Current Signal Transduction Therapy - Volume 10, Issue 2, 2015

Self-assembling peptides have very recently emerged as a new class of drug vehicles, as they hold unique advantages such as good biocompatibility, design flexibility, and controllable nanotructure. In this work, we report a self-assembling peptide containing D-amino acids (Nap- GDFDFDYGRGD) as the carrier of anticancer drug tetrandrine. Tetrandrine is a bis-benzylisoquinoline alkaloid isolated from the root of Hang-Fang-Chi (Stephania tetrandra S. Moore). The D-peptides were employed in this study as they have shown stronger resistance against proteases than their Lcounterpart with natural L-amino acids. The Nap-GDFDFDYGRGD peptides can self-assemble into nanofibers, which are able to efficiently encapsulate tetrandrine. The drug-loaded nanofibers are capable of sustained release of tetrandrine and being internalized by the LoVo cancer cells. The cytotoxicity studies indicate that the tetrandrine-loaded nanofibers possess similar cytotoxicity to free tetrandrine against LoVo cancer cells and the Nap- GDFDFDYGRGD nanofibers can be used as a safe vehicle.

Tetrandrine (Ted) has been demonstrated in a series of studies to have potential antitumor effect against several cancers. Its lipophilicity makes it an ideal model drug for nanoparticle encapsulation. We constructed Ted loaded nanoparticles (Ted-NP) with PLGA-PEG as drug carrier. Characterization of the nanoparticles showed that Ted-NP had a size of less than 100 nm and a slight negative surface charge. By adjusting the feeding ratio, the highest drug loading content and encapsulation efficiency were 13.6% and 87.2%, respectively. In vitro release indicated the sustained release pattern of Ted-NP. In vitro cytotoxicity test demonstrated that Ted-NP showed stronger cell growth inhibitory effect than free Ted did at equivalent doses. The antitumor effect was mediated by induction of apoptosis through a mitochondrial way. Therefore, the characteristic of amphiphilic copolymer based drug delivery system enables a more efficient way to deliver Ted for cancer treatment.

A novel candidate named 5-(3,5-dichloro-2-hydroxybenzylamino)-2- hydroxybenzoic acid (ZL006) can effectively treat focal cerebral ischemic stroke. However, the application potential of ZL006 was compromised by its poor solubility. In this study, ZL006 was loaded effectively into liposomes to improve the solubility and bioavailability. The particle size of ZL006-loaded liposomes (LPs) was about 115.5 nm with acceptable polydispersity index. The in vitro release profiles indicated that ZL006 could keep sustained release from LPs for more than 48 h. The results of pharmacokinetics study proved that the mean residence time of LPs group was 1.5-fold (P < 0.05) higher than that of free ZL006 group. Besides, the results of tissue distribution showed that the accumulation of ZL006 in brain tissue was significantly improved compared with the free ZL006 group at 1 h time after intravenous. Anti- ischemic stroke results showed that LPs could significantly enhance neuroprotection of ischemic stroke on middle cerebral artery occlusion (MCAO) rats model. In conclusion, LPs had been demonstrated to be a promising drug delivery system for ZL006 to treat ischemic stroke.

Kidney ischemia-reperfusion injury is a serious illnesses which could threaten to human health. However, there is lack of effective therapy for the disease. Recently, resveratrol (Res) has been reported as a potential antioxidant in treatment of ischemia/reperfusion injury through attenuating oxidative stress and apoptosis. Because of its insolubility and short half-time, the application of Res is limited. Latest evidence reveals the possibility of developing nanoparticle-based delivery systems with improved solubility, stability and cytotoxicity of lipophilic drug. Here, we use Res-loaded nanoparticles (Res-NPs) to evaluate the protective effect of Res-NPs on human renal proximal tubular epithelial (HK-2 cells) suffering hypoxia-reoxygenayion in vitro. The hypothesis is raised that Res-NPs could demonstrate enhanced renal protection compared to an equivalent dose of free Res at lower concentration. Res-NP can significantly improve the survival rate of HK-2 cells and reduce the number of apoptosis cell. It also can reduce the activity of reactive oxygen species (ROS), decrease the level of Caspse-3 & Bax and increase the level of Bcl-2. Res-NP can inhibit hypoxia reoxygenation of HK-2 cells apoptosis better than Res, which mechanism is related to its antioxidation. Res-NPs could be a potential treatment needing intensive research for ischemia/reperfusion.

