Jiedu Sangen decoction inhibits chemoresistance to 5-fluorouracil of colorectal cancer cells by suppressing glycolysis via PI3K/AKT/HIF-1α signaling pathway.

Drug resistance is a major obstacle in the development of effective colorectal cancer (CRC) therapy. Our study aimed to explore the reversal abilities of Jiedu Sangen decoction (JSD) on the 5-fluorouracil (5-FU) resistance and its underlying molecular mechanisms. Expression changes in HIF-1 of CRC tissues were firstly revealed by bioinformatics analysis. Afterwards, cell viabilities of JSD and 5-FU treatments on 5-FU resistant human colon cancer cells (HCT-8/5-FU) were determined. Expressions of phosphoinositide 3-kinase (PI3K), protein kinase B (AKT)/p-AKT, hypoxia-inducible factor 1 (HIF-1α), as well as glycolysis related proteins such as L-lactate dehydrogenase A (LDHA), Glucose transporter type 1 (Glut1), Hexokinase 2 (HKII), and cysteinyl aspartate specific proteinase (Caspase) family members in HCT-8/5-FU cells, HIF-1α silenced HCT-8/5-FU cells and tumor tissues were detected by western blotting. HIF-1α was found over expressed in CRC tissues according to public available datasets in Oncomine. Growth inhibition rates of HCT-8/5-FU cells were increased along with the increase of JSD concentrations. JSD caused down-regulated HIF-1α, PI3K, AKT/p-AKT, HKII and Glut1, as well as up-regulated Caspase3 and Caspase9 in HCT-8/5-FU cells and tumor tissues. In HIF-1α silenced HCT-8/5-FU cells, synergistic group showed significantly reduced expression levels of PI3K, AKT, p-AKT. Additionally, up-regulated expressions of Caspase6 and Caspase7 were observed. JSD combined with 5-FU also exhibited obvious inhibitory efficiency on tumor growth in vivo. JSD may reverse 5-FU resistance by suppressing glycolysis via PI3K/AKT/HIF-1α signaling pathway, thereby inhibiting glycolysis and induce apoptosis to enhance anti-tumor activity.

The prognostic value of 4.1 mRNA expression in non-small cell lung cancer.

BACKGROUND: The mechanism of 4.1 family in human cancer has not been elucidated. In this study we investigate the value as a prognostic factor of mRNA expression of 4.1 family in non-small cell lung cancer (NSCLC). METHODS: A survival analysis was carried out through the Kaplan-Meier plotter (KM plotter) database. KM's method was used to estimate the prognostic value of 4.1 mRNA expression in NSCLC. RESULTS: Expression of four members are linked to overall survival (OS) in NSCLC patients, among which 4.1G, 4.1B, 4.1R are concerned with first progression (FP), and 4.1G, 4.1R are correlated with post progression survival (PPS) besides. Only 4.1B expression is associated with OS in squamous cell carcinoma, as four members with OS in adenocarcinoma. What's more, 4.1G, 4.1N high mRNA are linked to better FP in adenocarcinoma, and 4.1R overexpression is linked to better PPS. The expression of 4.1G is associated with the prognosis in female, whereas 4.1R in male. Furthermore, 4.1G and 4.1B play as protective roles in non-smoking populations, while 4.1N overexpression is related to poorer PPS. All the four family members are associated with early stage in NSCLC 4.1G, 4.1B and 4.1R are closely related to surgical resection, yet 4.1N has no prognostic significance in patients receiving treatments. However, the results need to be verified in clinical trials further. CONCLUSIONS: Our results offer new opinion about the prognostic value of 4.1 protein family in NSCLC, which may contribute to the development of new therapy for NSCLC.

Inhibition to Epithelial-Mesenchymal Transition and Metastatic Potential In Colorectal Cancer Cell By Combination of Traditional Chinese Medicine Formulation Jiedu Sangen Decoction and PD-L1 Inhibitor.

BACKGROUND: Jiedu Sangen Decoction (JSD), a traditional Chinese medicine formula, has been widely applied in the treatment of gastrointestinal cancer, especially in colorectal cancer. Our study mainly aimed to assess the combined efficacy of Jiedu Sangen aqueous extract (JSAE) and a PD-L1 inhibitor (PI) in colon cancer cells migration and invasion, along with epithelial-mesenchymal transition, and then provide deep insights into the potential mechanism. METHODS: We explored the inhibitory effects on invasion and metastasis and the reverse effect on EMT process in CT-26 colon cancer cell via Transwell migration assay, Matrigel invasion assay and confocal laser scanning microscopy. Furthermore, regulation in expression of EMT-related proteins and molecular biomarkers and underlying signal pathway proteins were detected through Western blotting and IHC. RESULTS: The combination of JSD and PD-L1 inhibitor could inhibit migration, invasive ability and EMT of CT-26 cells in a concentration-dependent manner. Meanwhile, JSD combined with PD-L1 inhibitor could also remarkably reverse EMT and metastasis in vivo. In addition, the protein expression of N-cadherin, Slug, Snail, Vimentin was down-regulated along with E-cadherin s up-regulation with the combination of JSD and PD-L1 inhibitor, while that of PI3K/AKT was notably down-regulated. CONCLUSIONS: These findings indicated that JSAE and a PD-L1 inhibitor could drastically inhibit the migration and invasion of colorectal cancer by reversing EMT through the PI3K/AKT signaling pathway.

