Frenzel A, Zirath H, Vita M, Albihn A, Henriksson MA. "PLoS One. 2011"
Expression of MYC is deregulated inside a wide range of human cancers, and it is normally associated with aggressive illness and poorly differentiated tumor cells. Identification of compounds with selectivity for cells overexpressing MYC would therefore be advantageous for that therapy of those tumors.
For this goal we used cell lines with conditional MYCN or c-MYC expression, to screen a library of eighty standard cytotoxic compounds for their ability to minimize tumor cell viability and/or development in a MYC dependent way.
We discovered that 25% from the researched compounds induced apoptosis and/or inhibited proliferation in a MYC-specific method. The activities of the majority of those had been improved both by c-MYC or MYCN over-expression.
Interestingly, these compounds were acting on unique mobile targets, including microtubules (paclitaxel, podophyllotoxin, vinblastine) and topoisomerases (10-hydroxycamptothecin, camptothecin, daunorubicin, doxorubicin, etoposide) also as DNA, RNA and protein synthesis and turnover (anisomycin, aphidicholin, gliotoxin, MG132, methotrexate, mitomycin C).
Our data show that MYC overexpression sensitizes cells to disruption of precise pathways and that in most cases c-MYC and MYCN overexpression have similar results within the responses to cytotoxic compounds.
Treatment from the cells with topoisomerase I inhibitors led to down-regulation of MYC protein levels, when doxorubicin and also the small molecule MYRA-A was located to disrupt MYC-Max interaction.
We conclude the MYC pathway is simply specific by a subset of standard cytotoxic medications at the moment made use of inside the clinic. Elucidating the mechanisms underlying their specificity in direction of MYC might be of value for optimizing remedy of tumors with MYC deregulation.
Our data also underscores that MYC is an desirable target for novel therapies and that mobile screenings of Compound Libraries is usually a strong tool for figuring out compounds with a desired biological activity.
2012年1月4日星期三
Polymers for siRNA Delivery
Wagner E. "Acc Chem Res. 2011 Dec"
Synthetic small interfering RNA (siRNA). offers an exciting novel health-related chance. Though scientists consent that siRNA could have an awesome therapeutic impact, the needed extracellular and intracellular delivery of these molecules in to the disease-associated target cells offers the main roadblock for the broader translation of these molecules into medicines. Therefore, the style of adequate delivery technologies has utmost importance.
Viruses are natural masterpieces of nucleic acid delivery and current chemists and drug delivery specialists having a template for your design of synthetic carriers for synthetic nucleic acids for instance siRNA. They've been developed into gene vectors and have provided convincing successes in gene treatment.
Optimized by biological evolution, viruses are programmed to be dynamic and bioresponsive as they enter residing cells, and they carry out their features in a precisely defined sequence. However, since they are synthesized inside living cells and with in a natural way offered nucleotides and amino acids, the chemistry of viruses is limited.
With the use of diverse synthetic molecules and macromolecules, chemists can provide delivery remedies past the scope in the natural evolution of viruses. This Account describes the style and synthesis of "synthetic siRNA viruses."
These structures contain components that mimic the delivery features of viral particles and surface area domains that shield in opposition to undesired biological interactions and allow specific host cell receptor binding through the presentation of a number of concentrating on ligands. For example, cationic polymers can reversibly bundle one or a lot more siRNA molecules into nanoparticle cores to guard them against a degradative bioenvironment.
After internalization by receptor-mediated endocytosis to the acidifying endosomes of cells, artificial siRNA can escape from these vesicles by way of the activation of membrane-disruption domains as viruses do and attain the cytoplasm, the location of RNA interference. This multistep process presents an attractive problem for chemists.
Similar for the design of prodrugs, the functional domains of these methods need to be activated within a dynamic mode, triggered by conformational adjustments or bond cleavages in the related microenvironment such as the acidic endosome or disulfide-reducing cytoplasm. These chemical analogues of viral domains are usually synthetically easier and a lot more very easily available molecules than viral proteins.
Their exact assembly into multifunctional macromolecular and supramolecular structures is facilitated by enhanced analytical tactics, precise orthogonal conjugation chemistries, and sequence-defined polymer syntheses.
The chemical evolution of microdomains working with chemical libraries. and macromolecular and supramolecular evolution could give crucial strategies for optimizing siRNA carriers to chosen medical indications.
Synthetic small interfering RNA (siRNA). offers an exciting novel health-related chance. Though scientists consent that siRNA could have an awesome therapeutic impact, the needed extracellular and intracellular delivery of these molecules in to the disease-associated target cells offers the main roadblock for the broader translation of these molecules into medicines. Therefore, the style of adequate delivery technologies has utmost importance.
Viruses are natural masterpieces of nucleic acid delivery and current chemists and drug delivery specialists having a template for your design of synthetic carriers for synthetic nucleic acids for instance siRNA. They've been developed into gene vectors and have provided convincing successes in gene treatment.
Optimized by biological evolution, viruses are programmed to be dynamic and bioresponsive as they enter residing cells, and they carry out their features in a precisely defined sequence. However, since they are synthesized inside living cells and with in a natural way offered nucleotides and amino acids, the chemistry of viruses is limited.
With the use of diverse synthetic molecules and macromolecules, chemists can provide delivery remedies past the scope in the natural evolution of viruses. This Account describes the style and synthesis of "synthetic siRNA viruses."
These structures contain components that mimic the delivery features of viral particles and surface area domains that shield in opposition to undesired biological interactions and allow specific host cell receptor binding through the presentation of a number of concentrating on ligands. For example, cationic polymers can reversibly bundle one or a lot more siRNA molecules into nanoparticle cores to guard them against a degradative bioenvironment.
After internalization by receptor-mediated endocytosis to the acidifying endosomes of cells, artificial siRNA can escape from these vesicles by way of the activation of membrane-disruption domains as viruses do and attain the cytoplasm, the location of RNA interference. This multistep process presents an attractive problem for chemists.
Similar for the design of prodrugs, the functional domains of these methods need to be activated within a dynamic mode, triggered by conformational adjustments or bond cleavages in the related microenvironment such as the acidic endosome or disulfide-reducing cytoplasm. These chemical analogues of viral domains are usually synthetically easier and a lot more very easily available molecules than viral proteins.
Their exact assembly into multifunctional macromolecular and supramolecular structures is facilitated by enhanced analytical tactics, precise orthogonal conjugation chemistries, and sequence-defined polymer syntheses.
The chemical evolution of microdomains working with chemical libraries. and macromolecular and supramolecular evolution could give crucial strategies for optimizing siRNA carriers to chosen medical indications.
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