Anticancer peptides (ACPs) have gained significant attention in the past few years. Most ACPs only act toward intracellular targets. However, their low membrane penetrability often limits their ...anticancer efficacy. Here we developed a novel melittin-RADA28 (MR) hydrogel, composed of RADA28 and melittin, through a peptide fusion method in order to promote the membrane permeability of tumor cells with the membrane-disrupting ability of melittin. As a proof of concept, we loaded the MR hydrogel with a therapeutic peptide, KLA (KLAKLAKKLAKLAK), to show the enhanced delivery efficiency of the hydrogel. Our results demonstrated that the formed melittin-RADA28-KLA peptide (MRP) hydrogel has a nanofiber structure, sustained release profile, and attenuated hemolysis effects. Compared with free KLA, the MRP hydrogel markedly increased the cellular accumulation of KLA, produced the highest ratio of the depolarized mitochondrial membrane, and decreased cell viability in vitro. Following peritumoral injection, the MRP hydrogel treatment suppressed CT26 tumor growth by more than 85%, compared to controls. In summary, we provide a facile and efficient strategy to enhance the delivery of impermeable peptides to improve their therapeutic efficiency.
Immunosuppressive tumor microenvironments (TMEs) create tremendous obstacles for an effective cancer therapy. Herein, we developed a melittin-RADA
hybrid peptide hydrogel loaded with doxorubicin ...(DOX) for a potent chemoimmunotherapy against melanoma through the active regulation of TMEs. The formed melittin-RADA
-DOX (MRD) hydrogel has an interweaving nanofiber structure and exhibits excellent biocompatibility, controlled drug release properties both in vitro and in vivo, and an enhanced killing effect to melanoma cells. A single-dose injection of MRD hydrogel retarded the growth of primary melanoma tumors by more than 95% due to loaded melittin and DOX, with concomitant recruitment of activated natural killer cells in the tumors. Furthermore, MRD hydrogel can activate dendritic cells of draining lymph nodes, specifically deplete M2-like tumor-associated macrophages (TAMs), and produce active, cytotoxic T cells to further defend the cells against remaining tumors, providing potent anticancer efficacy against subcutaneous and metastatic tumors in vivo. Multidose injection of MRD hydrogel eliminated 50% of the primary tumors and provided a strong immunological memory effect against tumor rechallenge after eradication of the initial tumors. Owing to its abilities to perform controlled drug release, regulate innate immune cells, deplete M2-like TAMs, direct anticancer and immune-stimulating capabilities, and reshape immunosuppressive TMEs, MRD hydrogel may serve as a powerful tool for anticancer applications.
Vglycin, a novel natural polypeptide isolated from pea seeds, possesses antidiabetic properties. Our previous studies have shown that Vglycin can induce the differentiation of human colon ...adenocarcinoma cells. We aimed to determine the anticancer activity of Vglycin against colon cancer cells and to elucidate related apoptosis-inducing mechanisms. Treatment with purified Vglycin significantly reduced growth, viability, and colony formation of CT-26, SW480, and NCL-H716 colon cancer cells in a dose-dependent manner while down-regulating the expression of proliferating cell nuclear antigen. Mouse xenograft studies showed a 38% inhibition of colon cancer growth in mice treated with Vglycin (20 mg/kg/day) at day 21. Furthermore, the potential mechanisms involved in Vglycin-induced cell apoptosis were examined using cell cycle studies, ultrastructural examination, as well as apoptosis-associated pathway analysis. The results showed that Vglycin significantly promoted apoptosis and G1/S phase cell cycle arrest. As revealed by Western blot, the expression of CDK2 and Cyclin D1 was down-regulated in all three Vglycin-treated colon cancer cells, indicating that the CDK2/Cyclin D1 cell cycle pathway involved in the initiation and progression of colon cancer. Moreover, the inhibition of Vglycin-induced cell proliferation in colon cancer cells was accompanied by alteration of the expression levels of the apoptosis-related proteins Bax, Bcl-2 and Mcl-1, and an increase of caspase-3 activity. Together, our results suggest that Vglycin may be another plant-derived peptide that suppresses colon cancer, supporting the continued investigation of Vglycin as therapeutic agent for colon cancer. Impact statement The antidiabetic properties and the capability of inducing differentiation of human colon adenocarcinoma cells of Vglycin have been reported in our previous studies. However, the anticancer potential of Vglycin on colon cancer cells and its possible related mechanisms were still unknown. In this study, we found that Vglycin could reduce growth, viability, and colony formation or colony size of CT-26, SW480, and NCL-H716 colon cancer cells. Moreover, Vglycin decreased tumor volume by 38% in xenograft mice transplanted with CT-26 cells. The mechanisms of these phenomena may be due to the down-regulated CDK2 and Cyclin D1, G1/S phase cell cycle arrest, and the dysregulated expression of Bax, Bcl-2, and Mcl-1. The findings highlight the anticancer potential of Vglycin against colon cancer cells, and suggest Vglycin may be another colon cancer potential suppressive component of plant-derived peptides.
