Cimigenoside functions as a novel γ-secretase inhibitor and inhibits the proliferation or metastasis of human breast cancer cells by γ-secretase/Notch axis

Jia, Hui; Liu, Mingyue; Wang, Xinying; Jiang, Qiyu; Shu, Wang; Santhanam, Ramesh Kumar; Lv, Chongning; Lu, Jincai

doi:10.1016/j.phrs.2021.105686

Cited by 35 publications

(36 citation statements)

References 35 publications

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“…The cells were then re-suspended in binding buffer and measured with flow cytometry analysis (FACS) (BD Biosciences, Franklin Lakes, NJ, USA). Data was analyzed with Flow Jo.7.6.1 (Tree Star, Ashland, OR, USA) ( 41 , 42 ).…”

Section: Methodsmentioning

confidence: 99%

“…The most effective treatment for liver cancer is presently surgical resection. However, this treatment can only be performed when the liver has sufficient intrinsic function, therefore it is not an option for patients with cirrhosis ( 11 – 14 ). Understanding the molecular mechanisms of HCC oncogenesis is therefore critical to treating life-threatening liver cancers in patients who are not surgical candidates ( 15 , 16 ).…”

Section: Introductionmentioning

confidence: 99%

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CK-3, A Novel Methsulfonyl Pyridine Derivative, Suppresses Hepatocellular Carcinoma Proliferation and Invasion by Blocking the PI3K/AKT/mTOR and MAPK/ERK Pathways

Liu

et al. 2021

Front. Oncol.

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Hepatocellular carcinoma (HCC) is an aggressive tumor with a poor prognosis that highly expresses phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (ERK). The PI3K/AKT/mTOR and MAPK/ERK signaling pathways play a crucial role in HCC tumor formation, cell cycle, apoptosis and survival. However, no effective targeted therapies against these pathways is available, mainly due to the extensive and complex negative feedback loops between them. Here we used CK-3, a dual blocker of the PI3K/AKT/mTOR and MAPK/ERK pathways, against HCC cell lines to verify its anti-tumor activity in vitro. CK-3 exhibited cytotoxic activity against HCC, as demonstrated with MTT and colony formation assays. The anti-metastatic potential of CK-3 was demonstrated with wound healing and cell invasion assays. The ability of CK-3 to block both the PI3K/AKT/mTOR and MAPK/ERK pathways was also confirmed. CK-3 induced the apoptosis of Hep3B cells, while Bel7402 cells died via mitotic catastrophe (MC). Oral administration of CK-3 also inhibited the subcutaneous growth of BEL7402 cells in nude mice. Simultaneous PI3K/AKT/mTOR and MAPK/ERK pathway inhibition with CK-3 may be superior to single pathway monotherapies by inhibiting their feedback-regulation, and represents a potential treatment for HCC.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CK-3, A Novel Methsulfonyl Pyridine Derivative, Suppresses Hepatocellular Carcinoma Proliferation and Invasion by Blocking the PI3K/AKT/mTOR and MAPK/ERK Pathways

Liu

et al. 2021

Front. Oncol.

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“…MHCC97-H cells were cultured and TACT transfected with plasmids, such as miR-4277 or cyp3a4; the cells were then harvested and proteins were extracted as previously described by Wei et al (32) and Jia et al (32,33). Antibodies against CYP3A4 (Cat.…”

Section: Western Blotmentioning

confidence: 99%

Hsa-miR-4277 Decelerates the Metabolism or Clearance of Sorafenib in HCC Cells and Enhances the Sensitivity of HCC Cells to Sorafenib by Targeting cyp3a4

Sun

Jiang

et al. 2021

Front. Oncol.

