In late 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic emerged to severely impact the global population, creating an unprecedented need for effective treatments. This study aims to investigate the potential of Scutellaria barbata D. Don (SB) as a treatment for SARS-CoV-2 infection through the inhibition of the proteases playing important functions in the infection by SARS-CoV-2. FRET assay was applied to investigate the inhibitory effects of SB on the two proteases involved in SARS-CoV-2 infection, M^pro and TMPRSS2. Additionally, to measure the potential effectiveness of SB treatment on infection inhibition, cellular models based on the Calu3 and VeroE6 cells and their TMPRSS2- expressing derivatives were assessed by viral pseudoparticles (Vpp) infection assays. The experimental approaches were conjugated with LC/MS analyses of the aqueous extracts of SB to identify the major constituent compounds, followed by a literature review to determine the potential active components of the inhibitory effects on protease activities. Our results showed that SB extracts inhibited the enzyme activities of M^pro and TMPRSS2. Furthermore, SB extracts effectively inhibited SARS-CoV-2 Vpp infection through a TMPRSS2-dependent mechanism. The aqueous extract analysis identified six major constituent compounds present in SB. Some of them have been known associated with inhibitory activities of TMPRSS2 or M^pro. Thus, SB may effectively prevent SARS-CoV-2 infection and replication through inhibiting M^pro and TMPRSS2 protease activities.

Dedicator of cytokinesis 1 (DOCK1) is a critical regulator of cancer metastasis. Claudins are transmembrane proteins that play a role in epithelial barrier integrity. Due to a loss or low expression of claudins (CLDN), the claudin-low type of triple-negative breast cancer (TNBC) is characterized by a mesenchymal-like phenotype with strong metastatic potential. In order to elucidate the mechanism of DOCK1 in cancer metastasis, we first analyzed the transcriptomic changes using a clinical database of human TNBC and found that the increase in DOCK1 expression was highly correlated with the poor survival rate of TNBC patients. Interference with DOCK1 expression by shRNA resulted in re-expression of claudin-1 in conjunction with significant inhibition of cell viability and motility of claudin-low breast cancer cells. Accordingly, overexpression of claudin-1 suppressed cell viability and migration. Genetic knockdown and pharmacological blockade of Rac1/Rac2 up-regulated claudin-1. DOCK1 knockdown also caused a decrease in DNA methyltransferase (DNMT) expression and an increase in claudin-1 transcript and promoter activity. Furthermore, RRP1B mediated DOCK1 depletion, which up-regulated claudin-1 expression, cell viability, and motility in claudin-low breast cancer cells. This study demonstrated that DOCK1 mediates growth and motility through down-regulated claudin-1 expression via the RRP1B–DNMT–claudin-1 pathway and that claudin-1 serves as an important effector in DOCK1-mediated cancer progression and metastasis in claudin-low breast cancer cells.

Hypopharyngeal squamous cell carcinoma (HSCC) is usually diagnosed at an advanced stage, leading to a poor prognosis. Even after improvement of surgical techniques, chemotherapy, and radiation technology, the survival rate of HSCC remains poor. Metformin, which is commonly used for type 2 diabetes mellitus (DM), has been suggested to reduce the risk of various cancer types. However, only a few clinical studies mentioned the relationship between metformin use and HSCC. Hence, the aim of this study was to elucidate the specific effect and mechanism of action of metformin in hypopharyngeal cancer. We first assessed whether metformin use has an effect on hypopharyngeal cancer patients with DM by conducting a retrospective cohort study. Our results showed that DM hypopharyngeal cancer patients who used metformin exhibited significantly better overall survival rates than that without metformin treatment. The cell-based analysis further indicated that metformin treatment regulated p38/JNK pathway to reduce Cyclin D1 and Bcl-2 expressions. In addition, metformin activated the pathways of AMPKα and MEK/ERK to phosphorylate p27(Thr198) and reduce mTOR phosphorylation in cells. These actions direct cells toward G1 cell cycle arrest, apoptosis, and autophagy. Our results, through combining a clinical cohort analysis with an in vitro study, demonstrate that metformin can be used for drug repositioning in the treatment of DM patients with hypopharyngeal cancer.

