Targeting SRC family kinases in lung cancer

Lung cancer is the commonest cancer killer worldwide. This is mainly due to the rapid development of drug resistance and early metastatic dissemination of the disease. SRC family kinases (SFKs) are frequently over-expressed in various cancers and have been implicated in tumorigenesis through their ability to promote cancer cell proliferation, survival and invasiveness. Therefore, we sought to evaluate the involvement of SFKs in lung cancer biology and assess the possible therapeutic benefits of their inhibition, either alone or in combination with additional treatments. We demonstrate that SRC family kinases are over-expressed and activated in-vitro in a panel of lung cancer cell lines as compared to immortalised normal lung epithelial cells. SRC, FYN and LYN are expressed in a high proportion of lung cancer but not normal lung tissue sections. Furthermore, enhanced expression of LYN correlates with poor patients’ survival. Dasatinib is a novel SRC/ABL inhibitor which effectively blocks SFKs activity at nanomolar concentrations. Dasatinib reduces cell numbers in 10 out of 11 NSCLC cell lines tested, which correlates with a strong inhibition of DNA synthesis and cell proliferation, while apoptosis is moderately enhanced only in a few cell lines. Interestingly, dasatinib potently induces autophagy in all NSCLC cell lines tested. This appears to be a pro-survival mechanism as autophagy inhibition using chemical compounds or siRNA-mediated depletion of ATG5 sensitises NSCLC cells to dasatinib through enhanced apoptosis. Lastly, our results indicate that SFKs have both overlapping and isoform-specific functions in NSCLC cell biology, as demonstrated by the effects of siRNA-mediated knockdown of SRC, YES, FYN or LYN. Our results suggest that inhibition of SRC family kinases alone or in combination with autophagy inhibitors may be a beneficial therapeutic strategy in the management of lung cancer patients

Targeting SRC family kinases in lung cancer

Lung cancer is the commonest cancer killer worldwide. This is mainly due to the rapid development of drug resistance and early metastatic dissemination of the disease. SRC family kinases (SFKs) are frequently over-expressed in various cancers and have been implicated in tumorigenesis through their ability to promote cancer cell proliferation, survival and invasiveness. Therefore, we sought to evaluate the involvement of SFKs in lung cancer biology and assess the possible therapeutic benefits of their inhibition, either alone or in combination with additional treatments. We demonstrate that SRC family kinases are over-expressed and activated in-vitro in a panel of lung cancer cell lines as compared to immortalised normal lung epithelial cells. SRC, FYN and LYN are expressed in a high proportion of lung cancer but not normal lung tissue sections. Furthermore, enhanced expression of LYN correlates with poor patients’ survival. Dasatinib is a novel SRC/ABL inhibitor which effectively blocks SFKs activity at nanomolar concentrations. Dasatinib reduces cell numbers in 10 out of 11 NSCLC cell lines tested, which correlates with a strong inhibition of DNA synthesis and cell proliferation, while apoptosis is moderately enhanced only in a few cell lines. Interestingly, dasatinib potently induces autophagy in all NSCLC cell lines tested. This appears to be a pro-survival mechanism as autophagy inhibition using chemical compounds or siRNA-mediated depletion of ATG5 sensitises NSCLC cells to dasatinib through enhanced apoptosis. Lastly, our results indicate that SFKs have both overlapping and isoform-specific functions in NSCLC cell biology, as demonstrated by the effects of siRNA-mediated knockdown of SRC, YES, FYN or LYN. Our results suggest that inhibition of SRC family kinases alone or in combination with autophagy inhibitors may be a beneficial therapeutic strategy in the management of lung cancer patients.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Anhydride-Cured Epoxy Powder Coatings from Natural-Origin Resins, Hardeners, and Fillers

