ABSTRACT
Objective: To analyze and evaluate the role of the High-throughput Drug Sensitivity (HDS) screening strategy in identifying highly sensitive drugs against esophageal squamous cell carcinoma (ESCC). Methods: A total of 80 patients with progressive ESCC were randomly divided into the observation (40 cases) and the control groups (40 cases). In the observation group, primary ESCC cells were isolated from the tumor tissues with a gastroscope, and drug sensitivity screening was performed on cells derived from the 40 ESCC cases using the HDS method, followed by verification in a patient-derived tumor xenograft (PDX) mouse model. Finally, the differences in the therapeutic efficacy (levels of CEA, CYFRA21-1, SCCA after chemotherapy and the rates of overall survival, local progression, and distant metastasis at 12 months and 18 months time points after chemotherapy) were compared between the observation group (Screened drug-treated) and the control group (Paclitaxel combined with cisplatin regimen-treated). Results: Forty ESCC patients were screened for nine different high-sensitive chemotherapeutics, with the majority showing sensitivity to Bortezomib. Experiments on animal models revealed that the tumor tissue mass of PDX mice treated with the HDS-screened drug was significantly lower than that of the Paclitaxel-treated mice (p < 0.05), and the therapeutic efficacy of the observation group was better than the control group (p < 0.05). Conclusion: HDS screening technology can be beneficial in screening high-efficacy anticancer drugs for advanced-stage ESCC patients, thereby minimizing adverse drug toxicity in critically ill patients. Moreover, this study provides a new avenue for treating advanced ESCC patients with improved outcomes.
ABSTRACT
Currently, 5-Fluorouracil (5-FU) based chemotherapy is the primary option for colorectal cancer after surgery, whereas chemotherapy resistance related mortality is observed in a large proportion of patients. Anemoside B4 (AB4) is a triterpene saponin, which exhibits a considerable activity in oncotherapy. In this study, we explored the efficacy of AB4 in FU-based chemotherapy in colorectal cancer cells and the underlying molecular mechanisms. Our results indicated a significant synergistic activity of AB4 in 5-FU treated colorectal cancer cells. Furthermore, AB4 treatment eliminated colorectal cancer stem cells by promoting apoptotic cell death in 5-FU resistant colorectal cancer cells. Mechanically, AB4 activated caspase-9 pathway in 5-FU resistant colorectal cancer cells. Elevated Src activity induced cell apoptosis and cancer stem cells elimination effects in AB4 treated colorectal cancer cells. In conclusion, AB4 showed promising sensitization effect in the FU-based chemotherapy of colorectal cancer. Our study may pave a way to ameliorate FU-based chemotherapeutic efficiency in colorectal cancer.
Subject(s)
Antimetabolites, Antineoplastic/therapeutic use , Apoptosis/drug effects , Colorectal Neoplasms/drug therapy , Fluorouracil/therapeutic use , Proto-Oncogene Proteins pp60(c-src)/metabolism , Saponins/therapeutic use , Animals , Caspase 9/metabolism , Drug Resistance, Neoplasm/drug effects , Drug Synergism , HCT116 Cells/drug effects , Humans , Mice, Nude , Neoplasm Transplantation , Neoplastic Stem Cells/drug effectsABSTRACT
Formyl peptide receptor 2 (FPR2), a classical chemoattractant receptor of G-protein-coupled receptors, is reported to be involved in invasion and metastasis of some cancers, but the role of FPR2 in gastric cancer (GC) has not yet been elucidated. In this study, we found that the levels of FPR2 expression in GC were positively correlated with invasion depth, lymph node metastasis and negatively correlated with the patients' overall survival. Multivariate analysis indicated that FPR2 expression was an independent prognostic marker for GC patients. FPR2-knockdown significantly abrogated the migration and invasion stimulated by Hp(2-20) and Ac(2-26), two well-characterized ligands for FPR2 in GC cells. FPR2 deletion also reduced the tumorigenic and metastatic capabilities of GC cells in vivo. Mechanistically, stimulation with FPR2 ligands resulted in down-regulation of E-cadherin and up-regulation of vimentin, which were reversed by FPR2 knock-down, implying the involvement of epithelial-mesenchymal transition (EMT). Moreover, the activation of FPR2 was accompanied with ERK1/2 phosphorylation, which could be attenuated by FPR2 silencing or treatment with MEK inhibitor, PD98059. Altogether, our results demonstrate that FPR2 is functionally involved in invasion and metastasis, and potentially acts as a novel prognostic marker as well as a potential therapeutic target in human GC.
Subject(s)
Biomarkers, Tumor/genetics , Gene Expression Regulation, Neoplastic , Neoplasm Recurrence, Local/diagnosis , Receptors, Formyl Peptide/genetics , Receptors, Lipoxin/genetics , Stomach Neoplasms/diagnosis , Aged , Animals , Antigens, CD/genetics , Antigens, CD/metabolism , Biomarkers, Tumor/metabolism , Cadherins/genetics , Cadherins/metabolism , Cell Line, Tumor , Epithelial-Mesenchymal Transition , Female , Humans , Lymphatic Metastasis , Male , Mice , Mice, Nude , Middle Aged , Mitogen-Activated Protein Kinase 1/genetics , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/genetics , Mitogen-Activated Protein Kinase 3/metabolism , Neoplasm Grading , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Phosphorylation , Prognosis , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Receptors, Formyl Peptide/antagonists & inhibitors , Receptors, Formyl Peptide/metabolism , Receptors, Lipoxin/antagonists & inhibitors , Receptors, Lipoxin/metabolism , Signal Transduction , Stomach Neoplasms/genetics , Stomach Neoplasms/mortality , Stomach Neoplasms/pathology , Survival Analysis , Vimentin/genetics , Vimentin/metabolism , Xenograft Model Antitumor AssaysABSTRACT
There is a remarkable function on decreasing runoff and sediment in seabuckthorn and its mixed stands, but the effects on soil- and water conservation are different due to different structure and patterns of seabuckthorn and its mixed stands. The intensity of soil water use by seabuckthorn forest was different along with the month in growing season. In growing season, soil moisture in 0-500 cm layer was 5.1%, the lowest in the end of May and 8.8%, the highest in the end of October. This intensity was also different with forest age. 8 ages seabuckthorn forest consumed 231.2 mm of soil stored water in 0-500 cm layer annually, and soil moisture was 5.6%. Therefore, it should be cut for increasing soil moisture. In end of the third year after cutting, soil moisture in 0-160 cm layer could recover, and the value would be 10.3%-14.6%. Seabuckthorn forest could reduce the effect of slope location on soil moisture. Seabuckthorn and its mixed stands have similar intensity of soil water use, and there was a soil dry layer phenomenon in their stands.
