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Yesterday, 18 Ιουλίου 2016, 8:33:27 πμ
Targeting AMPK Signaling Pathway to Overcome Drug Resistance for Cancer Therapy
Yesterday, 18 Ιουλίου 2016, 8:33:31 πμ
Mulitdrug resistance (MDR) is one of critical factorslimiting the efficacy of cancer chemoor radiotherapy. Emerging evidence has indicated that MDR is a complex process regulated by multiple factors, among which stress response molecules are considered as central players. AMP-activated protein kinase (AMPK) is a major regulator balancing energy supply and ultimately protects cells from harmful stresses via coordinating multiple metabolic pathways Notably, AMPK activation was recently shown to mediate the metabolism reprogramming in drug resistant cancer cells including promoting Warburg effects and mitochondrial biogenesis. Furthermore, AMPK activity has also been shown to regulate the self-renewal ability of cancer stem cells that are often refractory to chemotherapy. In addition, AMPK phosphorylation was critical in mediating autophagy induction, a process demonstrated to be effective in chemosensitivity modulation via degrading cellular components to satisfy nutrients requirement under stressful condition. Meanwhile, drug discovery targeting AMPK has been developed to validate the pathological significance of AMPK in cancer prevention and treatment. Although conflicting evidence focusing on the AMPK modulation for cancer treatment is still remained, this might be attributed to differences in AMPK isotypes in specific tissues, off-targets effects, the degree and duration of drug administration and experimental setting of stress conditions. This review will focus on AMPK mediated resistance to cancer therapy and discuss its potential therapeutic implication and targeting drug development.
The Roles of Chromatin Remodeling Proteins in Cancer
Yesterday, 18 Ιουλίου 2016, 8:33:31 πμ
Chromatin remodeling complexes (chromatin remodelers) have been demonstrated as essential and powerful regulators for critical DNA-templated cellular processes, such as DNA replication, recombination, gene transcription/repression, and DNA damage repair. These molecular and genetic processes are important for a wide spectrum of cellular functions including, cell cycle, death, differentiation, pluripotency, and genome integrity. Not surprisingly, dysfunctions of chromatin remodeling proteins are observed in human developmental disorders and diseases. Specifically for human malignancies, genomic sequence analyses show that mutations and other genetic alternations of chromatin remodelers exist in almost all human tumor types. Using human cancer cell lines, xenograft models and genetically engineered mouse models, functions of chromatin remodelers in human cancers have been studied extensively in the last 10-15 years. In this review, we summarize the functional and mechanistic studies of chromatin remodelers in the initiation, progression and metastasis of human cancers.
Lipid Nanoparticles to Deliver miRNA in Cancer
Yesterday, 18 Ιουλίου 2016, 8:33:31 πμ
MicroRNAs (miRNAs) are a class of post-transcriptional gene expression modulators. In the past two decades, over 1500 human miRNAs were discovered. These small non-coding RNAs regulate various biological processes, including cell growth, proliferation, differentiation, and cell death. Thus, miRNAs have been proposed as new therapeutical agents in different multifactorial diseases such as cancer. Since miRNAs therapies represent a great promise, many research studies have been focused on the development of delivery strategies to overcome miRNAs biopharmaceutical issues. Lipid delivery systems are undoubtedly the non-viral carriers most largely investigated due to their biocompatibility, biodegradability, easy production, low toxicity and immunogenicity, possibility to easily modify the carriers for targeting strategies. In this mini-review we provide a rapid and updated overview on the lipid delivery system currently used to deliver miRNAs, pointing out the progresses achieved in the optimization of these nanovectors, which led up to the first clinical trial.
Development of Anti-CD20 Antigen-Targeting Therapies for B-cell Lymphoproliferative Malignancies - The State of the Art
Παρασκευή, 15 Ιουλίου 2016, 9:19:00 πμ
For decades, the available anticancer therapies were mostly based on nonspecific cytotoxic regimens. These cytostatic combinations, while effective in some subpopulations of patients, are often limited by extensive toxicity and/or development of tumor resistance. Although standard chemotherapy still remains a common therapeutic tool in the fight with cancer, immunotherapy increasingly revolutionizes treatment strategy for several hematologic malignancies. For a subset of patients with B-cell lymphoproliferative disease, the introduction of subsequently developed classes of anti-CD20 monoclonal antibodies (mAbs) has resulted in improved overall response rates and, to some extent, patient overall survival. Rituximab, the most thoroughly-explored chimeric mouse anti-human anti-CD20 mAb, has been widely and successfully introduced to oncohematology, but also to other fields of medicine, such as transfusiology or rheumatology. Currently, several new generation anti-CD20 mAbs are undergoing different stages of preclinical and clinical studies of assessment to further improve the outcome and overcome mechanisms of resistance. The nature of the direct mechanisms responsible for the anticancer properties of different classes of anti-CD20 mAbs is still not fully understood. This is reflected in different approaches during the investigation of novel anti-CD20 agents. So far, three classes of anti- CD20 mAb have been described. In this review, we focus on CD20 antigen-targeting therapies both currently available and undergoing preclinical or clinical investigation for B-cell lymphoproliferative malignancies.
Role of the Receptor Tyrosine Kinase Axl and its Targeting in Cancer Cells
Πέμπτη, 14 Ιουλίου 2016, 8:56:05 πμ
Aberrant expression and activation of receptor tyrosine kinases (RTK) is a frequent feature of tumor cells that may underlie tumor aggressiveness. Among RTK, Axl, a member of the Tyro3-Axl-Mer family, represents a potential therapeutic target in different tumor types given its over-expression which leads to activation of oncogenic signaling promoting cell proliferation and survival, as well as migration and invasion. Axl can promote aggressiveness of various cell types through PI3K/Akt and/or MAPK/ERK, and its expression can be transcriptionally regulated by multiple factors. Deregulated Axl expression and activation have been shown to be implicated in reduced sensitivity of tumor cells to target-specific and conventional antitumor agents, but the precise mechanism underlying these phenomena are still poorly understood. Several small molecules acting as Axl inhibitors have been reported, and some of them are undergoing clinical investigation. In this review, we describe Axl biological functions, its expression in cancer and in drug-resistant tumor cells and the development of inhibitors tailored to this receptor tyrosine kinase.
Peptides to Target Tumor Vasculature and Lymphatics for Improved Anti-Angiogenesis Therapy
Πέμπτη, 14 Ιουλίου 2016, 8:56:05 πμ
Cancer has become one of the leading causes of increased mortality. The currently employed diagnostic and therapeutic modality offers only minimal specificity towards cancerous cells and affects normal healthy cells. Targeted drug delivery systems have shown an improved efficiency in the diagnosis and treatment of various cancers, as the targeted molecules specifically reach the tumor cells without exerting any undesirable effects on the normal healthy cells. Recent findings have shown that disruption of blood vasculature and lymphatics is efficient in treating various cancers. As these vessels supply nutrient and oxygen, remove wastes and help in the metastasis; therapeutic agents targeting them will be highly useful. Of the various ligands used for targeting blood vasculature and lymphatics, peptides possess great advantage over other molecules. This review article is aimed at focusing the recent findings and developments on the peptides as targeting ligands for the improved anti-angiogenesis therapy.
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