Correction: Melittin-encapsulating peptide hydrogels for enhanced delivery of impermeable anticancer peptides.

Correction for 'Melittin-encapsulating peptide hydrogels for enhanced delivery of impermeable anticancer peptides' by Jue-Ping Feng et al., Biomater. Sci., 2020, 8, 4559-4569, DOI: .

Melittin-encapsulating peptide hydrogels for enhanced delivery of impermeable anticancer peptides.

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.

Overexpression of the mitochondrial chaperone tumor necrosis factor receptor-associated protein 1 is associated with the poor prognosis of patients with colorectal cancer.

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.

Tumor Ablation and Therapeutic Immunity Induction by an Injectable Peptide Hydrogel.

Immunosuppressive tumor microenvironments (TMEs) create tremendous obstacles for an effective cancer therapy. Herein, we developed a melittin-RADA32 hybrid peptide hydrogel loaded with doxorubicin (DOX) for a potent chemoimmunotherapy against melanoma through the active regulation of TMEs. The formed melittin-RADA32-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.

Famitinib versus placebo in the treatment of refractory metastatic colorectal cancer: a multicenter, randomized, double-blinded, placebo-controlled, phase II clinical trial.

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.

Melittin-Containing Hybrid Peptide Hydrogels for Enhanced Photothermal Therapy of Glioblastoma.

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-RADA32-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 RADA16 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 RADR16-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.

The soy-derived peptide Vglycin inhibits the growth of colon cancer cells in vitro and in vivo.

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.

Two variants on T2DM susceptible gene HHEX are associated with CRC risk in a Chinese population.

Increasing amounts of evidence has demonstrated that T2DM (Type 2 Diabetes Mellitus) patients have increased susceptibility to CRC (colorectal cancer). As HHEX is a recognized susceptibility gene in T2DM, this work was focused on two SNPs in HHEX, rs1111875 and rs7923837, to study their association with CRC. T2DM patients without CRC (T2DM-only, n=300), T2DM with CRC (T2DM/CRC, n=135), cancer-free controls (Control, n=570), and CRC without T2DM (CRC-only, n=642) cases were enrolled. DNA samples were extracted from the peripheral blood leukocytes of the patients and sequenced by direct sequencing. The χ2 test was used to compare categorical data. We found that in T2DM patients, rs1111875 but not the rs7923837 in HHEX gene was associated with the occurrence of CRC (p= 0.006). for rs1111875, TC/CC patients had an increased risk of CRC (p=0.019, OR=1.592, 95%CI=1.046-2.423). Moreover, our results also indicated that the two variants of HEEX gene could be risk factors for CRC in general population, independent on T2DM (p< 0.001 for rs1111875, p=0.001 for rs7923837). For rs1111875, increased risk of CRC was observed in TC or TC/CC than CC individuals (p<0.001, OR= 1.780, 95%CI= 1.385-2.287; p<0.001, OR= 1.695, 95%CI= 1.335-2.152). For rs7923837, increased CRC risk was observed in AG, GG, and AG/GG than AA individuals (p< 0.001, OR= 1.520, 95%CI= 1.200-1.924; p=0.036, OR= 1.739, 95%CI= 0.989-3.058; p< 0.001, OR= 1.540, 95%CI= 1.225-1.936). This finding highlights the potentially functional alteration with HHEX rs1111875 and rs7923837 polymorphisms may increase CRC susceptibility. Risk effects and the functional impact of these polymorphisms need further validation.

Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy improves survival of patients with peritoneal carcinomatosis from colorectal cancer: a case-control study from a Chinese center.

