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Molecular mechanism of anti-tumoral properties of DIM. The anti-cancer activities of DIM involve the positive (↑) and/or negative (↓) regulation of protein expression and activities, regulating cellular processes considered hallmarks of cancer. For details, see the text
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![Contents of total glucosinolates in edible cruciferous vegetables [47-51]](publication/373430238/figure/tbl1/AS:11431281183946322@1693141193139/Contents-of-total-glucosinolates-in-edible-cruciferous-vegetables-47-51_Q320.jpg)
Dietary compounds in cancer prevention have gained significant consideration as a viable method. Indole-3-carbinol (I3C) and 3,3′-diindolylmethane (DIM) are heterocyclic and bioactive chemicals found in cruciferous vegetables like broccoli, cauliflower, cabbage, and brussels sprouts. They are synthesized after glycolysis from the glucosinolate stru...
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... According to the studies described above, a research opportunity exists to evaluate the synergistic effect of MG with other compounds that have demonstrated anti-tumor properties, such as polyphenols [92,93]. The combined treatment of MG with gemcitabine and cisplatin or gemcitabine significantly reduces body weight loss and skeletal muscle atrophy compared to conventional chemotherapy in mice bearing bladder cancer [94]. ...
In recent years, magnolol (MG), a natural active compound of polyphenolic nature, has garnered significant interest for its anti-cancer effects. Numerous studies conducted on cell lines and animal models have indicated a positive impact of administering drugs or semi-synthesized products derived from MG, including a decreased incidence of various cancers. This review aims to illustrate the underlying cellular and molecular basis of its actions. The article includes in-depth explanations of phytochemistry, semi-synthetic derivatives, bioavailability, pharmacokinetics, preclinical research, anti-tumor mechanisms, human clinical studies, toxicity, side effects, and safety. It also demonstrates that, in contrast to the wealth of synthetic medications, MG is highly effective against bladder, colon, gastric, skin, liver, lung, gallbladder, and prostate cancers. The findings of this review indicate that MG is a promising candidate as an anti-tumor agent, and future research should focus on developing new semi-synthetic derivative compounds with potential anti-tumor properties.
... italica), an annual plant of the Brassicaceae family, is a cruciferous vegetable that is rich in antioxidants (Radünz et al. 2024). It is rich in a variety of natural components beneficial to human health, such as sulforaphane (SFN) (Abellán et al. 2021), 3,3′-diindolylmethane (DIM), and indole-3-carbinol (I3C) (Reyes-Hernández et al. 2023). DIM is formed during the autolysis and decomposition of glucobrassicin in brassica plants (Reyes-Hernández et al. 2023). ...
... It is rich in a variety of natural components beneficial to human health, such as sulforaphane (SFN) (Abellán et al. 2021), 3,3′-diindolylmethane (DIM), and indole-3-carbinol (I3C) (Reyes-Hernández et al. 2023). DIM is formed during the autolysis and decomposition of glucobrassicin in brassica plants (Reyes-Hernández et al. 2023). SFN is a dietary isothiocyanate (ITC) obtained by hydrolysis of glucosinolates via the myrosinase enzyme in broccoli (Mahn and Castillo 2021). ...
Arthritis is a disease characterized by joint pain, swelling, and limited mobility and is also a major cause of disability. Osteoarthritis (OA) and rheumatoid arthritis (RA) are the two most common manifestations of arthritis, and they share many common risk factors and pathogenic features. At present, there is no effective approach to prevent the disease or slow its progress. Nonetheless, many treatments can alleviate symptoms and improve the quality of life of patients. Among, antioxidant supplement therapy has become one of the most popular methods as it can inhibit the formation of reactive oxygen species (ROS) in chondrocytes, which is a key step in the pathogenesis of arthritis. Broccoli is rich in many essential nutrients, including fibers, vitamins, minerals, and various bioactive components. Thus, a dietary supplement of broccoli holds potential as a preventive measure against arthritis due to its widespread popularity, safety profile, and affordability. However, no review of the clinical and pre‐clinical studies of broccoli on arthritis is available so far. Therefore, this systematic review aims to critically evaluate the efficacy and safety of broccoli and its bioactive constituents in the treatment of arthritis. Although the current evidence falls short of establishing a definitive effect of broccoli on arthritis due to a limited number of clinical studies and significant heterogeneity among the existing research, current research provides overall support for the potential benefits of broccoli and its bioactive components in preventing and managing arthritis and the use of broccoli as an adjuvant treatment for individuals with arthritis.
