Troxerutin subdues hepatic tumorigenesis<i>via</i>disrupting the MDM2–p53 interaction

Thomas, Nisha Susan; George, Kiran; Selvam, Athavan Alias Anand

doi:10.1039/c8fo01111g

Cited by 18 publications

(12 citation statements)

References 48 publications

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“…The mast cell count in the duodenal segment of mucositis mice indicated that administration of TRX decreased the number of degranulated and granulated mast cells that were induced by 5-FU treatment. Another study has shown that TRX is capable of reversing mastocytosis [18]. According to Kheirollahi et al [53], flavonoids reverse tissue damage by preventing neutrophil and mast cell degranulation, which corroborates with the findings obtained in this study.…”

Section: Discussionsupporting

confidence: 91%

“…As shown by our study, TRX treatment (100 mg/kg) reverses the 5-FU-induced increase of MDA levels and prevents GSH consumption in mice. The antioxidant effect of TRX shown in the present study has also been reported by several published studies in different experimental models [17][18][19]21,[57][58][59][60][61].…”

Section: Discussionsupporting

confidence: 90%

“…Troxerutin (TRX) is a semi-synthetic flavonoid, derived from rutin, which is extracted from Dimorphandra gardneriana. This compound has various pharmacological activities, including antioxidant [17][18][19], anti-inflammatory [20], anti-apoptotic [21,22], and antiedematogenic [23,24]. Further, it is a potent therapeutic agent for neuropathic pain [25].…”

Section: Introductionmentioning

confidence: 99%

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Troxerutin Prevents 5-Fluorouracil Induced Morphological Changes in the Intestinal Mucosa: Role of Cyclooxygenase-2 Pathway

et al. 2020

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Intestinal mucositis is a common complication associated with 5-fluorouracil (5-FU), a chemotherapeutic agent used for cancer treatment. Troxerutin (TRX), a semi-synthetic flavonoid extracted from Dimorphandra gardneriana, has been reported as a potent antioxidant and anti-inflammatory agent. In the present study, we aimed to evaluate the effect of TRX on 5-FU-induced intestinal mucositis. Swiss mice were randomly divided into seven groups: Saline, 5-FU, TRX-50, TRX-100, TRX-150, Celecoxib (CLX), and CLX + TRX-100. The weight of mice was measured daily. After treatment, the animals were euthanized and segments of the small intestine were collected to evaluate histopathological alterations (morphometric analysis), levels of malondialdehyde (MDA), myeloperoxidase (MPO), glutathione (GSH), mast and goblet cell counts, immunohistochemical analysis, and cyclooxygenase-2 (COX-2) activity. Compared to the saline treatment, the 5-FU treatment induced intense weight loss and reduction in villus height. TRX treatment (100 mg/kg) prevented the 5-FU-induced histopathological changes and decreased oxidative stress by decreasing the MDA levels and increasing GSH concentration. TRX attenuated inflammatory process by decreasing MPO activity, intestinal mastocytosis, and COX-2 expression. TRX also reversed the depletion of goblet cells. Our findings suggest that TRX at a concentration of 100 mg/kg had chemopreventive effects on 5-FU-induced intestinal mucositis via COX-2 pathway.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Troxerutin Prevents 5-Fluorouracil Induced Morphological Changes in the Intestinal Mucosa: Role of Cyclooxygenase-2 Pathway

et al. 2020

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“…Also, it was shown that troxerutin reduces the nuclear translocation of NF-kB (p65 subunit) through LKKB downregulation and consequently, resulting in decreased inflammatory responses, proliferation and cell survival. In another study, the inhibitory effect of troxerutin on hepatic tumorigenesis was evaluated [49]. It was shown that troxerutin diminishes hepatic nodule formation, changes in enzymatic status, frequencies of glutathione-s-transferase and PCNA and marker of S phase progression.…”