The design of biocompatible and efficacious anticancer biomaterials to achieve relatively low tumor recurrence rates is the main pursuit of cancer photothermal therapy (PTT). RADA16-I is a synthetic ...amphiphilic peptide with the sequence RADARADARADARADA that can self-assemble into a peptide nanofiber hydrogel. In this study, we synthesized a novel melittin-RADA
-indocyanine green (ICG) hydrogel ("MRI hydrogel"), which contains melittin in the peptide hydrogel backbone and ICG in the hydrogel matrix, for enhanced PTT of glioblastomas. The MRI hydrogel exhibited physiologic characteristics similar to those of the RADA
hydrogel, while displaying concentration-dependent cytotoxicity to C6 glioma cells and photothermal effects. The in vivo biodistribution of the MRI hydrogel was visualized by near-infrared fluorescence and photoacoustic imaging. More importantly, in vivo PTT provided by the MRI hydrogel significantly reduced the tumor size and the tumor recurrence rate compared with the RADR
-ICG hydrogel and other controls, suggesting a synergistic effect of MRI hydrogel-carried melittin and ICG-based PTT treatment. Thus, MRI provides an alternative tool for the safe and efficient PTT treatment of tumors.
Background
Metastatic colorectal cancer (mCRC) patients with progressive disease after all available standard therapies need new medication for further treatment. Famitinib is a small‐molecule ...multikinase inhibitor, with promising anticancer activities. This multicenter, randomized, double‐blinded, placebo‐controlled, phase II clinical trial was designed to evaluate the safety and efficacy of famitinib in mCRC.
Methods
Famitinib or placebo was administered orally once daily. The primary endpoint was progression‐free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), quality‐of‐life (QoL), and safety.
Results
Between July 18, 2012 and Jan 22, 2014, a total of 167 patients were screened, and 154 patients were randomized in a 2:1 ratio to receive either famitinib (n = 99) or placebo (n = 55). The median PFS was 2.8 and 1.5 months in the famitinib and placebo groups (hazard ratio = 0.60, 95% confidence interval = 0.41–0.86, P = 0.004). The DCR was 59.8% and 31.4% (P = 0.002) and the ORR was 2.2% and 0.0% (P = 0.540) in the famitinib and placebo groups, respectively. The most frequent grade 3–4 adverse events were hypertension (11.1%), hand‐foot syndrome (10.1%), thrombocytopenia (10.1%), and neutropenia (9.1%). Serious adverse events occurred in 11 (11.1%) patients in the famitinib group and 5 (9.1%) in the placebo group (P = 0.788). The median OS of the famitinib and placebo groups was 7.4 and 7.2 months (P = 0.657).
Conclusion
Famitinib prolonged PFS in refractory mCRC patients with acceptable tolerability.