... I3C is found in many cruciferous vegetables (i.e., Brassicaceae), especially members of the Brassica genus including cabbage, cauliflower, and Brussels sprouts. The genus is native to Western Europe, the circum-Mediterranean region and the temperate regions of Asia, and studies have shown that consumption of the genus has an anti-cancer effect, and some species of the genus have been used medicinally, with a wide range of applications [10]. Studies have shown that DIM plays an anticancer role by inducing ferroptosis in gastric cancer cells through the BAP1-IP3R axis [11]. ...
... DIM is a heterocyclic, biologically active chemical found in cruciferous vegetables, such as broccoli, cauliflower, cabbage, and Brussels sprouts. It is synthesized from the glycolysis of thioglucoside structures [10]. The role of DIM in lung cancer is unknown. ...
Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor. In lung cancer, AHR activation stimulates cancer cell proliferation and promotes tissue invasion and metastasis, and targeting the AHR pathway is an effective way to prevent and treat lung cancer. In lung cancer, AHR binds to the NRF2 promoter region to promote carcinogenesis, but treatment research based on AHR/NRF2 pathway is insufficient. 3,3′-diindolylmethane (DIM), an active phytochemical derivative extracted from cruciferous vegetables, is a modulator of AHR. In this study, We investigated the medicinal value of DIM in NSCLC (non-small cell lung cancer) by in vivo and in vitro experiments and explored the underlying mechanisms. In vitro studies showed that DIM inhibited the viability of NSCLC and induced apoptosis and cycle arrest in cancer cells. DIM inhibited the migration and invasion of NSCLC cells by reversing the epithelial-mesenchymal transition. DIM induced ferroptosis in NSCLC cells; increased cellular Fe2+, ROS (reactive oxygen species), and MDA; decreased cellular GSH, AHR, NRF2, and GPX4; and disrupted the mitochondrial membrane potential. The effect of DIM-induced ferroptosis can be reversed by the AHR receptor antagonist CH-223191, ferroptosis inhibitor Fer-1, and ROS scavenger NAC. Overexpression of NRF2 reversed DIM-induced ferroptosis. Identical results were obtained in a nude mouse xenograft model. In summary, we have confirmed that DIM has significant potential in the treatment of non-small cell lung cancer. DIM induces cancer cell ferroptosis through the AHR/NRF2/GPX4 axis. These findings provide experimental basis for DIM treatment and future clinical research in non-small cell lung cancer.
... They also exhibit antioxidant and anti-inflammatory properties that could mitigate neurodegenerative processes [73]. In oncology, indole derivatives like indole-3-carbinol (I3C) have demonstrated anti-cancer potential by inducing apoptosis, suppressing cell proliferation, and modulating estrogen metabolism in hormone-responsive cancers [74]. However, the precise interplay of indoles in the neuro-cancer axis remains largely uncharted, warranting further investigation into their systemic and localized effects [75]; • Polyamines: Polyamines, including putrescine, spermidine, and spermine, are small, positively charged molecules produced by gut microbiota and host cells [76]. ...
The gut–brain–cancer axis represents a novel and intricate connection between the gut microbiota, neurobiology, and cancer progression. Recent advances have accentuated the significant role of gut microbiota metabolites in modulating systemic processes that influence both brain health and tumorigenesis. This paper explores the emerging concept of metabolite-mediated modulation within the gut–brain–cancer connection, focusing on key metabolites such as short-chain fatty acids (SCFAs), tryptophan derivatives, secondary bile acids, and lipopolysaccharides (LPS). While the gut microbiota’s impact on immune regulation, neuroinflammation, and tumor development is well established, gaps remain in grasping how specific metabolites contribute to neuro–cancer interactions. We discuss novel metabolites with potential implications for neurobiology and cancer, such as indoles and polyamines, which have yet to be extensively studied. Furthermore, we review preclinical and clinical evidence linking gut dysbiosis, altered metabolite profiles, and brain tumors, showcasing limitations and research gaps, particularly in human longitudinal studies. Case studies investigating microbiota-based interventions, including dietary changes, fecal microbiota transplantation, and probiotics, demonstrate promise but also indicate hurdles in translating these findings to clinical cancer therapies. This paper concludes with a call for standardized multi-omics approaches and bi-directional research frameworks integrating microbiome, neuroscience, and oncology to develop personalized therapeutic strategies for neuro-cancer patients.
