Roles and inhibitors of FAK in cancer: current advances and future directions.

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that exhibits high expression in various tumors and is associated with a poor prognosis. FAK activation promotes tumor growth, invasion, metastasis, and angiogenesis via both kinase-dependent and kinase-independent pathways. Moreover, FAK is crucial for sustaining the tumor microenvironment. The inhibition of FAK impedes tumorigenesis, metastasis, and drug resistance in cancer. Therefore, developing targeted inhibitors against FAK presents a promising therapeutic strategy. To date, numerous FAK inhibitors, including IN10018, defactinib, GSK2256098, conteltinib, and APG-2449, have been developed, which have demonstrated positive anti-tumor effects in preclinical studies and are undergoing clinical trials for several types of tumors. Moreover, many novel FAK inhibitors are currently in preclinical studies to advance targeted therapy for tumors with aberrantly activated FAK. The benefits of FAK degraders, especially in terms of their scaffold function, are increasingly evident, holding promising potential for future clinical exploration and breakthroughs. This review aims to clarify FAK's role in cancer, offering a comprehensive overview of the current status and future prospects of FAK-targeted therapy and combination approaches. The goal is to provide valuable insights for advancing anti-cancer treatment strategies.

Preclinical studies of the triazolo[1,5-a]pyrimidine derivative WS-716 as a highly potent, specific and orally active P-glycoprotein (P-gp) inhibitor.

Multidrug resistance (MDR) is the main cause of clinical treatment failure and poor prognosis in cancer. Targeting P-glycoprotein (P-gp) has been regarded as an effective strategy to overcome MDR. In this work, we reported our preclinical studies of the triazolo[1,5-a]pyrimidine-based compound WS-716 as a highly potent, specific, and orally active P-gp inhibitor. Through direct binding to P-gp, WS-716 inhibited efflux function of P-gp and specifically reversed P-gp-mediated MDR to paclitaxel (PTX) in multiple resistant cell lines, without changing its expression or subcellular localization. WS-716 and PTX synergistically inhibited formation of colony and 3D spheroid, induced apoptosis and cell cycle arrest at G2/M phase in resistant SW620/Ad300 cells. In addition, WS-716 displayed minimal effect on the drug-metabolizing enzyme cytochrome P4503A4 (CYP3A4). Importantly, WS-716 increased sensitivity of both pre-clinically and clinically derived MDR tumors to PTX in vivo with the T/C value of 29.7% in patient-derived xenograft (PDX) models. Relative to PTX treatment alone, combination of WS-716 and PTX caused no obvious adverse reactions. Taken together, our preclinical studies revealed therapeutic promise of WS-716 against MDR cancer, the promising data warrant its further development for cancer therapy.

Hierarchically Hybrid Porous Co3O4@NiMoO4/CoMoO4 Heterostructures for High-Performance Electrochemical Energy Storage.

Hierarchical, ultrathin, and porous NiMoO4@CoMoO4 on Co3O4 hollow bones were successfully designed and synthesized by a hydrothermal route from the Co-precursor, followed by a KOH (potassium hydroxide) activation process. The hydrothermally synthesized Co3O4 nanowires act as the scaffold for anchoring the NiMoO4@CoMoO4 units but also show more compatibility with NiMoO4, leading to high conductivity in the heterojunction. The intriguing morphological features endow the hierarchical Co3O4@NiMoO4@CoMoO4 better electrochemical performance where the capacity of the Co3O4@NiMoO4@CoMoO4 heterojunction being 272 mA·h·g-1 at 1 A·g-1 can be achieved with a superior retention of 84.5% over 1000 cycles. The enhanced utilization of single/few NiMoO4@CoMoO4 shell layers on the Co3O4 core make it easy to accept extra electrons, enhancing the adsorption of OH- at the shell surface, which contribute to the high capacity. In our work, an asymmetric supercapacitor utilizing the optimized Co3O4@NiMoO4@CoMoO4 activated carbon (AC) as electrode materials was assembled, namely, Co3O4@NiMoO4@CoMoO4//AC device, yielding a maximum high energy density of 53.9 W·h·kg-1 at 1000 W·kg-1. It can retain 25.92 W·h·kg-1 even at 8100 W·kg-1, revealing its potential and viability for applications. The good power densities are ascribed to the porous feature from the robust architecture with recreated abundant mesopores on the composite, which assure improved conductivity and enhanced diffusion of OH- and also the electron transport. The work demonstrated here holds great promise for synthesizing other heterojunction materials M3O4@MMoO4@MMoO4 (M = Fe, Ni, Sn, etc).

Latest therapeutic target for gastric cancer: Anthrax toxin receptor 1.