Carbon-neutral policy and technological race on the powder coatings market force to develop more advanced, safer, cheaper, and naturally sourced products. To meet the market needs, powder coating compositions and coatings were prepared from safe and natural-origin hardeners, resins, and fillers prepared from rosin, bio-diols, bio-epichlorohydrin, and halloysite, to investigate their thermal, mechanical, and functional properties in comparison with petroleum-based references: cross-linking behavior, glass transition temperature, thermal stability, hardness, cupping resistance, adhesion, chemical resistance, gloss, color, and anti-corrosive behavior in salt chamber. As a result, compositions containing up to 83 wt.% of natural resources, and showing comparable or better properties, as compared to references, were successfully prepared. Their application includes binders for future ecological powder paints for demanding protection of steel substrates

Composition and Properties of Protective Coatings Made of Biologically-Derived Polyester Reactive Binder

Biologically derived polymers are a very attractive subject for investigation, due to the strict pro-ecological requirements imposed by developed countries, including zero-waste and zero-carbon policies as well as volatile organic compound (VOC) limits. Synthesis of biologically-derived polyesters from natural rosin and bio-diols, showing softening temperatures suitable for application in VOC-free paints and varnishes, was performed to create a desired, future commercial product, that meet the aforementioned requirements regarding VOC and elimination of petroleum-based raw materials. Prepared polymers were used in the formulation of coating materials whose properties: cross-linking behavior, glass transition temperature, thermal stability, storage modulus, hardness, cupping resistance, adhesion, chemical resistance, gloss, haze, color, and anti-corrosive behavior in the salt chamber were investigated and discussed. As a result, coatings with prepared bio-polyesters contained over 80 wt.% of natural resources and showed competitive/better properties than petroleum-based references. They can be applied in the prototyping of “green” powder paints for the protection of steel substrates from corrosion and aggressive solvents

Farby ochronne z surowców naturalnych : kompozycja i właściwości

Climate changes and increasing cost of non-renewable resources cause the growing interest in technical materials prepared from natural resources. To meet this interest, prototype paints from rosin and bio-diols derivatives, and also halloysite, were formulated to check their thermal, mechanical, visual and functional properties, as protective coatings of steel. Prepared materials contained ca. 75 wt % of natural resources and exhibited considerably better corrosion protection, thermal stability, and also higher glass transition temperatures and hardness, than a commercial petroleum-based reference sample. The other parameters: cross-linking behavior, color, gloss, cupping resistance, adhesion and chemical resistance were within the range that is acceptable for potential users.Zmiany klimatyczne i rosnące koszty surowców nieodnawialnych powodują zwiększenie zainteresowania materiałami o znaczeniu technicznym, otrzymywanymi z surowców pochodzenia naturalnego. Wychodząc naprzeciw temu zainteresowaniu, opracowano prototypowe farby z pochodnych kalafonii i bio-dioli oraz haloizytu w celu sprawdzenia ich właściwości termicznych, mechanicznych, wizualnych i funkcjonalnych, jako powłok ochronnych dla stali. Przygotowane materiały zawierały ok. 75% mas. surowców naturalnych i wykazywały znacznie lepszą ochronę przed korozją, stabilność termiczną, a także wyższe temperatury zeszklenia i twardość niż komercyjna próbka referencyjna otrzymana z surowców ropopochodnych. Pozostałe parametry: kinetyka sieciowania, kolor, połysk, tłoczność, adhezja i odporność chemiczna, mieściły się w akceptowalnym zakresie dla potencjalnych użytkowników

Isopropyl Amino Acid Esters Ionic Liquids as Vehicles for Non-Steroidal Anti-Inflammatory Drugs in Potential Topical Drug Delivery Systems with Antimicrobial Activity

New derivatives of non-steroidal anti-inflammatory drugs were synthesized via conjugation with L-amino acid isopropyl esters. The characteristics of the physicochemical properties of the obtained pharmaceutically active ionic liquids were determined. It has been shown how the incorporation of various L-amino acid esters as an ion pair affects the properties of the parent drug. Moreover, the antimicrobial activity of the obtained compounds was evaluated. The proposed structural modifications of commonly used drugs indicate great potential for use in topical and transdermal preparations