... On the other hand, many researches indicate beneficial effects of consuming Brassicaceae vegetables [12,16,22,23]. Among the GSLs and their derivatives, SFN (1isothiocyanato-4-(methyl-sulfinyl)butane) formed from GRA, sinigrin-derived allyl ITC, and indole-3 carbinol derived from glucobrassicin, 2-phenylethyl ITC (from gluconasturtiin), benzyl ITC (from glucotropaeolin), and 3,3′ -diindolylmethane (product of indole-3-carbinol condensation) have attracted much attention [16,24,25]. As was mentioned above, the SFN that belongs to the ITCs undergoes conjugation with glutathione in the body and then, the conjugates hydrolyse and N-acetylcysteine derivatives-mercapturic acids-are formed [14]. ...
Sprouts and microgreens which belong to the Brassicaceae family contain significantly more glucosinolates than mature vegetables, and their composition often differs too. These plant growth stages can be a valuable supplement of the aforementioned compounds in the diet. The content and proportion of individual glucosinolates in sprouts and microgreens can be regulated by modifying the length and temperature of cultivation, the type of light, the use of mineral compounds, elicitation, primming, and cold plasma as well as storage conditions. The way in which sprouts are prepared for consumption affects the yield of glucosinolate hydrolysis. Genetic variation leading to different plant responses to the same factors (e.g., type of light) makes it necessary to conduct detailed studies involving species and variety diversity. Heat stress and the use of cold plasma appear to be fairly universal methods for increasing glucosinolate content. Studies on the use of light at different wavelengths do not provide unequivocal results. Despite experiments on the use of seed soaking solutions (e.g., sulfur and selenium compounds), there are no studies in the available literature on the effects of chemical and thermal seed disinfection methods on the glucosinolate content of the obtained sprouts and microgreens.
... Эпигенетические перестройки являются предиктором нарушения жизнедеятельности клеток (пролиферации, дифференцировки, регуляции клеточного цикла -КЦ, апоптоза, внутриклеточных сигнальных путей -СП, т.п.) и, соответственно, определяют готовность тканей к опухолевому росту. К одним из самых распространенных эпигенетических изменений можно отнести метилирование ДНК и модификацию гистонов, имеющих важные последствия для нашего генома [1][2][3][4]. ...
... Представлены результаты работ по изучению моделирующего влияния DIM на окислительный стресс, метаболизм половых стероидов, процессы клеточной миграции и метастазирования. ДНК-деметилирующие свойства и ингибирование деацетилаз ядерных белков позволяют отнести DIM к перспективным соединениям, которые можно было бы применять для профилактики наиболее распространенных форм ОЗ [3]. ...
The basis for the prevention of cancer is the correction of initial epigenetic disorders in the cell, i.e. implementation of pathological genome reversion. Convincing evidence has accumulated to support the potential antitumor activity of compounds derived from cruciferous vegetables of the genus Brassicaceae. Indole-3-carbinol and 3,3'-diindolylmethane (DIM) have been investigated for their use as chemopreventive agents. DIM is formed in the acidic environment of the stomach as a result of dimerization of indole-3-carbinol monomers. Currently, it is impossible to identify a specific vector of influence of DIM at the molecular level. In this review, we summarize the pleiotropic effects of DIM aimed at correcting reversible epigenetic changes in tumor cells. Emphasis will be placed on the major cellular and molecular events that are effectively modulated by DIM. The main profile of DIM competencies concerns the management of intracellular signal transmission and correction of initial molecular genetic changes at the level of key participants in signaling pathways (NF-κB/Wnt/Akt/mTOR) leading to the development of cancer. The ability of DIM to differentially modulate tumor cell apoptosis has been observed in preclinical studies. It has been suggested that using DIM it is possible to increase the effectiveness of chemotherapeutic compounds with different molecular targets, thereby increasing chemosensitization. DIM has entered phase III clinical trials, with preliminary results confirming its promise both as a stand-alone drug and in combination with other components of anticancer therapy. Establishing the range of epigenetic control of DIM molecular and genetic changes in various cancers will allow optimization of therapeutic epigenetics approaches.
