Emodin Sensitizes Hepatocellular Carcinoma Cells to the Anti-Cancer Effect of Sorafenib through Suppression of Cholesterol Metabolism

Kim, Young Seon; Lee, Yoon Mi; Oh, Taek In; Shin, Dong Hoon; Kim, Geon Hee; Kan, Sang Yeon; Kang, Hye-Ji; Kim, Ji Hyung; Kim, Byeong Mo; Yim, Woo Jong; Lim, Ji Hong

doi:10.3390/ijms19103127

Cited by 72 publications

(96 citation statements)

References 47 publications

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“…To measure mRNA expression, quantitative real-time PCR was performed as described previously [ 51 ]. Briefly, total RNA was isolated from cultured cells by using TRIzol reagent (Invitrogen, Carlsbad, CA, USA) and 2 μg of total RNA was used for cDNA synthesis by using a high-capacity cDNA reverse transcription kit (Applied Biosystems, Waltham, MA, USA).…”

Section: Methodsmentioning

confidence: 99%

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Cinobufagin Suppresses Melanoma Cell Growth by Inhibiting LEF1

Kim

Fang

Lim

et al. 2020

IJMS

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Constitutive activation of the β-catenin dependent canonical Wnt signaling pathway, which enhances tumor growth and progression in multiple types of cancer, is commonly observed in melanoma. LEF1 activates β-catenin/TCF4 transcriptional activity, promoting tumor growth and progression. Although several reports have shown that LEF1 is highly expressed in melanoma, the functional role of LEF1 in melanoma growth is not fully understood. While A375, A2058, and G361 melanoma cells exhibit abnormally high LEF1 expression, lung cancer cells express lower LEF1 levels. A luciferase assay-based high throughput screening (HTS) with a natural compound library showed that cinobufagin suppressed β-catenin/TCF4 transcriptional activity by inhibiting LEF1 expression. Cinobufagin decreases LEF1 expression in a dose-dependent manner and Wnt/β-catenin target genes such as Axin-2, cyclin D1, and c-Myc in melanoma cell lines. Cinobufagin sensitively attenuates cell viability and induces apoptosis in LEF1 expressing melanoma cells compared to LEF1-low expressing lung cancer cells. In addition, ectopic LEF1 expression is sufficient to attenuate cinobufagin-induced apoptosis and cell growth retardation in melanoma cells. Thus, we suggest that cinobufagin is a potential anti-melanoma drug that suppresses tumor-promoting Wnt/β-catenin signaling via LEF1 inhibition.

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Section: Methodsmentioning

confidence: 99%

“…The apoptotic cell population was measured by using Muse™ Annexin V and Dead Cell kit (Millipore, Burlington, MA, USA) in accordance with a previously described [51]. Initially, LEF1 stably overexpressing A375 and A2058 cells were generated with puromycin selection.…”

Section: Apoptosis Assaysmentioning

confidence: 99%

Cinobufagin Suppresses Melanoma Cell Growth by Inhibiting LEF1

Kim

Fang

Lim

et al. 2020

IJMS

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“…Natural drugs combined with traditional anti-tumor drugs to increase the sensitivity of cells to treatment are very promising. In the treatment of hepatocellular carcinoma, emodin has been used to increase the sensitivity of cells to sorafenib by regulating SREBP-2 (150). Although the evidence is promising, further research studies are warranted to investigate the mechanism of SREBPs involved in drug resistance.…”

Section: Provide Protection For Tumor Cellsmentioning

confidence: 99%

Role of the Sterol Regulatory Element Binding Protein Pathway in Tumorigenesis

2020

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Metabolic changes are a major feature of tumors, including various metabolic forms, such as energy, lipid, and amino acid metabolism. Sterol regulatory element binding proteins (SREBPs) are important modules in regulating lipid metabolism and play an essential role in metabolic diseases. In the previous decades, the regulatory range of SREBPs has been markedly expanded. It was found that SREBPs also played a critical role in tumor development. SREBPs are involved in energy supply, lipid supply, immune environment and inflammatory environment shaping in tumor cells, and as a protective umbrella to support the malignant proliferation of tumor cells. Natural medicine and traditional Chinese medicine, as an important part of drug therapy, demonstrates the multifaceted effects of SREBPs regulation. This review summarizes the core processes in the involvement of SREBPs in tumors and provides a comprehensive understanding of the pathways through which natural drugs target the SREBP pathway and regulate tumor progression.

