New insights into sorafenib resistance in hepatocellular carcinoma: Responsible mechanisms and promising strategies

Niu, Leilei; Liu, Liping; Yang, Shengli; Ren, Jianwei; Lai, Paul Bo San; Chen, George G.

doi:10.1016/j.bbcan.2017.10.002

Cited by 165 publications

(167 citation statements)

References 95 publications

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“…On the other hand, celecoxib is known to suppress prostacyclin and predisposes patients to thrombosis [38], and maybe coadministration with low-dose antithrombotic agent (eg, aspirin) can reduce celecoxib-induced cardiac events. Besides, multiple kinase inhibitors sorafenib and regorafenib can prolong survival of advanced HCC patients [3,39], but drug resistance has been shown in many sorafenib-treated hepatoma cells and HCC patients [40]. We also found that celecoxib can enhance sorafenib-induced cytotoxicity in rat N1-S1 and human Hep3B hepatoma cells (Fig.…”

Section: Celecoxib Improves Chemotherapy In Hccmentioning

confidence: 62%

Celecoxib enhances the therapeutic efficacy of epirubicin for Novikoff hepatoma in rats

Chu

Chan

et al. 2018

Cancer Medicine

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Epirubicin is a chemotherapy agent for hepatocellular carcinoma (HCC). However, the outcome of HCC patients receiving epirubicin remains unsatisfactory. Moreover, our previous study indicated that celecoxib suppresses HCC progression and liver cancer stemness. This study evaluated the potential of celecoxib to serve as a complementary therapy during epirubicin treatment. Cell proliferation, apoptosis, invasiveness, and anchorage‐independent growth were analyzed in hepatoma cells. Therapeutic efficacy was validated in rat orthotopic Novikoff hepatoma. After animal sacrifice, the antitumor mechanism of celecoxib and epirubicin combined therapy was investigated by histological analysis. Celecoxib enhanced the cytotoxic activity of epirubicin in HCC cells by promoting apoptosis. Besides, celecoxib potentiated the antineoplastic function of epirubicin in inhibiting the invasiveness and anchorage‐independent growth of HCC cells. Ultrasound monitoring showed that combined therapy was more potent than either therapy alone in perturbing HCC progression. Consistently, the size and weight of dissected HCC tissues from rats receiving combined therapy were smallest among all groups. HCC treated with combined therapy exhibited the highest prevalence of apoptotic cells, which was accompanied by reduced proliferating and angiogenic activities in tumor tissues. Moreover, the expression levels of cancer stemness markers (CD44 and CD133) and drug transporter MDR‐1 were significantly diminished in rats receiving combined therapy. Besides, celecoxib treatment increased the infiltration of cytotoxic T lymphocytes (CTLs) and reduced the number of regulatory T cells (Tregs), tumor‐associated macrophages (TAMs), and the expression of immune checkpoint PD‐L1 in HCC tissues during epirubicin therapy. Celecoxib augmented the therapeutic efficacy while modulated cancer stemness and antitumor immunity. Thus, celecoxib may serve as complementary therapy to improve the outcome of patients with advanced HCC during epirubicin treatment.

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Section: Celecoxib Improves Chemotherapy In Hccmentioning

confidence: 62%

Celecoxib enhances the therapeutic efficacy of epirubicin for Novikoff hepatoma in rats

Chu

Chan

et al. 2018

Cancer Medicine

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“…The standard therapeutic methods for the treatment of HCC include surgical resection, trans-arterial embolization, radiotherapy and chemotherapy. However, these treatments are often inadequate because of delays in diagnosis and metastasis, resulting in advanced HCC [5].…”

