Recent Advances of Curcumin Derivatives in Breast Cancer.

Curcumin is a potential plant-derived drug for the treatment of breast cancer. Poor solubility and bioavailability are the main factors that limit its clinical application. Various structural modification strategies have been developed to improve the anti-breast cancer activity of curcumin. This review focuses on the difference of modification sites and heterocyclic/non-heterocyclic modifications to systematically summarize curcumin derivatives with better anti-breast cancer activity.

VMP1 promotes exosome secretion and enhances 5-FU resistance in colon cancer cells.

BACKGROUND: Drug resistance of colon cancer cells is the key to affect the efficacy of colon cancer chemotherapy and lead to chemotherapy failure. Recent studies have found that exosomes play an important role in chemoresistance of colon cancer, while the expression of VMP1 may be involved in exosome secretion. METHOD: Drug sensitivity of colon cancer cells was detected by MTT. VMP1 expression levels were detected by qPCR and western blot. Expression of VMP1 was silenced in SW620 and HT-29 cell lines. Exosomes were isolated by ultracentrifugation, the particle size and concentration of exosomes were analyzed by NTA, and the morphology of exosomes was investigated by transmission electron microscopy. Exosome marker protein expression was detected by Western blot. The effect of exosomes on 5-FU sensitivity in SW620 and HT-29 cells was examined by MTT and western blot. RESULTS: VMP1 presented high expression in SW620 and HT-29 cells, their VMP1 gene and protein levels were significantly higher than those in SW480 and HCT116 cells, they were less sensitive to 5-FU, and exosome secretion was significantly reduced in SW620 and HT-29 cells after silencing of VMP1. Importantly, addition of exosomes to cells after silencing of VMP1 re-improved drug resistance. Co-incubation of exosomes secreted from SW620 and HT-29 cells with homologous cells significantly increased cell viability after 5-FU (50 µM) treatment, and increased the expression levels of the resistance protein ABCC1 and the anti-apoptotic protein Bcl-2. CONCLUSION: High expression of VMP1 in colon cancer cells is able to promote exosome secretion, which mediates the acquisition of more drug-resistant properties by cancer cells.

Downregulation of VMP1 confers aggressive properties to colorectal cancer.

Vacuole membrane protein 1 (VMP1) was recently found to be involved in the process of tumor metastasis and is also considered to play a vital role in balancing apoptosis and autophagy. In the present study, the expression of VMP1 in colorectal cancer and matched adjacent non­cancerous tissues was evaluated by immunohistochemistry (IHC) for studying the role of VMP1 in the process of colorectal cancer. Kaplan­Meier analysis and the log-rank test were used to calculate the correlation of classic clinicopathological characteristics related to survival and the expression of VMP1. In vitro, a VMP1 stable gene silencing cell model was constructed using a lentiviral vector. The invasive ability and proliferation of colorectal cancer cells were evaluated by Transwell and MTT assays, respectively, and the underlying signaling pathway was explored by western blotting. Additionally, drug susceptibility to cisplatin, oxaliplatin and 5-FU was tested before and after VMP1 knockout. Finally, an animal model was constructed to explore the role of VMP1 in the physiopathologic process of colorectal cancer. Our results indicated that VMP1 showed increased expression in the adjacent non-cancer tissues compared with that in the colorectal cancer tissues. For different stages of colorectal cancer, expression of VMP1 had a negative correlation with the malignancy of the cancer. In clinical research, we also found that the median survival of patients with low VMP1 expression was much shorter than the survival of patients with high expression. In vitro, after infection with the lentivirus, cells with VMP1 knockout gained significant aggressive properties in regards to invasion and proliferation, and the mechanisms may be related to the activation of the PI3K/Akt/ZO-1/E-cadherin pathway. We also found that shVMP1 cells were more sensitive to 5-FU, but not cisplatin and oxaliplatin. Finally, we found a higher number of formed nodules in nude mice after intraperitoneal injection with shVMP1 cells in the in vivo study.

Anticancer activity of stoppin based on a novel peptide delivery system.

Stoppin (L1) is a newly identified anticancer peptide, which is a potent p53­MDM2/MDMX inhibitor. Due to its limitation in cell delivery efficiency, a new peptide delivery system was developed based on a nucleic acid­polypeptide­liposome complex and its stability and effectiveness in vitro was investigated. The nucleic acid­stoppin­liposome complex was prepared and characterization of the complex was conducted. The stability of the complex was evaluated by enzyme digestion. Following transfection of the A549 cells with the complex, detection of green fluorescent protein (GFP) and luciferase activity was conducted to evaluate transfection efficiency. In addition, the anticancer activity of the complex was determined by 3­(4,5­dimethyl­thiazolyl­2)­2,5 diphenyltetrazolium bromide assay and apoptosis was detected by flow cytometry. The results indicated that the particle size of the complex was 102±10 nm and the encapsulation rate was ~100% when the ratio of liposome, L1 and plasmid was: 4 µl:1 µg:2 µg. The enzyme digestion experiment demonstrated that the complex was resistant to pancreatic and DNA enzyme degradation, indicating that the complex had biological stability. Cell transfection demonstrated that it had a mutual promotion effect on delivery, which could be confirmed by GFP fluorescence and luciferase assay. The cell­killing efficiency of this novel delivery system was three times higher than with stoppin alone at a low concentration. In conclusion, this novel stoppin peptide delivery system was stable. The nucleic acid­peptide­liposome complex can protect the internal component from the degradation of enzymes, promote entry of the peptide into the cells and enhance the anti­tumor activity of stoppin. Therefore, it is a promising approach for peptide delivery, which can be characterized and visualized using plasmids with GFP or luciferase.

IL-33-induced JNK pathway activation confers gastric cancer chemotherapy resistance.

Inflammation is regarded as one of the major hallmarks of tumors, and has a very close relationship with gastric cancer. Interleukin-33 (IL-33), a new member of the IL-1 family, plays an important role in both inflammatory disease and tumors. The present study was designed to explore the effects of IL-33 on the proliferation, drug sensitivity, and the invasiveness of gastric cancer cells in vitro. IL-33 at concentrations lower than 100 pg/ml did not alter the inhibitory rate of gastric cancer cells. Moreover, IL-33 at these low concentrations protected against platinum-induced apoptosis in various gastric cancer cell lines, yet not in normal gastric epithelial cells. We also found that IL-33 increased the activation of the JNK pathway, and enhanced the expression of ST2. Furthermore, SP600125, a selective inhibitor of the JNK pathway, significantly blocked the protective effects of IL-33 in gastric cancer cells. In addition, Matrigel invasion assay showed that IL-33 markedly promoted gastric cancer cell invasion. In conclusion, the present study demonstrated that IL-33 protected against platinum-induced apoptosis and promoted cell invasion via activation of the JNK pathway in gastric cancer cells. In light of the prevalence of platinum-based chemotherapeutics in the treatment of gastric cancer, our results suggest that the level of IL-33 should be monitored during the treatment of gastric cancer, particularly when using platinum-based chemotherapeutics.