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Increasing evidence has shown that the metabolism and clearance of molecular targeted agents, such as sorafenib, plays an important role in mediating the resistance of HCC cells to these agents. Metabolism of sorafenib is performed by oxidative metabolism, which is initially mediated by CYP3A4. Thus, targeting CYP3A4 is a promising approach to enhance the sensitivity of HCC cells to chemotherapeutic agents. In the present work, we examined the association between CYP3A4 and the prognosis of HCC patients receiving sorafenib. Using the online tool miRDB, we predicted that has-microRNA-4277 (miR-4277), an online miRNA targets the 3’UTR of the transcript of cyp3a4. Furthermore, overexpression of miR-4277 in HCC cells repressed the expression of CYP3A4 and reduced the elimination of sorafenib in HCC cells. Moreover, miR-4277 enhanced the sensitivity of HCC cells to sorafenib in vitro and in vivo. Therefore, our results not only expand our understanding of CYP3A4 regulation in HCC, but also provide evidence for the use of miR-4277 as a potential therapeutic in advanced HCC.

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“…After 2-3 weeks of injection, the length and width of the nude mice's subcutaneous tumors were measured. and the tumor volume was calculated as follows: tumor volume = subcutaneous tumor length × width × width/2, when the volume of the subcutaneous tumor reached approximately 1000-1200 mm 3 , the construction of the immunodeficiency nude mouse subcutaneous tumor model was completed (42)(43)(44)(45)(46). The Warburg effect related factors or EMT related factors in the were examined following the methods descripted by Yin et al, 2019 (47).…”

Section: Immunodeficiency Nude Mice Subcutaneous Tumor Formation Experimentsmentioning

confidence: 99%

“…The pharmacokinetic properties of Bay-876 were determined in subcutaneous tumor model following the methods described previously (21,(42)(43)(44)(45)(46)(47). Briefly, the BAY-876 solution or microcrystalline formulation was injected into the subcutaneous tumors and the tumor tissues were harvested at the indicated time points.…”

Section: Pharmacokinetics Of the Antitumor Activity By The Bay-876 Formulationmentioning

confidence: 99%

A Novel Microcrystalline BAY-876 Formulation Achieves Long-Acting Antitumor Activity Against Aerobic Glycolysis and Proliferation of Hepatocellular Carcinoma

et al. 2021

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BAY-876 is an effective antagonist of the Glucose transporter type 1 (GLUT1) receptor, a mediator of aerobic glycolysis, a biological process considered a hallmark of hepatocellular carcinoma (HCC) together with cell proliferation, drug-resistance, and metastasis. However, the clinical application of BAY-876 has faced many challenges. In the presence study, we describe the formulation of a novel microcrystalline BAY-876 formulation. A series of HCC tumor models were established to determine not only the sustained release of microcrystalline BAY-876, but also its long-acting antitumor activity. The clinical role of BAY-876 was confirmed by the increased expression of GLUT1, which was associated with the worse prognosis among advanced HCC patients. A single dose of injection of microcrystalline BAY-876 directly in the HCC tissue achieved sustained localized levels of Bay-876. Moreover, the single injection of microcrystalline BAY-876 in HCC tissues not only inhibited glucose uptake and prolonged proliferation of HCC cells, but also inhibited the expression of epithelial-mesenchymal transition (EMT)-related factors. Thus, the microcrystalline BAY-876 described in this study can directly achieve promising localized effects, given its limited diffusion to other tissues, thereby reducing the occurrence of potential side effects, and providing an additional option for advanced HCC treatment.

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Cimigenoside functions as a novel γ-secretase inhibitor and inhibits the proliferation or metastasis of human breast cancer cells by γ-secretase/Notch axis

Cited by 35 publications

References 35 publications

CK-3, A Novel Methsulfonyl Pyridine Derivative, Suppresses Hepatocellular Carcinoma Proliferation and Invasion by Blocking the PI3K/AKT/mTOR and MAPK/ERK Pathways

CK-3, A Novel Methsulfonyl Pyridine Derivative, Suppresses Hepatocellular Carcinoma Proliferation and Invasion by Blocking the PI3K/AKT/mTOR and MAPK/ERK Pathways

Hsa-miR-4277 Decelerates the Metabolism or Clearance of Sorafenib in HCC Cells and Enhances the Sensitivity of HCC Cells to Sorafenib by Targeting cyp3a4

A Novel Microcrystalline BAY-876 Formulation Achieves Long-Acting Antitumor Activity Against Aerobic Glycolysis and Proliferation of Hepatocellular Carcinoma

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