Cyclin E1 Inhibition can Overcome Sorafenib Resistance in Hepatocellular Carcinoma Cells Through Mcl-1 Suppression

Hsu, Chiun; Lin, Liang-In; Cheng, Yu‐Che; Feng, Zi-Rui; Shao, Yu‐Yun; Cheng, Ann‐Lii; Ou, Da-Liang

doi:10.1158/1078-0432.ccr-15-0499

Cited by 37 publications

(38 citation statements)

References 35 publications

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“…3B). Hsu et al (10) suggested that Mcl-1 suppression is critical to restore sorafenib-induced apoptosis in sorafenib-resistant HCC cells. The present results revealed that amentoflavone not only decreased sorafenib-induced anti-apoptotic protein levels (XIAP, Mcl-1 and C-FLIP) but also triggered sorafenib-induced pro-apoptotic protein expression (cleaved-Caspase-3, -8 and cytochrome c) in SK-Hep1R cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Cell cycle and anti-apoptosis associated proteins are overexpressed by sorafenib treatment in sorafenib-resistant HCC cells. In addition, Hsu et al (10) proposed that Cyclin-E1 and myeloid cell leukemia-1 (Mcl-1) overexpression inhibits sorafenib-induced apoptosis, whereas suppression of Cyclin-E1 and Mcl-1 enhances induction of apoptosis. Based on these previous studies, it was hypothesized that restoration of sorafenib-induced apoptosis by sorafenib sensitizers is a critical mechanism in overcoming sorafenib resistance in HCC cells.…”

Section: Amentoflavone Enhances Sorafenib-induced Apoptosis Through Ementioning

confidence: 99%

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Amentoflavone enhances sorafenib-induced apoptosis through extrinsic and intrinsic pathways in sorafenib-resistant hepatocellular carcinoma SK-Hep1 cells in vitro

et al. 2017

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Abstract. The present study aimed to evaluate the effects of amentof lavone on sorafenib-induced apoptosis in sorafenib-resistant hepatocellular carcinoma (HCC) cells. The sorafenib-resistant SK-Hep1 (SK-Hep1R) cell line was established for the present study. Initially, the differences in sorafenib-induced cytotoxicity and apoptosis between wild-type SK-Hep1 and SK-Hep1R cells were verified using the MTT assay and flow cytometry. The effects of amentoflavone on sorafenib-induced cytotoxicity and apoptosis were then investigated using MTT, flow cytometry, DNA gel electrophoresis and western blot analysis. The results demonstrated that cell viability of SK-Hep1R cells was increased compared with that of SK-Hep1 cells following treatment with different concentrations of sorafenib for 24 h. Apoptosis of SK-Hep1R cells was lower than that of SK-Hep1 cells following treatment with 20 µM sorafenib for 24 h. Amentoflavone alone did not inhibit cell viability but significantly triggered sorafenib-induced cytotoxicity and apoptosis in SK-Hep1R cells. Amentoflavone not only reversed sorafenib-induced anti-apoptotic protein levels but also enhanced sorafenib-induced pro-apoptotic protein expression in SK-Hep1R cells. In conclusion, amentoflavone may be used as a sorafenib sensitizer to enhance sorafenib-induced cytotoxicity and trigger sorafenib-induced apoptosis through extrinsic and intrinsic pathways in SK-Hep1R cells. IntroductionSorafenib, a multi-kinase inhibitor, has been approved by the US Food and Drug Administration to improve overall survival and time to progression of patients with advanced hepatocellular carcinoma (HCC) (1). Sorafenib induces apoptosis and inhibits angiogenesis in HCC through blockage of the rapidly accelerated fibrosarcoma/mitogen-activated protein kinase/extracellular signal-regulated kinase cascade, vascular endothelial growth factor and platelet-derived growth factor receptor tyrosine kinase signaling (2,3). Sorafenib has also been demonstrated to enhance the therapeutic efficacy of anticancer agents and radiotherapy via inhibition of nuclear factor-κB (NF-κB) or signal transducer and activator of transcription 3 (STAT3)-modulated resistance to anticancer treatments in HCC models in vitro and in vivo (4,5). However, long-term exposure to sorafenib for HCC cells induces sorafenib resistance and results in tumor progression (6,7). Therefore, development of sorafenib sensitizers, which reverse sorafenib resistance and results in sorafenib-inhibited tumor progression in sorafenib-resistant HCC cells, is important. Amentoflavone enhances sorafenib-induced apoptosis through extrinsic and intrinsic pathways in sorafenib-resistant hepatocellular carcinoma SK-Hep1 cells in vitro

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Section: Discussionmentioning

confidence: 99%

Section: Amentoflavone Enhances Sorafenib-induced Apoptosis Through Ementioning

confidence: 99%

Amentoflavone enhances sorafenib-induced apoptosis through extrinsic and intrinsic pathways in sorafenib-resistant hepatocellular carcinoma SK-Hep1 cells in vitro

et al. 2017

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“…69 Furthermore, the growth-inhibitory and apoptosis-inducing effects of sorafenib were enhanced by flavopiridol in HCC cells, and cyclin E1 inhibition can overcome sorafenib resistance. 70 Cyclin D was downregulated by lenvatinib in primary anaplastic thyroid cancer cells, which might further affect CDK4 and CDK6. 71 Palbociclib is the first clinically available CDK4/6 inhibitor for treating metastatic breast cancer approved by the FDA.…”