Harmine (HM), a β-carboline alkaloid extracted from the seeds of Peganum harmala L., has been reported to have antitumor effects. However, the effects and mechanism of action of HM in human gastric cancer cells remain unclear. This study evaluated the antitumor effects of HM in human gastric cancer in vitro. The in vitro cytotoxicity test indicated that HM inhibits gastric cancer cell viability in a dose- and time-dependent manner. Intracellular ROS production was measured using the fluorescent substrate DCFH-DA. The percentage of apoptotic cells was determined by flow cytometry analysis and DAPI staining. Western blot analysis showed the expression of p-AKT, Bcl-2, Bax and caspase-3 in SGC-7901 cells treated with various agents. We demonstrated that HM induces gastric cancer cell apoptosis through the ROS-mediated PI3K/AKT signaling pathway. Therefore, data from this study not only confirm the potential of HM for the treatment of gastric cancer but also offer a promising anticancer therapeutic strategy for treating gastric cancer.

Within the last decade, extensive research has revealed that curcumin can increase the sensitivity of tumor cells to high-energy X-ray radiation in vitro and dual-specificity phosphatase (DUSPs) are implicated in cancer, obesity, diabetes, inflammation and Alzheimer’s disease. To date, the article about the radiosensitizing effect of curcumin via enhancement of the DUSP-2 pathway was rarely reported. Here, we discuss the radiosensitizing effects of curcumin on suppressing glioma vivo growth. BALB-c nude mice bearing subcutaneous U87 xenografts were treated with curcumin and/or local radiation to assess their vivo response. Tumor growth, real-time PCR, western blotting, immunohistochemical assay and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) were performed to explore the possible mechanism involved. Curcumin in combination with irradiation significantly enhanced the tumor-suppressive effect in vivo compared with local radiotherapy alone. Both mRNA and protein levels of DUSP-2 were significantly upregulated in the curcumin in combination with radiation treatment group. Curcumin pretreatment inhibited radiationinduced extracellular signal-regulated kinases (ERK)/c-Jun N-terminal kinases (JNK) phosphorylation and enhanced radiation-induced tumor cell apoptosis in subcutaneous xenografts. In conclusion, curcumin significantly increased the radiosensitivity of U87 human glioma cells in vivo. The radiosensitizing effect of curcumin was found to be closely related to its pro-apoptosis activity via enhancement of the DUSP-2 pathway.

Objective: Bone is one of the most common sites of metastases in human small cell lung cancer (SCLC) which is often associated with skeletal-related events and poor prognosis. To explore the significance of Paeonol (Pae) in SCLC, we hypothesize that Pae can inhibit cell proliferation, migration and invasion, finally inhibit bone metastases of SCLC. Methods: The effects of Pae on proliferation of SCLC were detected by MTT assay in vitro. The effects of Pae on migration and invasion of SCLC were detected by Transwell assay in vitro. Furthermore, bone chip adhesion assay was used to explore the effects of Pae on the strength of bone adhesion and metastatic ability in SCLC cell line. Results: MTT results showed that Pae suppressed SCLC cell proliferation in a dose-dependent manner. Transwell assay results showed Pae suppressed SCLC cell migration and invasion in a dose-dependent manner. Furthermore, the cells treated by Pae showed decreased ability of bone adhesion and bone metastases in vitro compared with control. Conclusions: The study indicated Pae could suppress bone metastases of SCLC cells and Pae might be a promising medicine for therapy of SCLC bone metastases.

Pancreas is a retroperitoneally located organ, and thus general CT and MRI have a very limited specificity and sensitivity in diagnosing pancreatic diseases. However, endoscopic ultrasonography (EUS) with a better differential diagnostic capability of detecting pancreatic morphology and properties through gastric wall has been widely accepted by physicians and become one of the first-line methods compared with other techniques. Currently, common technologies used in the diagnosis and treatment of pancreatic diseases include EUS-guided fine needle aspiration (EUS-FNA), EUS-guided drainage, EUS-guided pancreatic cysts ablation, EUS-assisted radiotherapy, and EUS-guided celiac plexus neurolysis (EUS-CPN), etc. Recent innovative applications include contrast-enhanced EUS with Doppler mode, contrast-enhanced harmonic EUS, and EUS elastography. The clinical application of EUS in pancreatic diseases has been overviewed.

Post-operative liver failure is the deterioration of liver function following liver resection with high mortality. To assure safe liver treatment, accurate preoperative estimation of the functional reserve is crucial. Although the hepatic functional reserve is generally evaluated by the model for endstage liver disease (MELD) scores and Child-Pugh classification, their accuracy is unsatisfactory. In recent years, indocyanine green#136;ICG#137; excretion test is commonly used to examine the kinetics of liver function and possess considerable advantages. ICG, a near-infrared fluorophore, has high uptake and retention in liver. The distribution and elimination of ICG was measured using pulse dye densitometry by transcutaneous measurements, which is minimally invasive and automated. There are some studies concerning the clinical significance of the ICG excretion test showed that ICGR15 (indocyanine green retention rate at 15 minutes) is a sensitive indicator of liver function. The aims of this study were to compare the predictive value of ICG excretion test with Child- Pugh classification and MELD scores, and investigate the risk factors for hepatic insufficiency after treatment, which could provide more convenient and reliable method for evaluating liver functional reserve.