Anthrax toxin receptor 1 (ANTXR1), also known as tumor endothelial marker 8, is a highly conserved cell surface protein overexpressed in tumor-infiltrating vessels. It was first found in vascular endothelial cells of human colorectal cancer. Although our understanding of its physiological function is limited, it has been found that ANTXR1 binds collagen and promotes migration of endothelial cells in vitro. ANTXR1 is upregulated in vessels of different tumor types in mice and humans, and is also expressed by tumor cells themselves in some tumors, such as gastric, lung, intestinal and breast cancer. Developmental angiogenesis and wound healing were not disturbed in ANTXR1 knockout mice, but compared with wild-type mice, growth of melanoma was impaired after ANTXR1 knockout, indicating that host-derived ANTXR1 can promote tumor growth on the basis of immune activity. Previous studies have shown that ANTXR1 vaccines or sublethal doses of anthrax toxin can inhibit angiogenesis, slow tumor growth and prolong survival. These studies suggest that ANTXR1 is necessary for tumor rather than physiological angiogenesis. It has been found that ANTXR1 plays an important role in tumor angiogenesisas well as in the growth and metastasis of many kinds of tumors. This article reviews the physiological function of ANTXR1 and its role in different kinds of cancer.

Surgical outcomes and survival for T4 gastric cancer extending to the transverse colon.

BACKGROUND: For the treatment of locally advanced (T4) gastric cancer, extended multi-organ resection remains controversial. This study aimed to evaluate the surgical outcomes and survival of patients with T4 gastric cancer extending to the transverse colon. METHODS: A total of 2,652 gastric cancer patients underwent surgery between December 2011 and December 2015. Data from 40 of these patients who underwent curative resection for T4 gastric cancer extending to the transverse colon were obtained. Patient characteristics, related complications, long-term survival, and prognostic factors for T4 gastric cancer were analyzed. RESULTS: Postoperative morbidity occurred in 5 (12.5%) patients. All of the patients were cured with conservative treatment. No procedure-related mortality occurred. The 1-, 3-, and 5-year overall survival (OS) rates were 75.0%, 49.2%, and 36.9%, respectively, with a median survival time of 24 months. Univariate analysis revealed tumor size (P=0.049), advanced T stage (P=0.013), and lymph node metastasis (P=0.006) to be poor prognostic factors of OS. Advanced T stage and lymph node metastasis were identified by multivariate analysis as being independent prognostic factors. Further, it was observed that lymph node metastasis grade was associated with poorer OS. CONCLUSIONS: Patients with T4 gastric cancer extending to the transverse colon might benefit from curative resection with acceptable morbidity and mortality.

Steroidal dimer by001 inhibits proliferation and migration of esophageal cancer cells via multiple mechanisms.

OBJECTIVE: To investigate the potential inhibitory effects of structurally novel steroidal dimer by001 in esophageal cancer in vitro. METHODS: The cytotoxicity of by001 on esophageal, gastric, neuroblastoma and prostate cancer cells was examined MTT assay and colony formation assay. By001 induced apoptosis and production of intracellular reactive oxygen species on esophageal cancer cells Ec109, TE-1 and human normal gastric epithelial cells GES-1 was detected by flow cytometry. The effect of by001 on mitochondrial membrane potential was detected by fluorescence microscope through JC-1 staining. The level of intracellular reactive oxygen species was measured by fluorescence microscope and flow cytometry via DCFH-DA staining. The effect of by001 on members of Bcl-2 family, Fas, LC3, PARP and caspases was determined by Western blot. The effect of by001 on migration was measured by transwell assay. RESULTS: By001 effectively inhibited proliferation of esophageal, gastric, neuroblastoma and prostate cancer cells in a time- and concentration-dependent manner in vitro. By001 reduced the number and the size of colonies at low micromolar concentrations, elevated cellular ROS levels and caused mitochondrial dysfunction in esophageal cancer cells. Molecular mechanistic studies showed that by001 triggered apoptosis through regulating members of Bcl-2 family and Fas. CONCLUSIONS: These findings suggested that by001 may inhibited proliferation of esophageal cancer cells through mitochondria and death receptor-mediated apoptotic pathways, autophagy induction, as well as suppressed migration of esophageal cancer cells.

Decreased expression of miR-542-3p exerts growth inhibitory functions in esophageal cancer.

OBJECTIVE: Identification of novel biomarkers and related molecular pathways are critical for understanding the underlying biology of human malignancies, as well as to design effective cancer therapeutics. MicroRNAs (miRNAs) are classified as a kind of short non-coding RNAs that interfere with specific target mRNAs and therefore regulate multiple biological processes. We characterized here the expression and function of miR-542-3p in esophageal squamous cell carcinoma (ESCC). METHODS: Real-time PCR was used to examine the miR-542-3p expression. After transfections of its synthetical mimics or inhibitor, cell growth rate was explored by cell counting assay. In addition, its expression was further statistically analyzed to reveal its association with clinical characters. RESULTS: We show that miR-542-3p, a well-characterized tumor suppressor was significantly decreased in ESCC tissues and cell lines, whose downregulation is tightly associated with tumor grade. Furthermore, forced expression of miR-542-3p suppressed cell proliferation, while silencing its expression by a synthetical inhibitor could enhance cell growth rate. CONCLUSION: Taken together, our results indicated that miR-542-3p is a tumor suppressor of esophageal cancer acting at steps that regulate cell growth.