Section: Cyclin-dependent Kinase 4/6mentioning

confidence: 95%

“…Additionally, CDK4 and cyclin D1 could be inhibited by sorafenib, simultaneously increase expression of Fas, Fas‐L, and caspase‐3, and decreased the ratio of Bcl‐2 to Bax . Furthermore, the growth‐inhibitory and apoptosis‐inducing effects of sorafenib were enhanced by flavopiridol in HCC cells, and cyclin E1 inhibition can overcome sorafenib resistance . Cyclin D was downregulated by lenvatinib in primary anaplastic thyroid cancer cells, which might further affect CDK4 and CDK6 …”

Section: Biology and Regulation Of Cdks In Hccmentioning

confidence: 99%

Role of cyclin‐dependent kinases (CDKs) in hepatocellular carcinoma: Therapeutic potential of targeting the CDK signaling pathway

Shen

Dean²,

et al. 2019

Hepatology Research

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Liver cancer is the fourth leading cause of cancer related mortality in the world, with hepatocellular carcinoma (HCC) representing the most common primary subtype. Two‐thirds of HCC patients have advanced disease when diagnosed, and for these patients, treatment strategies remain limited. In addition, there is a high incidence of tumor recurrence after surgical resection with the current treatment regimens. The development of novel and more effective agents is required. Cyclin‐dependent kinases (CDKs) constitute a family of 21 different protein kinases involved in regulating cell proliferation, apoptosis, and drug resistance, and are evaluated in preclinical and clinical trials as chemotherapeutics. To summarize and discuss the therapeutic potential of targeting CDKs in HCC, recent published articles identified from PubMed were comprehensively reviewed. The key words included hepatocellular carcinoma, cyclin‐dependent kinases, and CDK inhibitors. This review focuses on the emerging evidence from studies describing the genetic and functional aspects of CDKs in HCC. We also present an overview of CDK inhibitors that have shown efficacy in laboratory studies of HCC. Although many of the studies assessing CDK‐targeting therapies in HCC are at the preclinical stage, there is significant evidence that CDK inhibitors used alone or in combination with established chemotherapy drugs could have significant applications in HCC.

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“…The changes of representative genes related to T-cell activation and function were confirmed by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) (The primer list for qRT-PCR and detailed methods are described in online suppl. Table S1) [31].…”

Section: Development Of Orthotopic Liver Cancer Modelsmentioning

confidence: 99%

Development of a PD-L1-Expressing Orthotopic Liver Cancer Model: Implications for Immunotherapy for Hepatocellular Carcinoma

Lin

Hsu

et al. 2018

Liver Cancer

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Background: Anti-programmed cell death-1(anti-PD1) treatment has shown promising antitumor efficacy in patients with advanced hepatocellular carcinoma (HCC). This study sought to explore the functional significance of programmed death ligand-1 (PD-L1) expression in tumor cells in the tumor microenvironment. Methods: The mouse liver cancer cell line BNL-MEA was transfected with PD-L1 plasmids and stable clones expressing PD-L1 were selected. An orthotopic HCC model was generated by implanting the cells into the subcapsular space of BALB/c mice. Cell growth features were measured by proliferation assay, colony formation, flow cytometry (in vitro), ultrasonography, and animal survival (in vivo). The changes in T-cell function were examined by cytokine assay, expression of T-cell related genes, and flow cytometry. The efficacy of anti-PD1 therapy was compared between the parental and PD-L1-expressing tumors. Results: PD-L1 expression did not affect growth characteristics of BNL-MEA cells but downregulated the expression of genes related to T-cell activation in the tumor microenvironment. Co-culture of PD-L1-expressing BNL-MEA cells with CD8+ T cells reduced T-cell proliferation and expression of cytokines IFNγ and TNFα. Tumors with PD-L1 expression showed better response to anti-PD1 therapy and depletion of CD8+ T cells abolished the antitumor effect. The difference in treatment response between parental and PD-L1-expressing tumors disappeared when a combination of anti-PD1 and sorafenib was given. Conclusions: PD-L1 expression in HCC cells may inhibit T-cell function in the liver tumor microenvironment. Anti-PD1 therapy appeared more effective in PD-L1-expressing than nonexpressing tumors, but the difference was diminished by the addition of sorafenib.

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Cyclin E1 Inhibition can Overcome Sorafenib Resistance in Hepatocellular Carcinoma Cells Through Mcl-1 Suppression

Cited by 37 publications

References 35 publications

Amentoflavone enhances sorafenib-induced apoptosis through extrinsic and intrinsic pathways in sorafenib-resistant hepatocellular carcinoma SK-Hep1 cells in vitro

Amentoflavone enhances sorafenib-induced apoptosis through extrinsic and intrinsic pathways in sorafenib-resistant hepatocellular carcinoma SK-Hep1 cells in vitro

Role of cyclin‐dependent kinases (CDKs) in hepatocellular carcinoma: Therapeutic potential of targeting the CDK signaling pathway

Development of a PD-L1-Expressing Orthotopic Liver Cancer Model: Implications for Immunotherapy for Hepatocellular Carcinoma

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