Emodin, a natural anthraquinone, suppresses liver cancer in vitro and in vivo by regulating VEGFR2 and miR-34a

Bai, Jianguo; Wu, Jianfei; Rui-feng, Tang; Sun, Chao; Ji, Jun-Wei; Yin, Zhaolin; Ma, Guangjun; Yang, Wei

doi:10.1007/s10637-019-00777-5

Cited by 49 publications

(43 citation statements)

References 73 publications

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“…study. Our findings are supported by previously published work [12,16,31,33]. For example, a study by Shia et al, 2010 utilized a similar solvent to propylene glycol (PEG 400) and showed comparable results using male Sprague-Dawley rats [33].…”

Section: Discussionsupporting

confidence: 90%

“…and P.O. administered emodin and is eliminated by 12 h. Despite inconsistencies in the literature, previous investigations have shown that emodin is typically cleared by 12 h after injection/ingestion [12,16,31]. We show in the present study that emodin is rapidly metabolized to its glucuronidated form, peaking at 1 h, and is completely cleared by 12 h when given both I.P.…”

Section: Discussionsupporting

confidence: 55%

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Safety of natural anthraquinone emodin: an assessment in mice

Sougiannis

Enos

VanderVeen

et al. 2021

BMC Pharmacol Toxicol

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Background Emodin, a natural anthraquinone, has shown potential as an effective therapeutic agent in the treatment of many diseases including cancer. However, its clinical development is hindered by uncertainties surrounding its potential toxicity. The primary purpose of this study was to uncover any potential toxic properties of emodin in mice at doses that have been shown to have efficacy in our cancer studies. In addition, we sought to assess the time course of emodin clearance when administered both intraperitoneally (I.P.) and orally (P.O.) in order to begin to establish effective dosing intervals. Methods We performed a subchronic (12 week) toxicity study using 3 different doses of emodin (~ 20 mg/kg, 40 mg/kg, and 80 mg/kg) infused into the AIN-76A diet of male and female C57BL/6 mice (n = 5/group/sex). Body weight and composition were assessed following the 12-week feeding regime. Tissues were harvested and assessed for gross pathological changes and blood was collected for a complete blood count and evaluation of alanine transaminase (ALT), aspartate transaminase (AST) and creatinine. For the pharmacokinetic study, emodin was delivered intraperitoneally I.P. or P.O. at 20 mg/kg or 40 mg/kg doses to male and female mice (n = 4/group/sex/time-point) and circulating levels of emodin were determined at 1, 4 and 12 h following administration via liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis. Results We found that 12 weeks of low (20 mg/kg), medium (40 mg/kg), or high (80 mg/kg) emodin feeding did not cause pathophysiological perturbations in major organs. We also found that glucuronidated emodin peaks at 1 h for both I.P. and P.O. administered emodin and is eliminated by 12 h. Interestingly, female mice appear to metabolize emodin at a faster rate than male mice as evidenced by greater levels of glucuronidated emodin at the 1 h time-point (40 mg/kg for both I.P. and P.O. and 20 mg/kg I.P.) and the 4-h time-point (20 mg/kg I.P.). Conclusions In summary, our studies establish that 1) emodin is safe for use in both male and female mice when given at 20, 40, and 80 mg/kg doses for 12 weeks and 2) sex differences should be considered when establishing dosing intervals for emodin treatment.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 55%

Safety of natural anthraquinone emodin: an assessment in mice

Sougiannis

Enos

VanderVeen

et al. 2021

BMC Pharmacol Toxicol

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“…This potent anti-tumor agent can suppress cancer metastasis via inhibiting epithelial-tomesenchymal transition (EMT) [204]. The anti-tumor activity of emodin is dose-dependent and can affect different molecular pathways, such as miRNA-34a and vascular endothelial growth factor receptor (VEGFR) [210]. In enhancing CP sensitivity of endometrial cancer cells, emodin targets ROS levels.…”