... I3C and its metabolite 3,3'-diindolylmethane (DIM) have been demonstrated to prevent various diseases, including diabetes mellitus, malignancy, cardiovascular diseases, bone-related diseases, and neurodegenerative diseases [11]. It is reported that I3C has anti-cancer effects by arresting cell cycle, proliferation, autophagy, and apoptosis [12,13]. Previous studies have found that I3C promotes apoptosis and suppresses metastasis, and its metabolite DIM arrests the G1 cell cycle in esophageal squamous cell carcinoma [14,15]. ...
Immunotherapy is a new treatment method for solid tumors, but its effect on esophageal carcinoma (ESCA) is not as good as expected. Indole-3-carbinol (I3C) has been demonstrated to have anti-cancer effect. This study aimed to investigate the effect of I3C on immune evasion and the molecular mechanism. T cell percentage was analyzed using flow cytometry and T cell killing ability was evaluated using a lactate dehydrogenase kit and enzyme-linked immunosorbent assay. The molecular mechanism was explored based on bioinformatic analysis, quantitative real-time polymerase chain reaction, RNA binding protein immunoprecipitation, and dual-luciferase reporter assay. The results indicated that I3C inhibited ESCA cell viability, increased CD3 ⁺ CD4 ⁺ and CD3 ⁺ CD8 ⁺ T cells, cytotoxic rate, as well as IFN-γ and IL-2 levels, suggesting that immune evasion was suppressed by I3C. Moreover, I3C elevated the expression of CES1, which expression was decreased in ESCA. Besides, CES1 interacted with PD-L1 to increase its expression. Rescue experiments demonstrated the effect of the I3C/CES1/PD-L1 axis on immune escape. Taken together, I3C suppresses immune evasion in ESCA by increasing CES1 expression, which interacts with PD-L1. These findings suggest that I3C may be used to improve the effectiveness of immunotherapy.
... 3`-дііндолілметан (ДІМ) -один з активних метаболітів індол-3-карбінолу, що утворюється з двох його молекул, має більш стабільну структуру, ефективно та безпечно нормалізує метаболізм естрогенів, володіє вираженими антипроліферативними властивостями [35]. ДІМ нормалізує метаболізм естрогенів шляхом зменшення кількості 16α-гідроксіестрону, що зумовлює проліферацію, збільшення кількості 2-гідроксіестрону, що захищає від гіперплазії, вибірково зв'язується з естрогенними рецепторами-β, пригнічує активність естрогенових рецепторів-α, що перешкоджає розвитку [36]. ...
Benign breast diseases (BBDs) are the most common group of diseases among women that negatively affect their quality of life. In fact, these pathological conditions are diagnosed at least 10 times more often than breast cancer. Up to 30% of women with BBDs will need treatment at some point in their lives. A triple assessment which is performed using imaging methods of clinical examination (ultrasound examination, mammography) and histopathological examination after a puncture biopsy during the initial consultation allows to exclude breast cancer in the majority of patients. `The main clinical manifestation of BBDs is mastalgia. In recent years, a variety of natural herbal remedies have played a significant role in the symptom-modifying therapy of mastalgia.The objective: to study the possibility of using an innovative phytocomplex as a symptom-modifying agent in the presence of BBDs, which is manifested by mastalgia.Materials and methods. Clinical monitoring of 60 patients between the ages of 22 and 46 years old with BBDs of various genesis was carried out. The study group included 30 women who used a phytocomplex containing 3,3`-diindolylmethane (200 mg), vitex extract (100 mg), epigallocatechin (45 mg), broccoli extract (0.4 mg), 1 tablet twice daily for 90 days. The reference group included 30 women who used a dietary supplement with indole-3-carbinol (200 mg) according to a similar scheme.Assessment of clinical symptoms of BBDs, measurement of interleukin-6 level in blood serum, fine-needle aspiration biopsy of pathological foci and immunocytochemical analysis of biopsies, assessment of patients’ quality of life were performed before and after treatment.Results. The innovative phytocomplex (diindolylmethane – DIM, Agni casti fructus) compared to the indole-3-carbinol monopreparation demonstrated a higher efficiency in creating conditions for the elimination of clinical manifestations of BBDs: discomfort, swelling, pain at rest and during palpation.A pronounced regression of clinical symptoms was observed in the study group: a decreased frequency of patients with chest discomfort from 100 to 36.7%, a decrease in pain at rest and during pressure – from 53.3 to 13.3% and from 33.3 to 13.3%, respectively, swelling – from 46.7 to 16.7%. The index of the quality of life of patients, which was determined by the sum of the scores of the questionnaire filled out by the patients themselves, showed a more pronounced tendency to increase in the study group.Conclusions. The innovative phytocomplex can be recommended as a preparation for phytotherapeutic correction in order to help reduce the intensity and eliminate mastalgia and other symptoms of BBDs.
