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Growth arrest-specific 6, also known as Gas6, is a human gene encoding the Gas6 protein, which was originally found to be upregulated in growth-arrested fibroblasts. Gas6 is a member of the vitamin K-dependent family of proteins expressed in many human tissues and regulates several biological processes in cells, including proliferation, survival and migration, by binding to its receptors Tyro3, Axl and Mer (TAM). In recent years, the roles of Gas6/TAM signalling in cancer cells and the tumour microenvironment have been studied, and some progress has made in targeted therapy, providing new potential directions for future investigations of cancer treatment. In this review, we introduce the Gas6 and TAM receptors and describe their involvement in different cancers and discuss the roles of Gas6 in cancer cells, the tumour microenvironment and metastasis. Finally, we introduce recent studies on Gas6/TAM targeting in cancer therapy, which will assist in the experimental design of future analyses and increase the potential use of Gas6 as a therapeutic target for cancer. [ABSTRACT FROM AUTHOR]

To investigate whether Portulaca oleracea extract affects tumor formation in colon cancer stem cells and its chemotherapy sensitivity. In addition, to analyze associated genetic changes within the Notch signal transduction pathway. Serum-free cultures of colon cancer cells (HT-29) and HT-29 cancer stem cells were treated with the chemotherapeutic drug 5-fluorouracil to assess sensitivity. Injections of the stem cells were also given to BALB/c mice to confirm tumor growth and note its characteristics. In addition, the effect of different concentrations of P. oleracea extract was tested on the growth of HT-29 colon cancer cells and HT-29 cancer stem cells, as determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide method. The effects of P. oleracea extract on the expression of β-catenin, Notch1, and Notch2 in the HT-29 cells were studied using reverse transcription polymerase chain reaction and Western blotting. The tumor volume of the HT29 cells was two times larger than that of HT29 cancer stem cells. Treatment with P. oleracea extract inhibited the proliferation of both HT-29 cancer cells and HT-29 cancer stem cells at doses from 0.07 to 2.25 µg/mL. Apoptosis of HT-29 cancer cells and HT-29 cancer stem cells was assessed by flow cytometry; it was enhanced by the addition of P. oleracea extract. Finally, treatment with P. oleracea extract significantly downregulated the expression of the Notch1 and β-catenin genes in both cell types. The results of this study show that P. oleracea extract inhibits the growth of colon cancer stem cells in a dose-dependent manner. Furthermore, it inhibits the expression of the Notch1 and β-catenin genes. Taken together, this suggests that it may elicit its effects through regulatory and target genes that mediate the Notch signal transduction pathway. [ABSTRACT FROM AUTHOR]

Summary In recent years, bioresponsive polymeric nanotherapeutics that facilitate tumor cell uptake and trigger drug release at the target site have emerged as a fascinating platform for safe and efficient cancer therapy. The naturally occurring environments such as tumor acidity, tumor extracellular enzymes like matrix metalloproteases (MMP), endo/lysosomal pH, elevated glutathione levels in the cytoplasm and cell nucleus, lysosomal enzymes, as well as reactive oxygen species (ROS) in the mitochondria have been exploited as potential internal stimuli to achieve active drug and protein release in the tumor tissue or cancer cells. These bioresponsive nanosystems present several unique features such as no need of an external device, precision control over site of response (from tumor tissue down to cellular organelle level) following accumulation in the tumor via either passive or active targeting, and spontaneous activation in the tumor site or inside the tumor cells. In this review, we highlight the design rationale and recent exciting development of bioresponsive polymeric nanotherapeutics for enhanced cancer treatments with low side effects. [ABSTRACT FROM AUTHOR]

Abstract: The clinical applications of protein drugs are restricted because of the absence of viable protein delivery vehicles. Here, we report on reduction- and pH--sensitive crosslinked polymersomes based on the poly(ethylene glycol)–poly(acrylic acid)–poly(2-(diethyl amino)ethyl methacrylate) (PEG–PAA–PDEA) triblock copolymer for efficient intracellular delivery of proteins and the potent induction of cancer cell apoptosis. PEG–PAA–PDEA (1.9–0.8–8.2kgmol−1) was synthesized by controlled reversible addition-fragmentation chain transfer polymerization and further modified with cysteamine to yield the thiol-containing PEG–PAA(SH)–PDEA copolymer. PEG–PAA(SH)–PDEA was water-soluble at acidic and physiological pH but formed robust and monodisperse polymersomes with an average size of ∼35nm upon increasing the pH to 7.8 or above followed by oxidative crosslinking. These disulfide-crosslinked polymersomes, while exhibiting excellent colloidal stability, were rapidly dissociated in response to 10mM glutathione at neutral or mildly acidic conditions. Notably, these polymersomes could efficiently load proteins like bovine serum albumin and cytochrome C (CC). The in vitro release studies revealed that protein release was fast and nearly quantitative under the intracellular-mimicking reducing environment. Confocal microscopy observations showed that these dual-sensitive polymersomes efficiently released fluorescein isothiocyanate-CC into MCF-7 cells in 6h. Most remarkably, MTT assays showed that CC-loaded dual-sensitive polymersomes induced potent cancer cell apoptosis, in which markedly decreased cell viabilities of 11.3%, 8.1% and 52.7% were observed for MCF-7, HeLa and 293T cells, respectively, at a CC dosage of 160μgml−1. In contrast, free CC caused no cell death under otherwise the same conditions. These dual-bioresponsive polymersomes have appeared as a multifunctional platform for active intracellular protein release. [Copyright &y& Elsevier]

