Indole-3-Carbinol (I3C) enhances the sensitivity of murine breast adenocarcinoma cells to doxorubicin (DOX) through inhibition of NF-κβ, blocking angiogenesis and regulation of mitochondrial apoptotic pathway

Hajra, Subhadip; Patra, Arup Ranjan; Basu, Aninda; Saha, Prosenjit; Bhattacharya, Sudin

doi:10.1016/j.cbi.2018.05.005

Cited by 26 publications

(16 citation statements)

References 75 publications

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“…From a broader perspective, our findings fit the puzzle of the pathomechanism of human breast cancer, as tryptophan and indole metabolism are tightly related to breast cancer and breast cancer survival [ 40 , 91 , 92 ]. Previously we showed that bacterial tryptophan metabolism is suppressed in early stages of breast cancer, releasing the brake on breast cancer cells [ 16 , 17 , 40 ].…”

Section: Discussionmentioning

confidence: 71%

Indoxylsulfate, a Metabolite of the Microbiome, Has Cytostatic Effects in Breast Cancer via Activation of AHR and PXR Receptors and Induction of Oxidative Stress

Sári

Mikó

Kovàcs

et al. 2020

Cancers

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Changes to bacterial metabolite-elicited signaling, in oncobiosis associated with breast cancer, plays a role in facilitating the progression of the disease. We show that indoxyl-sulfate (IS), a tryptophan metabolite, has cytostatic properties in models of breast cancer. IS supplementation, in concentrations corresponding to the human serum reference range, suppressed tumor infiltration to the surrounding tissues and metastasis formation in a murine model of breast cancer. In cellular models, IS suppressed NRF2 and induced iNOS, leading to induction of oxidative and nitrosative stress, and, consequently, reduction of cell proliferation; enhanced oxidative and nitrosative stress are crucial in the subsequent cytostasis. IS also suppressed epithelial-to-mesenchymal transition vital for suppressing cellular movement and diapedesis. Furthermore, IS rendered cells hypometabolic, leading to a reduction in aldehyde-dehydrogenase positive cells. Pharmacological inhibition of the pregnane-X receptor using CH223191 and the aryl-hydrocarbon receptor using ketoconazole diminished the IS-elicited effects, suggesting that these receptors were the major receptors of IS in these models. Finally, we showed that increased expression of the human enzymes that form IS (Cyp2E1, Sult1A1, and Sult1A2) is associated with better survival in breast cancer, an effect that is lost in triple negative cases. Taken together, IS, similar to indolepropionic acid (another tryptophan metabolite), has cytostatic properties and higher expression of the metabolic machinery responsible for the formation of IS supports survival in breast cancer.

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Section: Discussionmentioning

confidence: 71%

Indoxylsulfate, a Metabolite of the Microbiome, Has Cytostatic Effects in Breast Cancer via Activation of AHR and PXR Receptors and Induction of Oxidative Stress

Sári

Mikó

Kovàcs

et al. 2020

Cancers

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“…Nevertheless, indole-3-carbinole helped to reduce chromosomal aberrations, micronuclei DNA damage and apoptosis exerted by doxorubicin. 86 The combination of doxorubicin and indole-3-carbinol caused a reduction in LDH, CK-MB and troponin-I enzymes activities where improved swollen cardiac muscle fibers, interstitial edema and inflammatory infiltration in cardiac tissues were seen. Administration of indole-3-carbinol in a dose-dependent manner also resulted in the reduced production of inflammatory mediators, nitric oxide, TNF-α and IL-10.…”

Section: Indole-3-carbinolmentioning

confidence: 97%

“…TNF-α is pro-inflammatory cytokines thought to worsen cardiac damage, remodeling and damage in ventricles. [84][85][86]…”

Section: Indole-3-carbinolmentioning

confidence: 99%

Protective Effect of Natural Products against Chemotherapy-Induced Cardiotoxicity: A Review

Othman¹,

Lum²,

Gan³

et al. 2020

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To complete this review, relevant literatures were searched from several scientific databases including Google, Google Scholar, Scopus, Web of Science and Pubmed. The categories of keywords used for searching are "Natural Products" or "Phytoconstituents" or "Isolated Compounds" or "Natural Compounds" or "Curcumin" or "Mangiferin" or "Naringenin" or "Quercetin" or "6-Gingerol" or "Lycopene" or "Resveratrol" or "Apigenin" or "Proanthocyanidins" or "Indole-3carbinol" and "Cardioprotection" or "Anticancer" or "Chemotherapy" or "Cardiotoxicity" or "Cardiotonic". After screening of literatures from 2005 to 2019, a total of ten natural products investigated the protective effect against chemotherapy-induced cardiotoxicity and that were included in the present review.