Section: Anti-tumor Effectmentioning

confidence: 99%

Biological and Therapeutic Effects of Troxerutin: Molecular Signaling Pathways Come into View

et al. 2021

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Flavonoids consist a wide range of naturally occurring compounds which are exclusively found in different fruits and vegetables. These medicinal herbs have a number of favourable biological and therapeutic activities such as antioxidant, neuroprotective, renoprotective, anti-inflammatory, anti-diabetic and anti-tumor. Troxerutin, also known as vitamin P4, is a naturally occurring flavonoid which is isolated from tea, coffee and cereal grains as well as vegetables. It has a variety of valuable pharmacological and therapeutic activities including antioxidant, anti-inflammatory, anti-diabetic and anti-tumor. These pharmacological impacts have been demonstrated in in vitro and in vivo studies. Also, clinical trials have revealed the efficacy of troxerutin for management of phlebocholosis and hemorrhoidal diseases. In the present review, we focus on the therapeutic effects and biological activities of troxerutin as well as its molecular signaling pathways.

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“…Acetylshikonin can directly promote HepG2 cell apoptosis by activating p53/PUMA/Bax pathway 156 . Troxerutin can subdue hepatic tumorigenesis via disrupting the MDM2-p53 interaction by decreasing the expression of MDM2 and increasing that of wild-type p53 157 .…”

Section: Anti-hcc By Restoring P53 Function and Normalizing Mdm2-p53 mentioning

confidence: 99%

The role of MDM2–p53 axis dysfunction in the hepatocellular carcinoma transformation

et al. 2020

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Liver cancer is the second most frequent cause of cancer-related death globally. The main histological subtype is hepatocellular carcinoma (HCC), which is derived from hepatocytes. According to the epidemiologic studies, the most important risk factors of HCC are chronic viral infections (HBV, HCV, and HIV) and metabolic disease (metabolic syndrome). Interestingly, these carcinogenic factors that contributed to HCC are associated with MDM2-p53 axis dysfunction, which presented with inactivation of p53 and overactivation of MDM2 (a transcriptional target and negative regulator of p53). Mechanically, the homeostasis of MDM2-p53 feedback loop plays an important role in controlling the initiation and progression of HCC, which has been found to be dysregulated in HCC tissues. To maintain long-term survival in hepatocytes, hepatitis viruses have lots of ways to destroy the defense strategies of hepatocytes by inducing TP53 mutation and silencing, promoting MDM2 overexpression, accelerating p53 degradation, and stabilizing MDM2. As a result, genetic instability, chronic ER stress, oxidative stress, energy metabolism switch, and abnormalities in antitumor genes can be induced, all of which might promote hepatocytes' transformation into hepatoma cells. In addition, abnormal proliferative hepatocytes and precancerous cells cannot be killed, because of hepatitis viruses-mediated exhaustion of Kupffer cells and hepatic stellate cells (HSCs) and CD4 + T cells by disrupting their MDM2-p53 axis. Moreover, inefficiency of hepatic immune response can be further aggravated when hepatitis viruses co-infected with HIV. Unlike with chronic viral infections, MDM2-p53 axis might play a dual role in glucolipid metabolism of hepatocytes, which presented with enhancing glucolipid catabolism, but promoting hepatocyte injury at the early and late stages of glucolipid metabolism disorder. Oxidative stress, fatty degeneration, and abnormal cell growth can be detected in hepatocytes that were suffering from glucolipid metabolism disorder, and all of which could contribute to HCC initiation. In this review, we focus on the current studies of the MDM2-p53 axis in HCC, and specifically discuss the impact of MDM2-p53 axis dysfunction by viral infection and metabolic disease in the transformation of normal hepatocytes into hepatoma cells. We also discuss the therapeutic avenues and potential targets that are being developed to normalize the MDM2-p53 axis in HCC.

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Troxerutin subdues hepatic tumorigenesisviadisrupting the MDM2–p53 interaction

Abstract: Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most common cause of mortality worldwide.

Cited by 18 publications

References 48 publications

Troxerutin Prevents 5-Fluorouracil Induced Morphological Changes in the Intestinal Mucosa: Role of Cyclooxygenase-2 Pathway

Troxerutin Prevents 5-Fluorouracil Induced Morphological Changes in the Intestinal Mucosa: Role of Cyclooxygenase-2 Pathway

Biological and Therapeutic Effects of Troxerutin: Molecular Signaling Pathways Come into View

The role of MDM2–p53 axis dysfunction in the hepatocellular carcinoma transformation

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