Novel therapeutics are required to improve treatment outcomes in head and neck squamous cell carcinoma (HNSCC) patients. Histone lysine demethylases (KDM) have emerged recently as new potential drug targets for HNSCC therapy. They might also potentiate the action of the inhibitors of EGFR and PI3K signaling pathways. This study aimed at evaluating the anti-cancer effects of KDM4 (ML324) and KDM6 (GSK-J4) inhibitors and their combinations with EGFR (erlotinib) and PI3K (HS-173) inhibitors in HNSCC cells. The effect of the inhibitors on the viability of CAL27 and FaDu cells was evaluated using resazurin assay. The effect of the chemicals on cell cycle and apoptosis was assessed using propidium iodide and Annexin V staining, respectively. The effect of the compounds on gene expression was determined using qPCR and Western blot. The changes in cell cycle distribution upon treatment with the compounds were small to moderate, with the exception of erlotinib, which induced G1 arrest. However, all the compounds and their combinations induced apoptosis in both cell lines. These effects were associated with changes in the level of expression of CDKN1A, CCND1 and BIRC5. The inhibition of KDM4 and KDM6 using ML324 and GSK-J4, respectively, can be regarded as a novel therapeutic strategy in HNSCC.

2020-04-01·European journal of pharmacology3区 · 医学

Hesperetin ameliorates DSS-induced colitis by maintaining the epithelial barrier via blocking RIPK3/MLKL necroptosis signaling

3区 · 医学

Article

作者: Hu, Xue ; Dong, Weiguo ; Lei, Hongbo ; Zhang, Jixiang

Hesperetin, a flavonoid from citrus fruits, possess various pharmacological properties, including anti-inflammatory, anti-oxidative, anti-tumor potentials. However, the role and its mechanism in ulcerative colitis (UC) remains unclear. This study aimed to investigate the protective effects and mechanisms of hesperetin on dextran sodium sulfate (DSS) -induced colitis. Our results showed that hesperetin significantly relieved the symptoms of DSS -induced colitis and increased the expressions of zonula occludens-1 (ZO-1), occludin and mucin2 (MUC-2) as well as the decrease of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-18, HMGB1 and IL-6. Of note, results from immunohistochemistry (IHC) and western blotting indicated that hesperetin inhibited the expressions of receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL), the two key proteins of necroptosis pathway, and inactivated RIPK3/MLKL necroptosis signalling. Meanwhile, in the cell-coculture system between Caco-2 and RAW264.7 cells, hesperetin treatment significantly ameliorated the decrease of trans epithelial electric resistance (TEER) value while HS-173 (necroptosis inducer) could obviously influence the effect of hesperetin. In addition, hesperetin attenuated the LPS-induced increasing in 4-kDa fluorescein isothiocyanate-dextran (FD4) permeability while HS-173 could weaken the protective effect of hesperetin. Meanwhile, HS-173 reduced the changes in the expressions of phosphorylated RIPK3, phosphorylated MLKL, ZO-1, occludin and MUC-2 as well as TNF-α, IL-1β. These findings demonstrated hesperetin ameliorated DSS-induced colitis by maintaining the epithelial barrier via blocking the intestinal epithelial necroptosis.

Otorhinolaryngology-head and neck surgery

Differential compensation mechanisms define resistance to PI3K inhibitors in PIK3CA amplified HNSCC

Article

作者: Brenner, J Chad ; Leonard, Elizabeth ; Kulkarni, Aditi ; Michmerhuizen, Nicole L

OBJECTIVE:

Recent sequencing studies of head and neck squamous cell carcinomas (HNSCCs) have identified the phosphatidylinositol 3-kinase (PI3K) pathway as the most frequently mutated, oncogenic pathway in this cancer type. Despite the frequency of activating genomic alterations in PIK3CA (the gene encoding the catalytic subunit of PI3K, targeted inhibitors of PI3K have not shown clinical efficacy as monotherapies. We hypothesized that co-dependent pathways, including the Ras-MEK-ERK pathway, may still be functional in the presence of PI3K inhibitors and might serve as mediators of this resistance.

METHODS:

We assessed the hypothesis using resazurin cell viability and trypan blue exclusion assays. We also used Western blot to characterize Ras-MEK-ERK pathway activity.

STUDY DESIGN:

We evaluated this hypothesis in six PIK3CA-amplified, PI3K inhibitor-resistant HNSCC cell lines following treatment with pan and alpha-isoform selective PI3K inhibitors (BKM120 and HS-173 respectively). We also tested the effect of combination treatment with PI3K inhibitor HS-173 and MEK inhibitor trametinib or EGFR inhibitor gefitinib.

RESULTS:

Our results displayed maintenance of Ras-MEK-ERK pathway activity in 4 of 6 HNSCC cell lines after PI3K inhibitor treatment. We also found that UM-SCC-69 and UM-SCC-108 cells display synergistic responses to dual therapy.

CONCLUSION:

This study suggests that inhibition of the PI3K and Ras-MEK-ERK pathways might be effective in some HNSCC patients; however, it also prompts the study of additional resistance mechanisms to identify synergistic combination therapies for tumors resistant to these di-therapies.

100 项与 HS-173 相关的药物交易

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