Novel Naproxen Salts with Increased Skin Permeability

The paper presents the synthesis, full identification, and characterization of new salts-L-proline alkyl ester naproxenates [ProOR][NAP], where R was a chain from ethyl to butyl (including isopropyl). All obtained compounds were characterized by Nuclear Magnetic Resonance (NMR), Fourier transform infrared spectroscopy (FTIR), X-ray powder diffractometry (XRD), and in vitro dissolution studies. The specific rotation, phase transition temperatures (melting point), and thermal stability were also determined. In addition, their lipophilicity, permeability, and accumulation in pigskin were determined. Finally, toxicity against mouse L929 fibroblast cells was tested. The obtained naproxen derivatives showed improved solubility and higher absorption of drug molecules by biological membranes. Their lipophilicity was lower and increased with the increase in the alkyl chain of the ester. The derivative with isopropyl ester had the best permeability through pigskin. The use of L-proline isopropyl ester naproxenate increased the permeation of naproxen through the skin almost four-fold. It was also shown that the increase in permeability is not associated with additional risk: all compounds had a similar effect on cell viability as the parent naproxen

Salicylic Acid as Ionic Liquid Formulation May Have Enhanced Potency to Treat Some Chronic Skin Diseases

In recent years, numerous studies have shown that conversion of conventional drugs in ionic liquid (IL) formulation could be a successful strategy to improve their physicochemical properties or suggest a new route of administration. We report the synthesis and detailed characterization of eight salicylic acid-based ILs (SA-ILs) containing cation non-polar or aromatic amino acid esters. Using in vitro assays, we preliminary evaluated the therapeutic potency of the novel SA-ILs. We observed that conversion of the SA into ionic liquids led to a decrease in its cytotoxicity toward NIH/3T3 murine embryo fibroblasts and human HaCaT keratinocytes. It should be mentioned is that all amino acid alkyl ester salicylates [AAOR][SA] inhibit the production of the proinflammatory cytokine IL-6 in LPS-stimulated keratinocytes. Moreover, keratinocytes, pretreated with [PheOMe][SA] and [PheOPr][SA] seem to be protected from LPS-induced inflammation. Finally, the novel compounds exhibit a similar binding affinity to bovine serum albumin (BSA) as the parent SA, suggesting a similar pharmacokinetic profile. These preliminary results indicate that SA-ILs, especially those with [PheOMe], [PheOPr], and [ValOiPr] cation, have the potential to be further investigated as novel topical agents for chronic skin diseases such as psoriasis and acne vulgaris

Transdermal Delivery Systems for Ibuprofen and Ibuprofen Modified with Amino Acids Alkyl Esters Based on Bacterial Cellulose

The potential of bacterial cellulose as a carrier for the transport of ibuprofen (a typical example of non-steroidal anti-inflammatory drugs) through the skin was investigated. Ibuprofen and its amino acid ester salts-loaded BC membranes were prepared through a simple methodology and characterized in terms of structure and morphology. Two salts of amino acid isopropyl esters were used in the research, namely L-valine isopropyl ester ibuprofenate ([ValOiPr][IBU]) and L-leucine isopropyl ester ibuprofenate ([LeuOiPr][IBU]). [LeuOiPr][IBU] is a new compound; therefore, it has been fully characterized and its identity confirmed. For all membranes obtained the surface morphology, tensile mechanical properties, active compound dissolution assays, and permeation and skin accumulation studies of API (active pharmaceutical ingredient) were determined. The obtained membranes were very homogeneous. In vitro diffusion studies with Franz cells were conducted using pig epidermal membranes, and showed that the incorporation of ibuprofen in BC membranes provided lower permeation rates to those obtained with amino acids ester salts of ibuprofen. This release profile together with the ease of application and the simple preparation and assembly of the drug-loaded membranes indicates the enormous potentialities of using BC membranes for transdermal application of ibuprofen in the form of amino acid ester salts