The Plant Derived 3-3′-Diindolylmethane (DIM) Behaves as CB2 Receptor Agonist in Prostate Cancer Cellular Models

Tucci, Paolo; Brown, Iain; Bewick, Guy S.; Pertwee, Roger Guy; Marini, Pietro

doi:10.3390/ijms24043620

Cited by 6 publications

(4 citation statements)

References 61 publications

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“…50 For instance, the compound 3− 3′-diindolylmethane (DIM), which can be considered two skatole molecules fused together through the 3-positioned methyl group, has shown promising anticancer effects, as well as been found to be a CB2 receptor agonist. 51,52 Future investigations into the possible biological activity of these compounds and others reported here may further shed light on how they may influence the properties of specific varieties.…”

Section: Acs Omegamentioning

confidence: 76%

Minor, Nonterpenoid Volatile Compounds Drive the Aroma Differences of Exotic Cannabis

Oswald,

Paryani,

Sosa

et al. 2023

ACS Omega

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Cannabis sativa L. produces a wide variety of volatile secondary metabolites that contribute to its unique aroma. The major volatile constituents include monoterpenes, sesquiterpenes, and their oxygenated derivates. In particular, the compounds ß-myrcene, D-(+)-limonene, ß-caryophyllene, and terpinolene are often found in greatest amounts, which has led to their use in chemotaxonomic classification schemes and legal Cannabis sativa L. product labeling. While these compounds contribute to the characteristic aroma of Cannabis sativa L. and may help differentiate varieties on a broad level, their importance in producing specific aromas is not well understood. Here, we show that across Cannabis sativa L. varieties with divergent aromas, terpene expression remains remarkably similar, indicating their benign contribution to these unique, specific scents. Instead, we found that many minor, nonterpenoid compounds correlate strongly with nonprototypical sweet or savory aromas produced by Cannabis sativa L. Coupling sensory studies to our chemical analysis, we derive correlations between groups of compounds, or in some cases, individual compounds, that produce many of these diverse scents. In particular, we identified a new class of volatile sulfur compounds (VSCs) containing the 3-mercaptohexyl functional group responsible for the distinct citrus aromas in certain varieties and skatole (3-methylindole) as the key source of the chemical aroma in others. Our results provide not only a rich understanding of the chemistry of Cannabis sativa L. but also highlight how the importance of terpenes in the context of the aroma of Cannabis sativa L. has been overemphasized.

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Section: Acs Omegamentioning

confidence: 76%

Minor, Nonterpenoid Volatile Compounds Drive the Aroma Differences of Exotic Cannabis

Oswald,

Paryani,

Sosa

et al. 2023

ACS Omega

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“…RES and DIM are phytochemicals that have received considerable attention due to their bene cial health effects and anti-cancer properties. Both compounds modulate the activities of several signalling pathways including ERa and AHR dependent responses (22,41,42). RES activates ERa but inhibits AHR, while DIM activates both ERa and AHR.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol and 3,3’-diindolylmethane differentially regulate aryl hydrocarbon receptor and estrogen receptor alpha to modulate diverse signalling pathways in MCF-7 human breast cancer cells