Abstract: Objective: This study investigated the effects of rh-TRAIL with or without chemotherapeutic drugs on the apoptosis of the osteosarcoma cell line, MG-63, and the influence of chemotherapeutic drugs on changes in the expression of DR5 and Yin Yang1(YY1) in MG- 63 cells. Methods: The effects of treatment with rh-TRAIL alone and/or chemotherapeutic drugs on MG-63 cell growth inhibition and apoptosis were measured using the MTT assay, FACS analysis of Annexin V labeled cells, and the mRNA changes of DR5 and YY1 were detected by RT-PCR. Results: Rh-TRAIL protein inhibited the growth of MG-63 cells, and this inhibition was increased by adriamycin and IFN-γ. Adriamycin and IFN-γ significantly facilitated the induction of the expression of DR5 and reduced the expression of YY1. Conclusion: The apoptosis-inducing effect of rh-TRAIL in MG-63 cells was enhanced by chemotherapeutic drugs. [Copyright &y& Elsevier]

In order to elicit therapeutic effects, many drugs including small molecule anticancer drugs, proteins, siRNA, and DNA have to be delivered and released into the specific cellular compartments typically the cytoplasm or nucleus of target cells. Intracellular environment-responsive nanosystems that exhibit good extracellular stability while rapidly releasing drugs inside cancer cells have been actively pursued for effective cancer therapy. Here, we highlight novel designs of smart nanosystems that release drugs in response to an intracellular biological signal of cancer cells such as acidic pH in endo/lysosomal compartments, enzymes in lysosomes, and redox potential in cytoplasm and the cell nucleus. [Copyright &y& Elsevier]

Significance: The therapeutic effects of current micellar and vesicular drug formulations are restricted by slow and inefficient drug release at the pathological site. The development of smart polymeric nanocarriers that release drugs upon arriving at the target site has received a tremendous amount of attention for cancer therapy. Recent Advances: Taking advantage of a high reducing potential in the tumor tissues and in particular inside the tumor cells, various reduction-sensitive polymeric micelles and vesicles have been designed and explored for triggered anticancer drug release. These reduction-responsive nanosystems have demonstrated several unique features, such as good stability under physiological conditions, fast response to intracellular reducing environment, triggering drug release right in the cytosol and cell nucleus, and significantly improved antitumor activity, compared to traditional reduction-insensitive counterparts. Critical Issues: Although reduction-sensitive micelles and polymersomes have accomplished rapid intracellular drug release and enhanced in vitro antitumor effect, their fate inside the cells including the mechanism, site, and rate of reduction reaction remains unclear. Moreover, the systemic fate and performance of reduction-sensitive polymeric drug formulations have to be investigated. Future Directions: Biophysical studies should be carried out to gain insight into the degradation and drug release behaviors of reduction-responsive nanocarriers inside the tumor cells. Furthermore, novel ligand-decorated reduction-sensitive nanoparticulate drug formulations should be designed and explored for targeted cancer therapy in vivo. Antioxid. Redox Signal. 21, 755-767. [ABSTRACT FROM AUTHOR]

The therapeutic performance of biodegradablemicellar drugs isfar from optimal due to existing challenges like poor tumor cell uptakeand intracellular drug release. Here, we report on ligand-directedreduction-sensitive shell-sheddable biodegradable micelles based onpoly(ethylene glycol)-poly(ε-caprolactone) (PEG-PCL) copolymeractively delivering doxorubicin (DOX) into the nuclei of target cancercells, inducing superb in vitro antitumor effects. The micelles wereconstructed from PEG-SS-PCL and galactose-PEG-PCL (Gal-PEG-PCL) blockcopolymers, in which Gal-PEG-PCL was designed with a longer PEG thanthat in PEG-SS-PCL (6.0 vs 5.0 kDa) to fully expose Gal ligands ontothe surface of micelles for effective targeting to hepatocellularcarcinoma cells. PEG-SS-PCL combining with 10 or 20 wt % of Gal-PEG-PCLformed uniform micelles with average sizes of 56.1 and 58.2 nm (denotedas PEG-SS-PCL/Gal10 and PEG-SS-PCL/Gal20, respectively). The in vitrorelease studies showed that about 81.1 and 75.0% DOX was releasedin 12 h from PEG-SS-PCL/Gal10 and PEG-SS-PCL/Gal20 micelles undera reducing condition containing 10 mM dithiothreitol (DTT). In contrast,minimal DOX release (<12%) was observed for PEG-SS-PCL/Gal10 andPEG-SS-PCL/Gal20 micelles under nonreducing conditions as well asfor reduction-insensitive Gal-PEG-PCL and PEG-PCL/Gal20 micelles inthe presence of 10 mM DTT. MTT assays in HeLa and HepG2 cells showedthat DOX-loaded PEG-SS-PCL/Gal20 micelles exhibited apparent targetabilityand significantly enhanced antitumor efficacy toward asialoglycoproteinreceptor (ASGP-R)-overexpressing HepG2 cells with a particularly lowhalf maximal inhibitory concentration (IC50) of 1.58 μgDOX equiv/mL, which was comparable to free DOX and approximately sixtimes lower than that for nontargeting PEG-SS-PCL counterparts underotherwise the same conditions. Interestingly, confocal microscopyobservations using FITC-labeled PEG-SS-PCL/Gal20 micelles showed thatDOX was efficiently delivered and released into the nuclei of HepG2cells in 8 h. Flow cytometry revealed that cellular DOX level in HepG2cells treated with DOX-loaded PEG-SS-PCL/Gal20 micelles was much greaterthan that with reduction-insensitive PEG-PCL/Gal20 and nontargetingPEG-SS-PCL controls, signifying the importance of combining shell-sheddingand active targeting. Ligand-directed, reduction-sensitive, shell-sheddable,and biodegradable micelles have emerged as a versatile and potentplatform for targeted cancer chemotherapy. [ABSTRACT FROM AUTHOR]