SREBP-1 inhibitor Betulin enhances the antitumor effect of Sorafenib on hepatocellular carcinoma via restricting cellular glycolytic activity

Yin, Fang‐Fang; Feng, Fan; Wang, Lei; Wang, Xiaoning; Li, Zongwei; Cao, Yu

doi:10.1038/s41419-019-1884-7

Cited by 87 publications

(67 citation statements)

References 75 publications

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“…The tumor weight and volume reflected the inhibitory effect of agents on the subcutaneous growth of MHCC97-H cells. 57,58 In addition, we acknowledge that the nude mouse model is absent host immunity so its generalizability for larger animal or human use is limited.…”

Section: Cell Line and Cell-survival Examinationmentioning

confidence: 99%

<p>Novel mTOR Inhibitor Enhances the Sensitivity of Hepatocellular Carcinoma Cells to Molecular Targeting Agents</p>

Feng¹,

Li²,

Feng³

et al. 2020

OTT

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Background: Although molecular-targeted agents are still the first choice for advanced hepatocellular carcinoma (HCC) treatment, the therapeutic efficacy of these agents is not satisfactory. Recently, the mammalian target of rapamycin (mTOR) is considered to be a promising molecular target that can enhance the sensitivity of HCC cells to antitumor therapy. However, the reported mTOR inhibitors have some shortcomings, and novel mTOR inhibitors need to be developed to enhance the antitumor effect of molecularly targeted agents on advanced HCC. Methods: In this study, five small-molecular compounds that could serve as potential mTOR-specific inhibitors were identified by virtual screening. The activity of tert-butyl (4-(9-(2-(1,3-dioxolan-2-yl)ethyl)-6-morpholino-9H-purin-2-yl)phenyl)carbamate (compound 4) was measured by enzyme test and Western blot, and its antitumor effect on HCC was examined in nude mice subcutaneous tumor model. Results: The results showed that 4 is the most effective one in inhibiting the activation of mTOR kinase (mTOR IC 50 = 17.52±3.67 nmol/L) among the five lead compounds. Further research in this study indicated that treatment with 4 enhanced the sensitivity of HCC cells to the molecular-targeted agents, such as sorafenib, regorafenib, lenvatinib, anlotinib, and apatinib. In addition, this research indicated that mTOR was correlated with the poor prognosis in patients with advanced HCC who received sorafenib. Conclusion: Our study identified a new type of small-molecular inhibitors of mTOR and confirmed their ability to enhance the antitumor effect of molecular-targeted agents on advanced HCC.

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Section: Cell Line and Cell-survival Examinationmentioning

confidence: 99%

<p>Novel mTOR Inhibitor Enhances the Sensitivity of Hepatocellular Carcinoma Cells to Molecular Targeting Agents</p>

Feng¹,

Li²,

Feng³

et al. 2020

OTT

Self Cite

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“…The tumor volumes or tumor weights were determined following the methods described by Jia et al 37 . The inhibition rates of olaparib were calculated by the tumor volumes or tumor weights 38 .…”

Section: The In Vivo Antitumor Effect Of Olaparibmentioning

confidence: 99%

FBI-1 enhanced the resistance of triple-negative breast cancer cells to chemotherapeutic agents via the miR-30c/PXR axis

Yang

Ren²,

Wang³

et al. 2020

Cell Death Dis

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The factor that binds to the inducer of short transcripts‐1 (FBI-1) is a transcription suppressor and an important proto‐oncogene that plays multiple roles in carcinogenesis and therapeutic resistance. In the present work, our results indicated that FBI-1 enhanced the resistance of triple-negative breast cancer (TNBC) cells to chemotherapeutic agents by repressing the expression of micoRNA-30c targeting the pregnane X receptor (PXR). The expression of FBI-1 was positively related to PXR and its downstream drug resistance-related genes in TNBC tissues. FBI-1 enhanced the expression of PXR and enhanced the activation of the PXR pathway. The miR-30c decreased the expression of PXR by targeting the 3′-UTR of PXR, and FBI-1 increased the expression of PXR by repressing miR-30c’s expression. Through the miR-30c/PXR axis, FBI-1 accelerated the clearance or elimination of antitumor agents in TNBC cells (the TNBC cell lines or the patients derived cells [PDCs]) and induced the resistance of cells to antitumor agents. Therefore, the results indicated that the miR-30c/PXR axis participates in the FBI-1-mediated drug-resistance of TNBC cells.

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“…The positive expression of SREBP-1c correlates with a shorter 3-year overall and disease-free survival of HCC patients [ 58 ]. High SREBP-1 expression also correlates with a shorter overall survival of HCC patients who received sorafenib treatment [ 59 ]. Targeting SREBP-1c may be a therapeutic option for HCC patients.…”

Section: Sterol Regulatory Element-binding Protein In Liver Diseasmentioning

confidence: 99%

“…Betulin directly binds to the SCAP, therefore inhibiting SREBP-1 activation, and improves hyperlipidemia and insulin resistance ( Figure 1 ) [ 60 ]. Betulin enhances the antitumor effects of sorafenib on HCC cells and xenograft liver tumor growth [ 59 ]. Consistently, hepatocyte-specific conditional knockout of Scap decreases DEN-induced hepatocarcinogenensis [ 61 ].…”

Section: Sterol Regulatory Element-binding Protein In Liver Diseasmentioning

confidence: 99%

NASH, Fibrosis and Hepatocellular Carcinoma: Lipid Synthesis and Glutamine/Acetate Signaling

Sunami

2020

IJMS

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Primary liver cancer is predicted to be the sixth most common cancer and the fourth leading cause of cancer mortality worldwide. Recent studies identified nonalcoholic fatty liver disease (NAFLD) as the underlying cause in 13–38.2% of patients with hepatocellular carcinoma unrelated to viral hepatitis and alcohol abuse. NAFLD progresses to nonalcoholic steatohepatitis (NASH), which increases the risk for the development of liver fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD is characterized by dysregulation of lipid metabolism. In addition, lipid metabolism is effected not only in NAFLD, but also in a broad range of chronic liver diseases and tumor development. Cancer cells manipulate a variety of metabolic pathways, including lipid metabolism, in order to build up their own cellular components. Identifying tumor dependencies on lipid metabolism would provide options for novel targeting strategies. This review article summarizes the research evidence on metabolic reprogramming and focuses on lipid metabolism in NAFLD, NASH, fibrosis, and cancer. As alternative routes of acetyl-CoA production for fatty acid synthesis, topics on glutamine and acetate metabolism are included. Further, studies on small compound inhibitors targeting lipid metabolism are discussed. Understanding reprogramming strategies in liver diseases, as well as the visualization of the metabolism reprogramming networks, could uncover novel therapeutic options.

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SREBP-1 inhibitor Betulin enhances the antitumor effect of Sorafenib on hepatocellular carcinoma via restricting cellular glycolytic activity

Cited by 87 publications

References 75 publications

<p>Novel mTOR Inhibitor Enhances the Sensitivity of Hepatocellular Carcinoma Cells to Molecular Targeting Agents</p>

<p>Novel mTOR Inhibitor Enhances the Sensitivity of Hepatocellular Carcinoma Cells to Molecular Targeting Agents</p>

FBI-1 enhanced the resistance of triple-negative breast cancer cells to chemotherapeutic agents via the miR-30c/PXR axis

NASH, Fibrosis and Hepatocellular Carcinoma: Lipid Synthesis and Glutamine/Acetate Signaling

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