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“…The angiogenic process is regulated by numerous molecules, in addition to MMPs, such as growth factors (vascular endothelial growth factor [VEGF], bFGF, angiopoietins, EGF, and TGF), integrins, and interleukins (IL1, IL2, IL6, IL8, IL12, and IL17) ( 149 ). The most studied among them is VEGF and there is evidence that ITCs and I3C inhibit angiogenesis by downregulating VEGF ( 152 , 155 ). Treatment of HUVEC and PC3 cells with PEITC inhibited neovascularization and cell migration with suppression of VEGF secretion, downregulation of VEGF receptor 2 protein levels, and inactivation of Akt ( 156 ).…”

Section: Biological Effects Of Itcs and Mechanismsmentioning

confidence: 99%

“…Thejass et al showed that AITC and PEITC treatment downregulated VEGF and pro-inflammatory IL1β, IL6, and TNFα, but increased the anti-inflammatory effects of IL2 and inhibition of metalloproteinase (TIMP1) ( 158 ). Among mice, Hajra et al reported that I3C blocked angiogenesis by inhibiting VEGF-A and MMP-9 ( 155 ). One important factor that stimulates angiogenesis is hypoxia that results from tumor growth or due to other situations such as increase in adipose tissue caused by obesity, leading to the activation of hypoxia inducible factor-1α (HIF-1α) which in turn stimulates VEGF ( 152 ).…”

Section: Biological Effects Of Itcs and Mechanismsmentioning

confidence: 99%

Mechanisms Underlying Biological Effects of Cruciferous Glucosinolate-Derived Isothiocyanates/Indoles: A Focus on Metabolic Syndrome

Esteve

2020

Front. Nutr.

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An inverse correlation between vegetable consumption and the incidence of cancer has long been described. This protective effect is stronger when cruciferous vegetables are specifically consumed. The beneficial properties of vegetables are attributed to their bioactive components like fiber, antioxidants vitamins, antioxidants, minerals, and phenolic compounds. Cruciferous vegetables contain all these molecules; however, what makes them different are their sulfurous components, called glucosinolates, responsible for their special smell and taste. Glucosinolates are inactive biologically in the organism but are hydrolyzed by the enzyme myrosinase released as a result of chewing, leading to the formation of active derivatives such as isothiocyanates and indoles. A considerable number of in vitro and in vivo studies have reported that isothiocyanates and indoles elicit chemopreventive potency through multiple mechanisms that include modulation of phases I and II detoxification pathway enzymes, regulation of cell cycle arrest, and control of cell growth, induction of apoptosis, antioxidant activity, anti-angiogenic effects, and epigenetic regulation. Nuclear erythroid 2-related factor 2 (Nrf2) and Nuclear factor-κB (NF-κB) are key and central regulators in all these processes with a main role in oxidative stress and inflammation control. It has been described that isothiocyanates and indoles regulate their activity directly and indirectly. Today, the metabolic syndrome (central obesity, insulin resistance, hyperlipidemia, and hypertension) is responsible for a majority of deaths worldwide. All components of metabolic syndrome are characterized by chronic inflammation with deregulation of the PI3K/AKT/mTOR, MAPK/EKR/JNK, Nrf2, and NF-κB signaling pathways. The effects of GLSs derivatives controlling these pathways have been widely described in relation to cancer. Changes in food consumption patterns observed in the last decades to higher consumption of ultra-processed foods, with elevation in simple sugar and saturated fat contents and lower consumption of vegetables and fruits have been directly correlated with metabolic syndrome prevalence. In this review, it is summarized the knowledge regarding the mechanisms by which cruciferous glucosinolate derivatives (isothiocyanates and indoles) directly and indirectly regulate these pathways. However, the review places a special focus on the knowledge of the effects of glucosinolates derivatives in metabolic syndrome, since this has not been reviewed before.

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Indole-3-Carbinol (I3C) enhances the sensitivity of murine breast adenocarcinoma cells to doxorubicin (DOX) through inhibition of NF-κβ, blocking angiogenesis and regulation of mitochondrial apoptotic pathway

Cited by 26 publications

References 75 publications

Indoxylsulfate, a Metabolite of the Microbiome, Has Cytostatic Effects in Breast Cancer via Activation of AHR and PXR Receptors and Induction of Oxidative Stress

Indoxylsulfate, a Metabolite of the Microbiome, Has Cytostatic Effects in Breast Cancer via Activation of AHR and PXR Receptors and Induction of Oxidative Stress

Protective Effect of Natural Products against Chemotherapy-Induced Cardiotoxicity: A Review

Mechanisms Underlying Biological Effects of Cruciferous Glucosinolate-Derived Isothiocyanates/Indoles: A Focus on Metabolic Syndrome

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