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1.
J Cell Mol Med ; 24(9): 5387-5401, 2020 05.
Article in English | MEDLINE | ID: mdl-32237037

ABSTRACT

Oesophageal squamous cell carcinoma (ESCC), the most common form of oesophageal malignancies in the Asia-Pacific region, remains a major clinical challenge. In this study, we found that ivermectin, an effective antiparasitic drug that has been approved for patients to orally treat onchocerciasis for over 30 years, displayed potent antitumour activity against ESCC cells in vitro and in nude mice. We demonstrated that ivermectin significantly inhibited cell viability and colony formation, and induced apoptosis through a mitochondrial-dependent manner in ESCC cells. Ivermectin also abrogated ESCC cell migration, invasion, as well as the protein levels of MMP-2 and MMP-9. Mechanistically, ivermectin strongly inhibited the expression of PAK1; by further gain- and loss-of-function experiments, we confirmed that PAK1 played a crucial role in ivermectin-mediated inhibitory effects on ESCC cells. In addition, the data indicated that ivermectin promoted PAK1 degradation through the proteasome-dependent pathway. Additionally, ivermectin synergized with chemotherapeutic drugs including cisplatin and 5-fluorouracil to induce apoptosis of ESCC cells. Interestingly, the in vivo experiments also confirmed that ivermectin effectively suppressed tumour growth and lung metastasis of ESCC. Collectively, these results indicate that ivermectin exerts a potent antitumour activity against ESCC and is a promising therapeutic candidate drug for ESCC patients, even those carrying metastasis.


Subject(s)
Esophageal Neoplasms/drug therapy , Esophageal Neoplasms/pathology , Esophageal Squamous Cell Carcinoma/drug therapy , Esophageal Squamous Cell Carcinoma/pathology , Ivermectin/therapeutic use , Proteolysis , p21-Activated Kinases/metabolism , Animals , Apoptosis/drug effects , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Cisplatin/pharmacology , Cisplatin/therapeutic use , Down-Regulation/drug effects , Down-Regulation/genetics , Esophageal Neoplasms/genetics , Esophageal Squamous Cell Carcinoma/genetics , Fluorouracil/pharmacology , Fluorouracil/therapeutic use , Gene Expression Regulation, Neoplastic/drug effects , Humans , Ivermectin/pharmacology , Male , Mice, Inbred BALB C , Mice, Nude , Mitochondria/drug effects , Mitochondria/metabolism , Neoplasm Invasiveness , Neoplasm Metastasis , Proteolysis/drug effects , Signal Transduction/drug effects , Ubiquitin/metabolism
2.
Front Oncol ; 10: 10, 2020.
Article in English | MEDLINE | ID: mdl-32047721

ABSTRACT

Esophageal squamous cell carcinoma (ESCC) is a common gastrointestinal malignancy and is one of the most important cause of cancer related mortalities in the world. However, there is no clinically effective targeted therapeutic drugs for ESCC due to lack of valuable molecular therapeutic targets. In the present study, we investigated the biological function and molecular mechanisms of maternal embryonic leucine zipper kinase (MELK) in ESCC. The expression of MELK mRNA and protein was determined in cell lines and clinical samples of ESCC. MTT, focus formation and soft agar assays were carried out to measure cell proliferation and colony formation. Wound healing and transwell assays were used to assess the capacity of tumor cell migration and invasion. Nude mice models of subcutaneous tumor growth and lung metastasis were performed to examine the function of MELK in tumorigenecity and metastasis of ESCC cells. High expression of MELK was observed in ESCC cell line and human samples, especially in the metastatic tumor tissues. Moreover, overexpression of MELK promoted cell proliferation, colony formation, migration and invasion, and increased the expression and enzyme activity of MMP-2 and MMP-9 in ESCC cells. More importantly, enhanced expression of MELK greatly accelerated tumor growth and lung metastasis of ESCC cells in vivo. In contrast, knockdown of MELK by lentiviral shRNA resulted in an opposite effect both in vitro and in animal models. Mechanistically, MELK facilitated the phosphorylation of FOXM1, leading to activation of its downstream targets (PLK1, Cyclin B1, and Aurora B), and thereby promoted tumorigenesis and metastasis of ESCC cells. In conclusion, MELK enhances tumorigenesis, migration, invasion and metastasis of ESCC cells via activation of FOXM1 signaling pathway, suggesting MELK is a potential therapeutic target for ESCC patients, even those in an advanced stage.

3.
Front Pharmacol ; 10: 864, 2019.
Article in English | MEDLINE | ID: mdl-31427973

ABSTRACT

Esophageal squamous cell carcinoma (ESCC) is a common malignant diagnosed cancer with increasing incidence rate and few treatment options. As a specific small-molecule inhibitor of the Wee1 tyrosine kinase, AZD1775 has previously shown potent antitumor effect on multiple types of cancer in various preclinical studies and clinical trials. However, the expression of Wee1 and the role of AZD1775 in ESCC remain unclear. In the present study, we found that the expression of Wee1 was much higher in ESCC cell lines and clinical samples than that of the corresponding controls. In addition, we demonstrated that AZD1775 exhibited strong inhibitory effect against Wee1 kinase in both tested ESCC cells at nanomolar concentrations. Moreover, AZD1775 effectively suppressed ESCC cell growth and triggered apoptosis via the mitochondrial-dependent signaling pathway. AZD1775 also diminished cell migration and invasion as well as the expression of MMP-2 and MMP-9. Interestingly, knockdown of Wee1 displayed a similar inhibitory effect of AZD1775 on ESCC cells. In addition, there was a synergism between AZD1775 and 5-fluorouracil or cisplatin in inducing cell death. More importantly, the in vivo experiments also demonstrated that AZD1775 potently inhibited ESCC cell growth and metastasis. In summary, our data suggest that the Wee1 inhibitor AZD1775 may be a potential therapeutic agent and warrants a clinical trial for patients with ESCC, even those with metastasis.