Taxanes, particularly docetaxel (DTX), has been widely used for combination therapy of head and neck squamous cell carcinoma (HNSCC). For locally advanced unresectable HNSCC, DTX combined with cisplatin and 5-fluorouracil as a revolutionary treatment revealed an advantage in the improvement of patient outcome. In addition, DTX plus immune check inhibitors (ICIs) showed low toxicity and an increased response of patients with recurrent or metastatic HNSCC (R/M HNSCC). Accumulated data indicate that taxanes not only function as antimitotics but also impair diverse oncogenic signalings, including angiogenesis, inflammatory response, ROS production, and apoptosis induction. However, despite an initial response, the development of resistance remains a major obstacle to treatment response. Taxane resistance could result from intrinsic mechanisms, such as enhanced DNA/RNA damage repair, increased drug efflux, and apoptosis inhibition, and extrinsic effects, such as angiogenesis and interactions between tumor cells and immune cells. This review provides an overview of taxanes therapy applied in different stages of HNSCC and describe the mechanisms of taxane resistance in HNSCC. Through a detailed understanding, the mechanisms of resistance may help in developing the potential therapeutic methods and the effective combination strategies to overcome drug resistance.

Bladder cancer poses a significant challenge to chemotherapy due to its resistance to cisplatin, especially at advanced stages. Understanding the mechanisms behind cisplatin resistance is crucial for improving cancer therapy. The enzyme glutathione S‐transferase omega class 1 (GSTO1) is known to be involved in cisplatin resistance in colon cancer. This study focused on its role in cisplatin resistance in bladder cancer. Our analysis of protein expression in bladder cancer cells stimulated by secretions from tumor‐associated macrophages (TAMs) showed a significant increase in GSTO1. This prompted further investigation into the role of GSTO1 in bladder cancer. We found a strong correlation between GSTO1 expression and cisplatin resistance. Mechanistically, GSTO1 triggered the release of large extracellular vesicles (EVs) that promoted cisplatin efflux, thereby reducing cisplatin–DNA adduct formation and enhancing cisplatin resistance. Inhibition of EV release effectively counteracted the cisplatin resistance associated with GSTO1. In conclusion, GSTO1‐mediated EV release may contribute to cisplatin resistance caused by TAMs in bladder cancer. Strategies to target GSTO1 could potentially improve the efficacy of cisplatin in treating bladder cancer.

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) are used to treat BRCA -mutated (BRCAm) cancer patients; however, resistance has been observed. Therefore, biomarkers to indicate PARPi resistance and combination therapy to overcome that are urgently needed. We identified a high prevalence of activated FGF receptor 3 (FGFR3) in BRCAm triple-negative breast cancer (TNBC) cells with intrinsic and acquired PARPi resistance. FGFR3 phosphorylated PARP1 at tyrosine 158 (Y158) to recruit BRG1 and prolong chromatin-loaded MRE11, thus promoting homologous recombination (HR) to enhance PARPi resistance. FGFR inhibition prolonged PARP trapping and synergized with PARPi in vitro and in vivo. High-level PARP1 Y158 phosphorylation (p-Y158) positively correlated with PARPi resistance in TNBC patient–derived xenograft models, and in PARPi-resistant TNBC patient tumors. These findings reveal that PARP1 p-Y158 facilitates BRG1-mediated HR to resolve the PARP-DNA complex, and PARP1 p-Y158 may indicate PARPi resistance that can be relieved by combining FGFR inhibitors (FGFRis) with PARPis. In summary, we show that FGFRi restores PARP trapping and PARPi antitumor efficacy in PARPi-resistant breast cancer by decreasing HR through the PARP1 p-Y158/BRG1/MER11 axis, suggesting that PARP1 p-Y158 is a biomarker for PARPi resistance that can be overcome by combining FGFRis with PARPis.