... However, the precise mechanism of action by which they exert their apoptosisinducing and anti-cancer properties is not yet fully understood. [135,[166][167][168] Anthocyanins Anthocyanins, particularly cyanidin-3-O-glucoside, have strong apoptosis, antiproliferative, and antiinflammatory activities. ...
Prostate cancer is a widespread malignancy among men, with a substantial global impact on morbidity and mortality. Despite advances in conventional therapies, the need for innovative and less toxic treatments remains a priority. Emerging evidence suggests that dietary plant metabolites possess epigenetic-modifying properties, making them attractive candidates for prostate cancer treatment. The present work reviews the epigenetic effects of dietary plant metabolites in the context of prostate cancer therapy. We first outline the key epigenetic mechanisms involved in prostate cancer pathogenesis, including histone modifications, DNA methylation, and miRNA or Long Noncoding RNA (lncRNA) dysregulation. Next, we delve into the vast array of dietary plant metabolites that have demonstrated promising anti-cancer effects through epigenetic regulation. Resveratrol, minerals, isothiocyanates, curcumin, tea polyphenols, soy isoflavones and phytoestrogens, garlic compounds, anthocyanins, lycopene, and indoles are among the most extensively studied compounds. These plant-derived bioactive compounds have been shown to influence DNA methylation patterns, histone modifications, and microRNA expression, thereby altering the gene expression allied with prostate cancer progression, cell proliferation, and apoptosis. We also explore preclinical and clinical studies investigating the efficacy of dietary plant metabolites as standalone treatments or in combination with traditional treatments for people with prostate cancer. The present work highlights the potential of dietary plant metabolites as epigenetic modulators to treat prostate cancer. Continued research in this field may pave the way for personalized and precision medicine approaches, moving us closer to the goal of improved prostate cancer management.
... The primary mode of action of these chemotherapies is to bind tubulin and block microtubule formation, leading to cell cycle arrest [65]. Cruciferous vegetables such as broccoli, brussels sprouts, cabbage, and cauliflower contain bisindole 3,3 -diindolylmethane (DIM), which has shown anticancer effects in clinical studies [66], and it is used as a dietary supplement. Its mechanism of action is believed to involve NF-κB, Akt, Wnt, PI3K/Akt/mTOR, and AhR signaling [66]. ...
... Cruciferous vegetables such as broccoli, brussels sprouts, cabbage, and cauliflower contain bisindole 3,3 -diindolylmethane (DIM), which has shown anticancer effects in clinical studies [66], and it is used as a dietary supplement. Its mechanism of action is believed to involve NF-κB, Akt, Wnt, PI3K/Akt/mTOR, and AhR signaling [66]. DIM also shows anti-inflammatory [67] and antibiotic [68] activity and shares these activities with dragmacidin D. ...
Cancer cells grown in 3D spheroid cultures are considered more predictive for clinical efficacy. The marine natural product dragmacidin D induces apoptosis in MDA-MB-231 and MDA-MB-468 triple-negative breast cancer (TNBC) spheroids within 24 h of treatment while showing no cytotoxicity against the same cells grown in monolayers and treated for 72 h. The IC50 for cytotoxicity based on caspase 3/7 cleavage in the spheroid assay was 8 ± 1 µM in MDA-MB-231 cells and 16 ± 0.6 µM in MDA-MB-468 cells at 24 h. No cytotoxicity was seen at all in 2D, even at the highest concentration tested. Thus, the IC50 for cytotoxicity in the MTT assay (2D) in these cells was found to be >75 µM at 72 h. Dragmacidin D exhibited synergy when used in conjunction with paclitaxel, a current treatment for TNBC. Studies into the signaling changes using a reverse-phase protein array showed that treatment with dragmacidin D caused significant decreases in histones. Differential protein expression was used to hypothesize that its potential mechanism of action involves acting as a protein synthesis inhibitor or a ribonucleotide reductase inhibitor. Further testing is necessary to validate this hypothesis. Dragmacidin D also caused a slight decrease in an invasion assay in the MDA-MB-231 cells, although this failed to be statistically significant. Dragmacidin D shows intriguing selectivity for spheroids and has the potential to be a treatment option for triple-negative breast cancer, which merits further research into understanding this activity.