Comparison of Immune Checkpoint Inhibitors between Older and Younger Patients with Advanced or Metastatic Lung Cancer: A Systematic Review and Meta-Analysis.

OBJECTIVES: Despite the fact that it is widely acknowledged that immune checkpoint inhibitors (ICIs) rely on the presence of immune response to take their antitumor effect, little is known whether there is an influence exerted on the efficacy of ICIs based on patients' age. We performed a systematic review and meta-analysis to explore the efficacy of ICIs between younger and older patients. MATERIALS AND METHODS: We searched online database and major conference proceedings for randomized controlled trials (RCTs) published of ICIs and included RCTs that conducted subgroup comparisons of age with available combination of hazard ratios (HRs) and 95% confidence interval (95%CI). Subsequently, we figured out the pooled HR and 95%CI in younger and older patients with a random-effects model and evaluated the within-study heterogeneity by using subgroup, sensitivity, and meta-regression analysis. RESULTS AND CONCLUSION: A total of 12 eligible RCTs included in our study, which reported OS according to patients' age. The overall estimated random-effects for HR was 0.75 with 95% CI of 0.65-0.87 in younger arm versus 0.81 with 95% CI of 0.72-0.92 in older arm. ICIs can improve OS for patients with advanced or metastatic lung cancer when compared to controls, especially for those patients with NSCLC, anti-PD-1/PD-L1 inhibitors, non-squamous, Pembrolizumab or Atezolizumab used as well as subsequent-line setting, and the magnitude of benefit in OS had comparable efficacy in both younger and older arms using a cut-off of 65 yr. Conversely, we also drew a statically significant conclusion that older patients failed to acquire benefit from ICIs when subdivided with a further cut-off of 75 yr.

Association between the overexpression of Her3 and clinical pathology and prognosis of colorectal cancer: A meta-analysis.

BACKGROUND: This study aimed to investigate the association between the overexpression of human epidermal growth factor receptor-3 (Her3) and the clinicopathological parameters and survival of patients with colorectal cancer (CRC). METHODS: Relevant studies on the overexpression of Her3 (measured by immunohistochemistry) and overall survival (OS) in patients with CRC were searched for in PubMed, EMBASE, and Cochrane Library. Published data were extracted and computed into odds ratios (ORs) for assessing the association of Her3 overexpression with tumor differentiation, tumor node metastasis (TNM) stage, position of colon cancer, sex, and age. Prognostic data were computed into hazard ratios (HRs) for OS. RESULTS: Eight studies including 1716 patients with CRC were included in this meta-analysis. The results revealed a significant association between Her3 overexpression and tumor differentiation [OR = 2.38; 95% confidence interval (95% CI): 1.76-3.22; P < .001], TNM tumor stage (OR = 0.71; 95% CI: 0.53-0.96; P = .03), and position of colon cancer (OR = 1.71; 95% CI: 1.28-2.27; P < .001). While patients with Her3 overexpression demonstrated a worse tumor response (OR = 0.31; 95% CI: 0.16-0.60; P < .001) and OS after treatment with cetuximab (HR = 1.86; 95% CI: 1.24-2.79; P = .003), they demonstrated better OS after symptomatic treatment (HR = 0.65; 95% CI: 0.50-0.85; P = .002). Her3 overexpression was not associated with sex (OR = 1.03; 95% CI: 0.83-1.28; P = .79), age (OR = 0.96; 95% CI: 0.75-1.24; P = .77), colon or rectum site (OR = 0.79; 95% CI: 0.44-1.43; P = .44), and total OS (HR = 1.09; 95% CI: 0.69-1.72; P = .72). CONCLUSION: Her3 expression is associated with the clinical pathology and prognosis of CRC, which explains the nonefficacy of cetuximab treatment in patients with CRC.

The Role of Combination Maintenance with Pemetrexed and Bevacizumab for Advanced Stage Nonsquamous Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis.

PURPOSE: To evaluate the effect of combination maintenance therapy of pemetrexed plus bevacizumab for patients with advanced non-small cell lung cancer. METHODS: We identified relevant studies by electronic search (Embase, PubMed, Cochrane, and Web of Science from 1 January 1960 to 29 October 2016) and manual search. The primary outcome of interest was progression-free survival (PFS) and secondary end point included overall survival (OS) and toxicities. The data was pooled for quantitative analysis and the final effect size was reported as hazard ratio (HR) for survival outcomes and relative risk (RR) for safety outcomes, both with a random-effects model. RESULTS: Three randomized controlled trials enrolling 1302 patients with advanced non-small cell lung cancer were included in this meta-analysis. An evident PFS improvement (HR = 0.73, 95% CI = 0.63-0.83, P < 0.01) was observed in patients with pemetrexed and bevacizumab combination maintenance therapy compared with single-agent maintenance therapy, yet it did not subsequently lead to a significant improvement in OS (HR = 0.97, 95% CI = 0.84-1.10, P = 0.66). Our analysis also showed statistically increased risks for provoking grade 3-4 adverse events in patients managed using pemetrexed plus bevacizumab combination (RR = 1.59, 95% CI = 1.07-2.36, P = 0.022). CONCLUSIONS: Pemetrexed plus bevacizumab combination maintenance therapy leads to significant improvement in PFS but not in OS for patients with advanced non-small cell lung cancer, which also increases the risks of grade 3-4 adverse events. Yet, in view of the limitation of existing studies and this meta-analysis, current evidence is not adequate to support routine use of pemetrexed-bevacizumab maintenance.