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“…26 Pharmacological researches show that emodin not only has various pharmacological effects such as antibacterial and fungal infections, anti-inflammatory, antioxidant, anti-allergic, etc, but also can regulate the expression of various cancer-related proteins such as Akt/mTOR, NF-κB, HIF1α, and STAT3 to achieve the effects of inhibiting cell proliferation and migration, promoting cell apoptosis, and inhibiting multidrug resistance in a variety of malignant tumors. 23,27,28 In 2013, Zhang et al 29 found that the combined use of emodin and gemcitabine significantly reduced the expression of NF-κB, XIAP and survivin in pancreatic cancer cells, thereby making BxPC-3 cells that were originally resistant to gemcitabine have…”

Section: Discussionmentioning

confidence: 99%

<p>Emodin Reverses Gemcitabine Resistance of Pancreatic Cancer Cell Lines Through Inhibition of IKKβ/NF-κB Signaling Pathway</p>

Tong¹,

Huang²,

Chen³

et al. 2020

OTT

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Background: Pancreatic cancer is one of the most malignant tumors, and gemcitabine has been considered as the standard treatment and been widely utilized as a first-line drug for advanced pancreatic cancer, but gemcitabine-resistance always occurs after a short period of treatment. Methods: Two pancreatic cancer cell lines Panc-1 and MIA-PaCa-2 were used as the study subject and their gemcitabine-resistant cells were established. Both drug-resistant cells were divided into four groups: blank, emodin, gemcitabine, and emodin+gemcitabine. Cell viability was detected by MTT assay. Flow cytometry was performed to detect cell apoptosis rate and P-gp function. Quantitative real-time polymerase chain reaction and Western blotting were used to detect Survivin, XIAP, Caspase-9/3, NF-κB p65, IKKβ and IκB-α mRNA/ protein expressions, respectively. Electrophoretic mobility shift assay (EMSA) was performed to detect NF-κB binding activity. Rhodamine 123 efflux assay was used to detect P-gp function. Results: Emodin could inhibit cell activity in all cell lines. Both emodin and gemcitabine can significantly increase the apoptosis rate, and the combination of the two drugs can further significantly increase the apoptosis rate in normal pancreatic cancer cell lines. In both drugresistant pancreatic cancer cell lines, it can be observed that although gemcitabine can increase the apoptosis rate, the effect of promoting apoptosis is significantly lower than that of emodin; the drug combination can still significantly increase the apoptosis rate on the basis of emodin alone. Emodin can significantly reduce the mRNA and protein expression levels of Survivin, XIAP, NF-κB, and IKKβ, and significantly increase the mRNA and protein expression levels of Caspase-3/9 and IκB-α. Emodin significantly reduced NF-κB activity and emodin significantly promoted P-gp fluorescence intensity from Rhodamine 123 efflux assay. Conclusion: Emodin inhibits the expression of IKKβ, thereby inhibiting the expression and activity of downstream NF-κB, and inhibits P-gp function at the same time, ultimately achieving the purpose of reversing the drug-resistance of pancreatic cancer cell lines.

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Emodin Sensitizes Hepatocellular Carcinoma Cells to the Anti-Cancer Effect of Sorafenib through Suppression of Cholesterol Metabolism

Cited by 72 publications

References 47 publications

Cinobufagin Suppresses Melanoma Cell Growth by Inhibiting LEF1

Cinobufagin Suppresses Melanoma Cell Growth by Inhibiting LEF1

Role of the Sterol Regulatory Element Binding Protein Pathway in Tumorigenesis

<p>Emodin Reverses Gemcitabine Resistance of Pancreatic Cancer Cell Lines Through Inhibition of IKKβ/NF-κB Signaling Pathway</p>

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