Antifungal agent Terbinafine restrains tumor growth in preclinical models of hepatocellular carcinoma via AMPK-mTOR axis

Zhang, Er‐Bin; Zhang, Xiuping; Wang, Kang; Zhang, Fengkun; Chen, Tianwei; Ma, Ning; Ni, Qian‐Zhi; Wang, Yikang; Zheng, Qian-Wen; Cao, Hui‐Jun; Ji, Xia; Xu, Sheng; Ding, Xue; Wang, Xiang; Li, Zhigang; Cheng, Shuqun; Xie, Dong; Li, Jingjing

doi:10.1038/s41388-021-01934-y

Cited by 14 publications

(18 citation statements)

References 42 publications

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“…Though bias existed in the study, our results demonstrated PI3K/Akt is involved in SQLE-mediated cholesterol synthesis and tumor progression, which was consistent with the conclusions of other studies. Also, Zhang et al reported terbinafine significantly inhibited HCC cells proliferation by suppressing mTORC1 signaling [27]. In our results based on KEGG pathway analysis, AMPK signaling was enriched, suggesting complicated relationship between AMPK and PI3K/Akt/ mTOR signaling involve in SQLE-mediated HNSCC progression.…”

Section: Discussionsupporting

confidence: 54%

“…Recently, SQLE upregulation was reported and identified as a prognostic marker in a variety of disease, such as non-alcoholic steatohepatitis [26], hepatocellular carcinoma [27] and breast cancer [28].…”

Section: Discussionmentioning

confidence: 99%

“…A previous study has indicated that terbinafine could inhibit tumor progression of breast cancer [28]. Also, Zhang et al reported terbinafine intensely alleviated the growth of HCC cells by suppressing mTORC1 signaling [27]. However, the potential application of SQLE inhibitors to treat HNSCC has not been explored until now.…”

Section: Discussionmentioning

confidence: 99%

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Upregulation of SQLE Contributes to Poor Survival in Head and Neck Squamous Cell Carcinoma

Li¹,

Yang²,

Wang³

et al. 2022

Int. J. Biol. Sci.

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Recently, increasing attention has been paid to the role of Squalene epoxidase (SQLE) in several types of cancers. However, its functional role in tumor progression of head and neck squamous cell carcinoma (HNSCC) is still unclear. We performed bioinformatic analyses and relative experiments to assess the potential mechanism of SQLE-mediated HNSCC malignancy. And the results showed that SQLE was significantly upregulated in tumor samples compared with peritumor samples. Mechanistically, miR-584-5p downregulation may lead to the upregulation of SQLE in HNSCC. Moreover, high SQLE expression in HNSCC was associated with TNM stage, distant metastasis, and poor survival, indicating that SQLE be involved in the progression of HNSCC. Furtherly, SQLE boosted proliferation, migration, invasion of HNSCC cells in vitro and in vivo. Bioinformatic studies showed that PI3K/Akt signaling participated in HNSCC progression mediated by SQLE overexpression, which is confirmed by in vitro and in vivo analysis. Particularly, treatment with terbinafine, an inhibitor of SQLE widely used in the treatment of fungal infections, showed a therapeutic influence on HNSCC. Our findings demonstrate that SQLE plays a vital role in HNSCC progression, providing research evidence for SQLE as a prospective HNSCC therapeutic target and for terbinafine as a candidate drug of HNSCC treatment in the future

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Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

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Upregulation of SQLE Contributes to Poor Survival in Head and Neck Squamous Cell Carcinoma

Li¹,

Yang²,

Wang³

et al. 2022

Int. J. Biol. Sci.

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“…SQLE inhibitors (terbinafine and NB-598) have been confirmed to suppress cell proliferation, blunt cell viability, promote cell death in vitro , and retrain tumor growth in vivo across various types of cancers in a dosage-dependent manner ( 17 , 22 , 66 ). Retardation of the cell cycle at the G0/G1 phase and enhancement of apoptosis are involved in the antitumor function of terbinafine, while there is no impact on normal cells ( 91 ).…”

Section: Sqle-targeted Therapeutic Strategies For Cancer Treatmentmentioning

confidence: 99%

Targeting the key cholesterol biosynthesis enzyme squalene monooxygenasefor cancer therapy

et al. 2022

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Cholesterol metabolism is often dysregulated in cancer. Squalene monooxygenase (SQLE) is the second rate-limiting enzyme involved in cholesterol synthesis. Since the discovery of SQLE dysregulation in cancer, compelling evidence has indicated that SQLE plays a vital role in cancer initiation and progression and is a promising therapeutic target for cancer treatment. In this review, we provide an overview of the role and regulation of SQLE in cancer and summarize the updates of antitumor therapy targeting SQLE.

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“…Liver cancer is the third leading cause of cancer-related deaths worldwide ( Sung et al, 2021 ) that includes hepatocellular carcinoma (HCC), cholangiocellular carcinoma and secondary carcinoma of liver. HCC is the major type of liver cancer with unsatisfactory treatment options and extremely poor outcome ( Zhang et al, 2021 ). Although sorafenib, the first-line agent that targets multiple kinases for the treatment of advanced HCC, has been clinically applied in patients for over decades, less than 10% patients respond to the therapy or even develop drug resistance( Zhu et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

ARV-771 Acts as an Inducer of Cell Cycle Arrest and Apoptosis to Suppress Hepatocellular Carcinoma Progression

Deng

Chen

et al. 2022

Front. Pharmacol.

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Hepatocellular carcinoma (HCC) is the most commonly diagnosed liver cancer with limited treatment options and extremely poor prognosis worldwide. Recently, the proteolysis targeting chimeras (PROTACs), which aim to induce proteasome-mediated degradation of interesting proteins via recruiting E3 ligases, have become the advanced tools and attractive molecules for cancer treatment. However, the anticancer effects of PROTACs in HCC remain to be clarified. Here, we evaluate the anticancer activity of ARV-771, a previously reported PROTAC compound designed for bromodomain and extra-terminal domain (BET) proteins, in HCC. We show that ARV-771 suppresses the cell viability and colony formation of HCC cells via arresting cell cycle progression and triggering apoptosis. Further investigations reveal that ARV-771 notably downregulates multiple non-proteasomal deubiquitinases which are critical to the development of cancers. Additionally, HCC cells can decrease their sensitivity to ARV-771 via activating the MEK/ERK and p38 MAPKs. ARV-771 also inhibits HCC progression in vivo. Moreover, we show that ARV-771 and sorafenib, a Raf inhibitor that clinically used for targeted therapy of liver cancer, can synergistically inhibit the growth of HCC cells. Overall, this study not only explores the anticancer activity of ARV-771 and its underlying mechanisms in HCC, but also deepens our understanding of deubiquitinases, MAPKs, cell cycle, and apoptosis induction in cancer therapy.

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Antifungal agent Terbinafine restrains tumor growth in preclinical models of hepatocellular carcinoma via AMPK-mTOR axis

Cited by 14 publications

References 42 publications

Upregulation of SQLE Contributes to Poor Survival in Head and Neck Squamous Cell Carcinoma

Upregulation of SQLE Contributes to Poor Survival in Head and Neck Squamous Cell Carcinoma

Targeting the key cholesterol biosynthesis enzyme squalene monooxygenasefor cancer therapy

ARV-771 Acts as an Inducer of Cell Cycle Arrest and Apoptosis to Suppress Hepatocellular Carcinoma Progression

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