DIM (22) and 2,3Ј-DIM (25)] were synthesized using the methods reported by Nagarajan and Perumal 11) and usual organic synthetic methods as shown in Charts 1 and 2. Briefly, DIM (1) and its derivatives (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) were obtained by the reaction of indole or methylindole with various aldehydes or ketones (Chart 1).…”

Section: Resultsmentioning

confidence: 99%

“…Briefly, DIM (1) and its derivatives (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) were obtained by the reaction of indole or methylindole with various aldehydes or ketones (Chart 1). Bis(1-benzenesulfonyl-1H-indol-2-yl)methanol (20) and (1-benzenesulfonyl-1H-indol-2-yl)(1-benzenesulfonyl-1H-indol-3-yl)methanol (24) was obtained by the reaction of 2-(19) or 3-formyl-1-benzenesulfonyl-1H-indole (23) with 1-benzenesulfonyl-1H-indole (18), followed by reduction and desulfonylation to give 2,2Ј-DIM (22) or 2,3Ј-DIM (25) (Chart 2).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Enhancement of Chemically-Induced HL-60 Cell Differentiation by 3,3'-Diindolylmethane Derivatives

et al. 2009

View full text Add to dashboard Cite

3,3Ј-Diindolylmethane (DIM, 1) is a major metabolite (spontaneously formed product in intragastric acid condition) of indole-3-carbinol (I3C, 2) which is a phytochemical expressed in brassica vegetables, including broccoli, brussels sprouts, kales and the cabbages, and has been thought to be associated with the anticancer/cancer chemopreventive activities of vegetable consumption.1) DIM (1) controls proliferation of various tumor cells, including cells of breast cancer, prostate cancer, ovary cancer, lung cancer and pancreatic cancer, by inducing G 1 /S arrest of the cell cycle and apoptosis.2) In addition, DIM (1) modulates metabolism of estrogen and testosterone, 3,4) which act as indigenous tumor promoters for several hormone-dependent cancers. DIM (1) is also reported to be a weak agonist for the arylhydrocarbon receptor (AhR) and blocks the effects of estrogens via inhibition of AhR-estrogen receptor cross talk.5) In addition, DIM (1) possesses other various activities, including immunomodulatory effect.6) All the experimental studies suggest that DIM (1) has incredible potential both for prevention and for treatment of cancer.Although the molecular basis of cancer chemopreventive and cancer chemotherapic effects of DIM (1) is unclear, effects of DIM (1) on cell differentiation would be one of candidate mechanisms underlying the biological activities elicited by DIM (1). In fact, Kim et al. recently reported that indirubin, another AhR agonist with a structure related to that of DIM (1), and its derivatives show enhancing effect on 1,25-dihydroxyvitamin D 3 (1,25-VD 3 )-and all-trans retinoic acid (ATRA)-induced cell differentiation of HL-60 leukemia cells. 7)Under such circumstances, we investigated the enhancing effect on chemically-induced HL-60 cell differentiation of DIM (1) and its derivatives in combination with various cell differentiation inducers, including ATRA, tamibarotene (Am80, 3), 1,25-VD 3 , 12-O-tetradecanoyl phorbol-13-acetate (TPA) and dimethyl sulfoxide (DMSO). All of these chemicals are known to induce terminal differentiation in leukemic cell lines, including HL-60 and U937 cells. ATRA and Am80 are therapeutic agents for acute promyelocytic leukemia (APL) and induce differentiation of HL-60 cells to mature granulocytes.8) On the other hand, 1,25-VD 3 and TPA have been established to induce differentiation of HL-60 cells to mature monocytes. 9) DMSO is another typical cell differentiation inducer. 10) Results and DiscussionChemistry DIM (1), its derivatives (4-17), and isomers of DIM [2,2Ј-DIM (22) and 2,3Ј-DIM (25) Bunkyo-ku, Tokyo 113-0032, Japan. Received January 8, 2009; accepted February 19, 2009; published online February 24, 2009 3,3-Diindolylmethane (DIM, 1) and its derivatives have been prepared, and their enhancing effects on chemically-induced HL-60 cell differentiation were analyzed. Among the prepared compounds, IndDIM (12) showed the most potent enhancing effect on HL-60 cell differentiation induced by chemicals, including retinoids, 1,25-dihydroxyvitamin D 3 , 12-O-...

show abstract

3,3′-Diindolylmethane stimulates murine immune function in vitro and in vivo

Cited by 37 publications

References 73 publications

Mitochondria-Dependent Reactive Oxygen Species-Mediated Programmed Cell Death Induced by 3,3′-Diindolylmethane through Inhibition of F0F1-ATP Synthase in Unicellular Protozoan ParasiteLeishmania donovani

Mitochondria-Dependent Reactive Oxygen Species-Mediated Programmed Cell Death Induced by 3,3′-Diindolylmethane through Inhibition of F0F1-ATP Synthase in Unicellular Protozoan ParasiteLeishmania donovani

Lipid G Protein-coupled Receptor Ligand Identification Using β-Arrestin PathHunter™ Assay

Enhancement of Chemically-Induced HL-60 Cell Differentiation by 3,3'-Diindolylmethane Derivatives

Contact Info

Product

Resources

About