BACKGROUND: Advanced colorectal cancer (CRC) is prone to developing peritoneal carcinomatosis (PC). This case-control study was to compare the efficacy and safety of cytoreductive surgery (CRS) versus CRS plus hyperthermic intraperitoneal chemotherapy (HIPEC) in Chinese patients with CRC PC. METHODS: The 62 consecutive PC patients were treated with CRS (Control group, n = 29) or CRS + HIPEC (Study group, n = 33). The primary end point was overall survival (OS), the secondary end points were perioperative safety profiles. RESULTS: For the comparison of Control versus Study groups, the peritoneal cancer index (PCI) ≤20 was 13 (44.8%) versus 16 (48.5%) patients (P = 0.78), complete cytoreduction (CC0-1) was achieved in 9 (31.0%) versus 14 (42.4%) cases (P = 0.36). At the median OS was 8.5 (95% confidence interval [CI] 4.7-12.4) versus 13.7 (95% CI 10.0-16.5) months (P = 0.02), the 1-, 2-, and 3-year survival rates were 27.5% versus 63.6%, 12.0% versus 20.0%, and 0.0% versus 16.0%, respectively. Serious adverse events in postoperative 30 days were 9.4% versus 28.6% (P = 0.11). Multivariate analysis revealed that CRS + HIPEC, CC0-1, adjuvant chemotherapy ≥6 cycles were independent factors for OS benefit. CONCLUSION: CRS + HIPEC could improve OS for CRC PC patients, with acceptable perioperative safety.

[Impact of 5-fluorouracil on glucose metabolism and pancreatic pathology in rats].

OBJECTIVE: To explore the impact of 5-fluorouracil (5-FU) on glucose metabolism and pancreatic pathology. METHODS: 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 ß cells were observed by transmission electron microscope. RESULTS: 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 response to glucose load was significantly diminished in animals treated with 5-FU at day 2. Insulin level was significantly lower in the 5-FU group than that in the control group at 30 min (P<0.01). The peak secretion time of plasma insulin in 5-FU group was at 60 min, similar to the control group; and plasma insulin level decreased more slowly. Plasma insulin level was higher in 5-FU groups than in control groups on 120 min and 180 min. At day 7, Insulin level was lower in the 5-FU group than that in the control group on 60 min, and the peak secretion time of plasma insulin was delayed to 120 min. Plasma insulin level was significantly increased in 5-FU group than that in control group on 180 min(P<0.01). No gross histopathological damage to the pancreas was observed at day 2 and 7 following administration of 5-FU. The structural changes of mitochondria were mainly the quantities of secretory granule diminished at day 7 under transmission electron microscope. Dilated rough endoplasmic reticula, swollen mitochondria, and the presence of adipose drops in lysosomes were found in few cells. CONCLUSIONS: 5-FU-induced hyperglycemia appears to be mediated in part by a relatively deficient insulin secretion to glucose stimulation. A relative deficiency in insulin secretion following 5-FU treatment appears to be related to ß cells function impairs with islet cell ultrastructural changes induced by 5-FU.

[Association of MLH1 gene 415G/C polymorphism with colorectal cancer in Chinese].

OBJECTIVE: To study the possible etiological role of MLH1 gene 415G/C polymorphism in sporadic Chinese colorectal cancer (CRC) patients. METHODS: Ninety-seven sporadic CRC patients and 138 normal controls were collected from Hubei Provincial Cancer Hospital and the People's Hospital of Wuhan University. In addition, five CRC families including 6 patients and their 19 first-degree relatives were also recruited. Genomic DNA was extracted from peripheral blood samples. Gene mutation was analyzed by PCR-RFLP. MLH1 mRNA expression in colorectal mucosa was analyzed by RT-PCR. RESULTS: The frequency of MLH1 gene CC genotype was significantly higher in sporadic CRC patients than that in controls (P=0.035, OR=5.29, 95% CI: 1.07-26.04). In the CRC families, the C allele frequency of CRC patients and their relatives was increased, compared with sporadic CRC patients and normal controls, respectively (P=0.003 and P=0.006). MLH1 mRNA expression of colorectal mucosa was similar in different genotypes. CONCLUSION: MLH1 gene 415G/C polymorphism might be a risk factor to sporadic CRC in Chinese. The mutation does not affect the MLH1 mRNA expression. For first-degree relatives from CRC families, carriers of MLH1 415C allele have a high risk to CRC.