Section: Introductionmentioning

confidence: 99%

Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis

Jiao

Dai

Mao

et al. 2020

J Exp Clin Cancer Res

141

127

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Background: Hepatocellular carcinoma (HCC) is a common primary malignant tumor which usually progresses to an advanced stage because of late diagnosis. Sorafenib (Sora) is a first line medicine for advanced stage HCC; however, it has been faced with enormous resistance. Simvastatin (Sim) is a cholesterol-lowering drug and has been reported to inhibit tumor growth. The present study aims to determine whether Sora and Sim co-treatment can improve Sora resistance in HCC. Methods: The HCC cell line LM3 and an established Sora-resistant LM3 cell line (LM3-SR) were used to study the relationship between Sora resistance and aerobic glycolysis. Cell proliferation, apoptosis and glycolysis levels were analyzed by western blotting, flow cytometry analysis and biomedical tests. A xenograft model was also used to examine the effect of Sim in vivo. Detailed mechanistic studies were also undertaken by the use of activators and inhibitors, and lentivirus transfections.Results: Our results demonstrated that the resistance to Sora was associated with enhanced aerobic glycolysis levels. Furthermore, LM3-SR cells were more sensitive to Sim than LM3 cells, suggesting that combined treatment with both Sora and Sim could enhance the sensitivity of LM3-SR cells to Sora. This finding may be due to the suppression of the HIF-1α/PPAR-γ/PKM2 axis. Conclusions: Simvastatin can inhibit the HIF-1α/PPAR-γ/PKM2 axis, by suppressing PKM2-mediated glycolysis, resulting in decreased proliferation and increased apoptosis in HCC cells, and re-sensitizing HCC cells to Sora.

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“…We therefore examined the downstream pathway involved in TMEM147-induced HCC proliferation, invasion, and glycolysis, and showed that RTK-mediated MAPK signal pathway activation was enriched by TMEM147 in HCC. EGFR is known to be an important oncoprotein in HCC, and provides a therapeutic target for drugs such as sorafenib [26]. Activation of EGFR by ligands such as EGF can mediate abnormal activation of multiple signaling pathways in cancer cells, most notably the MAPK pathway [27].…”

Section: Discussionmentioning

confidence: 99%

TMEM147 promotes hepatocellular carcinoma progress by inducing EGFR/MAPK activity

Sun¹,

Xu²,

Tian³

et al. 2020

Preprint

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Backgroud: Hepatocellular carcinoma (HCC) is characterized by rapid early proliferation and distant metastasis and is extremely difficult to treat. Aerobic glycolysis is a hallmark of abnormal glucose metabolism in cancer cells as has been shown to be associated with tumor proliferation and metastasis; however, the mechanisms underlying aerobic glycolysis remain unclear.Methods: Immunohistochemistry (IHC) and qRT-PCR was performed to investigate the association between TMEM147 expression and the clinicopathological characteristics and prognosis of patients with HCC. Loss-and gain-of function assays were performed to investigate the role of TMEM147 in proliferation, metastasis and glycolysis in vitro and vivo. Bioinformatic analysis and rescue assay were used to demonstrated the TMEM147 interacted with EGFR and promoted its retromer-mediated recycling back to the plasma membrane.Results: we identified TMEM147 as a protein that was highly expressed and associated with poor survival in patients with HCC. Both gain-and loss-of-function studies revealed that TMEM147 acted as a key oncoprotein by promoting HCC growth, metastasis, and glycolysis via the EGFR/ MAPK signaling pathway. Mechanistically, TMEM147 interacted with EGFR and promoted its retromer-mediated recycling back to the plasma membrane, thus increasing the stability of EGFR and prolonging activation of the downstream MAPK pathway. Conclusion:Collectively, these results demonstrated the role and functional mechanism of TMEM147 in HCC, and indicated that TMEM147 may represent a prognostic biomarker and potential therapeutic target for HCC. BackgroundHepatocellular carcinoma (HCC) is the second-leading cause of cancer-related death worldwide [1].Although improvements in many therapeutic strategies, including surgical resection, liver transplantation, and radiofrequency ablation, have improved the 5-year survival rate of HCC patients, its prognosis remains unsatisfactory [2]. Survival is associated with the use of targeted treatments, such as the tyrosine kinase inhibitor sorafenib, in patients with advanced stage cancer with vascular invasion and distant metastasis [3,4]. Clarifying the biological processes and molecular mechanisms

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New insights into sorafenib resistance in hepatocellular carcinoma: Responsible mechanisms and promising strategies

Cited by 165 publications

References 95 publications

Celecoxib enhances the therapeutic efficacy of epirubicin for Novikoff hepatoma in rats

Celecoxib enhances the therapeutic efficacy of epirubicin for Novikoff hepatoma in rats

Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis

TMEM147 promotes hepatocellular carcinoma progress by inducing EGFR/MAPK activity

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