[Screening of endophytic fungi from Huperzia serrata for acetylcholinesterase inhibitory activity and its taxonomic identification].

OBJECTIVE: To screen out fungus strains with acetylcholinesterase inhibitory activity from Huperzia serrata. METHOD: Endophytic fungi fermentation products from 59 H. serrata strains were stained with acetylcholinesterase hydrolyzed alpha-naphthaleneacetic ethyl ester and fast blue B salt, and screened for acetylcholinesterase inhibitory activity with thin-layer chromatography-bioautography. Target strains were classified and identified through the sequence analysis on 18s rDNA and 5.8s rDNA combined with morphological characteristics. RESULT: Fungus strain LQ2F01 from H. serrata showed positive color reaction in the screening for acetylcholinesterase inhibitory activity. The sequence analysis on 18s rDNA and 5.8s rDNA combined with morphological characteristics showed the strain LQ2F01 belonged to Acremonium. CONCLUSION: Endophytic Fungi LQ2F01 from H. serrata shows identical acetylcholinesterase inhibitory activity with the host plant, which is of great significance to the development of natural medicines and the studies on the relationship between the endophytic gungi and the host plant.

[The utility of trnH-psbA gene for phylogenetic analysis of Huperziaceae and plant barcoding].

OBJECTIVE: The purpose of study was to discover the phylogenetic relations and plant barcoding of 17 plants from Huperziaceae. METHODS: Phylogenetic tree of chloroplast trnH-psbA gene of 17 plants from Huperziaceae was constructed by software. RESULTS: It showed that Huperziaceae could be divided into two genera Huperzia and Phlegmariurus and bootstrap value reached 91%. CONCLUSIONS: Holub and Qing' taxonomy was supported and 17 species in Huperziaceae were monophyletic groups and it suggested that trnH-psbA could be used as a DNA barcode to identify plants.

[Effect of alpha-terthienyl on protein, esterase and lipid peroxidation of Aedes albopictus larvae].

OBJECTIVE: To study the effect of alpha-terthienyl (alpha-T) on protein, esterase and lipid peroxidation of Aedes albopictus larvae. METHODS: Sensitive and resistant strains of Aedes albopictus stage IV larvae were used. Bradford method was used to detect protein content. The breeding fluid of experiment group contained alpha-T (5.34 microg/L), and control group contained only acetone (3.95 microg/L). Histochemistry method was used to detect esterase activity. Larvae in the experiment group were cultured in fluid containing alpha-T (6.24 microg/L) but no alpha-T in the control group. TBA method was used to detect malondialdehyde (MDA). Larvae of the sensitive strain were divided into 5 sub-groups: A - acetone control (containing acetone 3.95 microg/L), B - ultra-violet irradiation (UV) control (same with A but treated by UV), C, D, E - experiment groups with alpha-T (4.58, 5.34 and 6.24 microg/L respectively). All groups were kept in dark condition for 1 hour, followed by UV for 1 hour (except group A), then fed under normal condition. RESULTS: With UV and alpha-T, the protein content of experiment group (1.225 mg/ml) was higher than that of control (1.120 mg/ml) (P<0.05) in sensitive strain; that of experiment group (1.199 mg/ml) was higher than that of control (1.114 mg/ml) (P<0.05) in the resistant strain. After 2, 4, 6, and 8 hour treated by both alpha-T and UV, the esterase activity all decreased in experiment group, and reached to the lowest 8 hours later (P<0.05). MDA contents was 2.286 nmol/mg protein in acetone control group and 2.322 nmol/mg protein in UV control, but 3.156, 4.188 and 4.684 nmol/mg protein respectively in the 3 experiment groups after treated by alpha-T and UV. The higher dose of alpha-T, the higher content of MDA (P<0.05). CONCLUSION: Under UV, alpha-T can increase the protein and MDA content of the larvae of Ae. albopictus but decrease the esterase activity.

Inhibition of lung metastasis in mice by intravascular injection of dendritic cells and natural killer cells.

To investigate the efficacy of dendritic cells and natural killer cells in the inhibition of lung metastasis, we injected dendritic cells and natural killer cells intravascularly into mice bearing B16F10 tumour melanoma cells. This efficiently inhibited tumor growth and prolonged survival. In addition, surviving mice developed a long-lasting memory response against the original tumor when re-challenged with live tumor cells. Intravenous administration of dendritic cells and natural killer cells may be a potential way to treat lung metastasis in patients.