Section: Therapeutic Targetingmentioning

confidence: 99%

Elucidating Role of Reactive Oxygen Species (ROS) in Cisplatin Chemotherapy: A Focus on Molecular Pathways and Possible Therapeutic Strategies

et al. 2021

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The failure of chemotherapy is a major challenge nowadays, and in order to ensure effective treatment of cancer patients, it is of great importance to reveal the molecular pathways and mechanisms involved in chemoresistance. Cisplatin (CP) is a platinum-containing drug with anti-tumor activity against different cancers in both pre-clinical and clinical studies. However, drug resistance has restricted its potential in the treatment of cancer patients. CP can promote levels of free radicals, particularly reactive oxygen species (ROS) to induce cell death. Due to the double-edged sword role of ROS in cancer as a pro-survival or pro-death mechanism, ROS can result in CP resistance. In the present review, association of ROS with CP sensitivity/resistance is discussed, and in particular, how molecular pathways, both upstream and downstream targets, can affect the response of cancer cells to CP chemotherapy. Furthermore, anti-tumor compounds, such as curcumin, emodin, chloroquine that regulate ROS and related molecular pathways in increasing CP sensitivity are described. Nanoparticles can provide co-delivery of CP with anti-tumor agents and by mediating photodynamic therapy, and induce ROS overgeneration to trigger CP sensitivity. Genetic tools, such as small interfering RNA (siRNA) can down-regulate molecular pathways such as HIF-1α and Nrf2 to promote ROS levels, leading to CP sensitivity. Considering the relationship between ROS and CP chemotherapy, and translating these findings to clinic can pave the way for effective treatment of cancer patients.

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“…Male nude mice were purchased from Beijing Vital River Laboratory Animal Technology Company, Beijing, China. The nude mice (weighing approximately 18‐20 g and aged 6 weeks) were randomly divided into HepG2‐NC and HepG2‐P7TP3 groups . The left upper armpit of the mice in the HepG2‐P7TP3 group was s.c. injected with 0.1 mL of 1 × 10 6 /mL cell suspension .…”

Section: Methodsmentioning

confidence: 99%

“…were randomly divided into HepG2-NC and HepG2-P7TP3 groups. 19 The left upper armpit of the mice in the HepG2-P7TP3 group was s.c. injected with 0.1 mL of 1 × 10 6 /mL cell suspension. 20 Tumor size was continuously observed and measured with a Vernier caliper.…”

mentioning

confidence: 99%

P7TP3 inhibits tumor development, migration, invasion and adhesion of liver cancer through the Wnt/β‐catenin signaling pathway

et al. 2020

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The effect of hepatitis C virus p7 trans‐regulated protein 3 (P7TP3) in the development of hepatocellular carcinoma (HCC) is still unknown. The present study aimed to investigate the role and mechanism of P7TP3 in HCC. P7TP3 was significantly decreased in HCC tissues when compared with corresponding liver tissues immediately around the tumor (LAT) from seven HCC patients. Fewer and smaller colonies originated from HepG2‐P7TP3 cells when compared to HepG2‐NC cells. Overexpression of P7TP3 in HepG2 cells significantly repressed the growth of HCC xenografts in nude mice. Furthermore, wound‐healing tests, Transwell assays, Matrigel Transwell assays, adhesion assays, CCK‐8 assays, flow cytometry and western blotting analysis showed that P7TP3 protein expression inhibited migration, invasion, adhesion, proliferation and cell cycle progression in HCC cell lines. Moreover, P7TP3 suppressed the activity of the Wnt/β‐catenin signaling pathway, and was restored by Wnt3a, which is an activator of the Wnt/β‐catenin signaling pathway. Consistently, β‐catenin was highly expressed by P7TP3 silencing, and restored by XAV939, an inhibitor of the Wnt/β‐catenin signaling pathway. Finally, microRNA (miR)‐182‐5p suppressed the expression of target gene P7TP3 by directly interacting with the 3′‐UTR region. Taken together, P7TP3, the direct target gene of miR‐182‐5p, inhibited HCC by regulating migration, invasion, adhesion, proliferation and cell cycle progression of liver cancer cell through the Wnt/β‐catenin signaling pathway. These findings provide strong evidence that P7TP3 functions as a new promising tumor suppressor in HCC.

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Emodin, a natural anthraquinone, suppresses liver cancer in vitro and in vivo by regulating VEGFR2 and miR-34a

Cited by 49 publications

References 73 publications

Safety of natural anthraquinone emodin: an assessment in mice

Safety of natural anthraquinone emodin: an assessment in mice

Elucidating Role of Reactive Oxygen Species (ROS) in Cisplatin Chemotherapy: A Focus on Molecular Pathways and Possible Therapeutic Strategies

P7TP3 inhibits tumor development, migration, invasion and adhesion of liver cancer through the Wnt/β‐catenin signaling pathway

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