4.
Cell Commun Signal ; 17(1): 31, 2019 04 11.
Article in English | MEDLINE | ID: mdl-30971268

ABSTRACT

BACKGROUND: p21-activated kinase 1 (PAK1) plays a fundamental role in promoting the development and progression of several cancers and is a potential therapeutic target. However, the biological function and underlying mechanism of PAK1 in esophageal squamous cell carcinoma (ESCC) remain unclear. METHODS: The expression of PAK1 was detected in both ESCC cell lines and clinical samples. Cell growth was measured by MTT, focus formation and soft agar assays. Cell migration and invasion were detected by wound healing and transwell assays. Animal models of subcutaneous tumourigenicity and tail vein metastasis were performed to determine the inhibitory effect of pharmacological inhibitor IPA-3 on tumor growth and metastasis of ESCC cells. RESULTS: We found that PAK1 was frequently overexpressed in ESCC. Ectopic expression of PAK1 promoted cellular growth, colony formation and anchorage-independent growth. Overexpressing PAK1 also enhanced migration, invasion and the expression of MMP-2 and MMP-9 in ESCC cells. In contrast, silencing PAK1 by lentiviral knockdown or a specific inhibitor IPA-3 resulted in a contrary effect. Subsequent investigations revealed that Raf1/MEK1/ERK signaling pathway was involved in PAK1-mediated effect. Enhanced expression of Raf1 attenuated the inhibitory functions of PAK1 shRNA. Whereas blocking of Raf1 by shRNA or specific inhibition of MEK1 by U0126 antagonized the oncogenetic effect of PAK1 on ESCC cells. More importantly, Pharmacological inhibition of PAK1 by IPA-3 significantly suppressed tumor growth and lung metastasis of ESCC cells in vivo. CONCLUSIONS: These data support that PAK1 is an ideal target for the development of potential therapeutic drugs for ESCC patients even with metastasis.


Subject(s)
Disulfides/pharmacology , Esophageal Neoplasms/drug therapy , Esophageal Squamous Cell Carcinoma/drug therapy , Naphthols/pharmacology , Protein Kinase Inhibitors/pharmacology , p21-Activated Kinases/antagonists & inhibitors , Aged , Aged, 80 and over , Animals , Carcinogenesis , Cell Line, Tumor , Cell Movement , Cell Proliferation , Disease Progression , Disulfides/therapeutic use , Esophageal Neoplasms/pathology , Esophageal Squamous Cell Carcinoma/secondary , Humans , MAP Kinase Kinase 1/metabolism , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/physiology , Male , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Mice, Inbred BALB C , Middle Aged , Naphthols/therapeutic use , Neoplasm Metastasis , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-raf/genetics , Proto-Oncogene Proteins c-raf/metabolism , RNA, Small Interfering/metabolism
5.
Front Chem ; 6: 386, 2018.
Article in English | MEDLINE | ID: mdl-30298127

ABSTRACT

Physiological characteristics of human malignancies are increased glycolysis and overexpression of glucose transporters (GLUTs). 18Flurodeoxyglucose-positron emission tomography (FDG-PET) has successfully developed as clinical modality for the diagnosis and staging of many cancers based on the Warburg effect. To leverage this glucose transporter mediated metabolic disparity between normal and malignant cells, in the current report, protected, and de-protected glucose, mannose, galactose, rhamnose, maltose, and lactose-conjugated platinum(IV) complexes were designed and synthesized. The suggested potential of facilitated intravenous to oral switching of glycosylated platinum(IV) prodrugs with cancer-targeting properties were evaluated for glucose transporter 1 (GLUT1) and organic cation transporter 2 (OCT2)-mediated selective properties in vitro and in vivo. The cytotoxicity of 2d, 5d, and 6d were ~23-fold greater than that of the positive controls cisplatin, oxaliplatin, and satraplatin, respectively. The leading compound 6d, the IC50 of which with the GLUT1 inhibitor 4,6-oethylidene-α-D-glucose (EDG) and phloretin (31.80 and 38.71 µM) are 36- and 44-folds higher, respectively, than the 48 h IC50 (0.89 µM), is superior to the reported 5-8, exhibiting enhanced cancer targeting. The compounds also showed reduced toxicity to normal cells (293T IC50 = 12.06 µM and 3T3 cells IC50 > 100 µM) and exhibited no cross-resistance to cisplatin. Moreover, the encouraging selectivity of 6d for MCF-7 cells in vivo indicated that the pyranoside performs an important function in cancer targeting.

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