Trial registration This study was registered on ClinicalTrials.gov (NCT01762293) and was orally presented in the 2015 ASCO‐Gastrointestinal Symposium
Tumor necrosis factor receptor-associated protein-1 (TRAP-1), a mitochondrial chaperone, contributes significantly to the progression of cancer. However, the understanding of its involvement in the ...clinicopathological characteristics and prognosis of colorectal cancer (CRC) remains limited. The aim of the present study was to assess the significance of TRAP-1 expression in CRC. The expression of TRAP-1 was evaluated in corresponding cancerous, paracancerous, lymph node and distant metastatic tissues of 256 cases of CRC by immunohistochemistry. The associations between TRAP-1 expression and the clinicopathological parameters and survival rates of patients was assessed. Out of 256 patients with CRC, TRAP-1 expression was detected in 203 (79.3%). TRAP-1 expression was significantly increased in cancerous tissue compared with that in corresponding paracancerous tissues (P<0.001). Overexpression of TRAP-1 was significantly associated with differentiation (P=0.011), depth of invasion (P=0.006), lymph node metastasis (P<0.001) and tumor-node-metastasis stage (P<0.001). In patients with high TRAP-1 expression, the 5-year overall survival (OS) rate was 38.0%, in contrast to 56.5% in patients with low TRAP-1 expression (P=0.003). Similarly, the 5-year progression-free survival (PFS) was 26.6% for patients with high TRAP-1 expression and 53.3% for patients with low TRAP-1 expression (P<0.001). Multivariate analyses indicated the TRAP-1 expression is an independent prognostic factor for poorer OS P=0.015; hazard ratio (HR), 1.914 and PFS (P<0.001; HR, 2.534). Thus, TRAP-1 may serve as a potential biomarker for predicting the prognosis of patients with CRC. Specifically, overexpression of TRAP-1 may predict progression and poor survival in cases of CRC.
We aimed to investigate the change of serum metabolomics in response to n-3 fatty acid supplements in Chinese patients with type 2 diabetes (T2D). In a double-blind parallel randomised controlled ...trial, 59 Chinese T2D patients were randomised to receive either fish oil (FO), flaxseed oil (FSO) or corn oil capsules (CO, served as a control group) and followed up for 180 days. An additional 17 healthy non-T2D participants were recruited at baseline for cross-sectional comparison between cases and non-cases. A total of 296 serum metabolites were measured among healthy controls and T2D patients before and after the intervention. Serum 3-carboxy-4-methyl-5-propyl-2-furanpropanoate (CMPF) (P-interaction = 1.8 × 10(-7)) was the most significant metabolite identified by repeated-measures ANOVA, followed by eicosapentaenoate (P-interaction = 4.6 × 10(-6)), 1-eicosapentaenoylglycerophosphocholine (P-interaction = 3.4 × 10(-4)), docosahexaenoate (P-interaction = 0.001), linolenate (n-3 or n-6, P-interaction = 0.005) and docosapentaenoate (n-3, P-interaction = 0.021). CMPF level was lower in T2D patients than in the healthy controls (P = 0.014) and it was significantly increased in the FO compared with CO group (P = 1.17 × 10(-7)). Furthermore, change of CMPF during the intervention was negatively correlated with change of serum triglycerides (P = 0.016). In conclusion, furan fatty acid metabolite CMPF was the strongest biomarker of fish oil intake. The association of CMPF with metabolic markers warrants further investigation.
To explore the impact of 5-fluorouracil (5-FU) on glucose metabolism and pancreatic pathology.
Twenty Wistar rats were divided into 5-FU group(n=10, chemotherapy was administered intraperitoneally to ...animals at a dose of 20 mg/kg daily for continuous 5 days) and control group (n=10, sodium chloride was administered intraperitoneally to animals with the same dose at the same time ). Glucose tolerance was evaluated 2 and 7 days following 5-FU treatment by serial measurement of blood glucose before and after an oral glucose load. Plasma insulin concentration was determined by radioimmunoassay. Pancreatic pathology was examined with morphological method and the ultrastructural changes of β cells were observed by transmission electron microscope.
Fasting blood glucose level was significantly higher in the 5-FU group than that in the control group (7.6±0.9) mmol/L vs. (4.6±0.6) mmol/L at day 2; (8.9±1.0) mmol/L vs. (4.7±0.6) mmol/L at day 7, P<0.01. Insulin releasing test indicated that the early phase insulin re
PDF