Das,

Ulven,

Matthews

2023

Preprint

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Background Inhibitory crosstalk between estrogen receptor alpha (ERα) and aryl hydrocarbon receptor (AHR) regulates 17β-estradiol (E2)-dependent breast cancer cell signalling. ERα and AHR are ligand activated transcription factors that mediate the actions of E2 and pollutants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), respectively. Like ERα, AHR binds many dietary compounds, including resveratrol (RES) and 3,3´diindolylmethane (DIM) often found in berries and cruciferous vegetables, respectively. RES activates ERα but inhibits AHR, whereas DIM activates ERα and AHR. Thus, dietary intake of RES and DIM will modulate both receptor activities. Here we used chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq) and transcriptomics (RNA-seq) to study ERα and AHR crosstalk after treatment of MCF-7 human breast cancer cells with DIM, RES, E2 or TCDD alone or in combination. Methods and Results 1 h or 6 h ligand treated MCF-7 cells were profiled for ERα and AHR binding sites using ChIP-seq or gene expression changes using RNA-seq, respectively. E2 resulted in 866 differentially expressed genes (DEGs), 532 of which were also bound by ERα. DIM and RES resulted in 577 and 446 DEGs, respectively, with 278 of the RES and 393 of the DIM DEGs also bound by ERα. An estrogen response element (ERE) was enriched after treatments with all three ligands, while an AHR response element (AHRE) was also enriched in the DIM-ERα but not after E2-ERα bound sites. An ERE was enriched in E2 + TCDD and DIM AHR bound sites but not for the TCDD-AHR bound sites. We found that 90% of the DEGs closest to an AHR binding site after DIM or E2 + TCDD also had an ERE and 60% of coregulated genes were common to both treatments. Collectively, our data show that DIM activates ERα and AHR like that of E2 + TCDD, while RES activates ERα but inhibits AHR. Conclusion The dietary compounds DIM and RES differentially regulate ERα and AHR action and likely other signalling pathways, which need to be considered to properly interpret their cellular and biological responses. These data further highlight the complex crosstalk between ERa and AHR and suggest that when both receptors are activated ERa dominants causing the preferential recruitment of AHR to ERa target genes.

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“…RES and DIM are phytochemicals that have received considerable attention due to their beneficial health effects and anti-cancer properties. Both compounds modulate the activities of several signaling pathways including ERα-and AHR-dependent responses [22,31,32]. RES activates ERα but inhibits AHR, while DIM activates both ERα and AHR.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol and 3,3′-Diindolylmethane Differentially Regulate Aryl Hydrocarbon Receptor and Estrogen Receptor Alpha Activity through Multiple Transcriptomic Targets in MCF-7 Human Breast Cancer Cells

Das,

Somisetty,

Ulven

et al. 2023

IJMS

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Inhibitory crosstalk between estrogen receptor alpha (ERα) and aryl hydrocarbon receptor (AHR) regulates 17β-estradiol (E2)-dependent breast cancer cell signaling. ERα and AHR are transcription factors activated by E2 and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), respectively. Dietary ligands resveratrol (RES) and 3,3′diindolylmethane (DIM) also activate ERα while only DIM activates AHR and RES represses it. DIM and RES are reported to have anti-cancer and anti-inflammatory properties. Studies with genome-wide targets and AHR- and ERα-regulated genes after DIM and RES are unknown. We used chromatin immunoprecipitation with high-throughput sequencing and transcriptomics to study ERα as well as AHR coregulation in MCF-7 human breast cancer cells treated with DIM, RES, E2, or TCDD alone or E2+TCDD for 1 and 6 h, respectively. ERα bound sites after being DIM enriched for the AHR motif but not after E2 or RES while AHR bound sites after being DIM and E2+TCDD enriched for the ERE motif but not after TCDD. More than 90% of the differentially expressed genes closest to an AHR binding site after DIM or E2+TCDD also had an ERα site, and 60% of the coregulated genes between DIM and E2+TCDD were common. Collectively, our data show that RES and DIM differentially regulate multiple transcriptomic targets via ERα and ERα/AHR coactivity, respectively, which need to be considered to properly interpret their cellular and biological responses. These novel data also suggest that, when both receptors are activated, ERα dominates with preferential recruitment of AHR to ERα target genes.

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The Plant Derived 3-3′-Diindolylmethane (DIM) Behaves as CB2 Receptor Agonist in Prostate Cancer Cellular Models

Cited by 6 publications

References 61 publications

Minor, Nonterpenoid Volatile Compounds Drive the Aroma Differences of Exotic Cannabis

Minor, Nonterpenoid Volatile Compounds Drive the Aroma Differences of Exotic Cannabis

Resveratrol and 3,3’-diindolylmethane differentially regulate aryl hydrocarbon receptor and estrogen receptor alpha to modulate diverse signalling pathways in MCF-7 human breast cancer cells

Resveratrol and 3,3′-Diindolylmethane Differentially Regulate Aryl Hydrocarbon Receptor and Estrogen Receptor Alpha Activity through Multiple Transcriptomic Targets in MCF-7 Human Breast Cancer Cells

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