Application of microfluidic chips in anticancer drug screening

With the continuous development of drug screening technology, new screening methodologies and technologies are constantly emerging, driving drug screening into rapid, efficient and high-throughput development. Microfluidics is a rising star in the development of innovative approaches in drug discovery. In this article, we summarize the recent years' progress of microfluidic chip technology in drug screening, including the developmental history, structural design, and applications in different aspects of microfluidic chips on drug screening. Herein, the existing microfluidic chip screening platforms are summarized from four aspects: chip structure design, sample injection and drive system, cell culture technology on a chip, and efficient remote detection technology. Furthermore, this review discusses the application and developmental prospects of using microfluidic chips in drug screening, particularly in screening natural product anticancer drugs based on chemical properties, pharmacological effects, and drug cytotoxicity.Peer reviewe

In Vivo Radioprotective Potential of Newly Synthesized Azomethine and Styrylquinoline Derivatives and a Natural Polyphenol: A Preliminary Study

The aim of the present study was to investigate the radioprotective activity of silymarin, a plant substance with hepatoprotective activity, of four newly synthesized structural derivatives of anthranilic acid azomethines, and alkyl-2-styrylquinolinic acid, as well as to establish and assess the influence of the solvent type and bioactive compound dose on the in vivo radioprotective potential of the natural and novel synthetic compounds. Male Wistar strain rats weighing 110–120 g were used for the in vivo experiments. Fifteen minutes after i.p. injection of the compounds, the experimental animals were irradiated by 8 Gy. Results indicate that the compound 2-{[(3,5-dihydro-2-hydroxyphenyl)methylen] amino}-benzoic acid in a dose of 60 mg/kg body weight exhibited the highest radioprotective effect, whereas the natural extract silymarin did not manifest radioprotective potential, even in high doses

Organic dyes in contemporary medicinal chemistry and biomedicine. I. From the chromophore to the bioimaging/bioassay agent

AbstractThe present review was provoked by the demand of a comprehensive overview on the recent scientific achievements revealing new horizons for advanced applications of organic dyes in service of contemporary medicinal chemistry, pharmacy and biomedicine. The review outlines the basic structural characteristics, physicochemical properties and biological activity of various dye families and suggests modified classifications of dyes according to their structural moieties and bioorganic functionalities serving the necessities of modern analytical chemistry and biochemistry. A major part of the review focuses on the pros and cons of the use of dyes as vectors in bioanalytic assays. The latter is based on comparative analyses of the limitations of some widely applied classical methodologies vs. the advantages and outcomes of the application of newly-designed dye molecules in modern dye-based bioassay techniques

Inhibition of the Pentose-phosphate Pathway Selectively Sensitizes Leukemia Lymphocytes to Chemotherapeutics by ROS-independent Mechanism.

The aim of the present study was to investigate: (i) the possibility of sensitizing leukemia lymphocytes to anticancer drugs by inhibiting pentose-phosphate pathway using 6-aminonicotinamide (6-ANA); (ii) to find combinations with synergistic cytotoxic effect on leukemia lymphocytes and to investigate their cytotoxicity towards normal lymphocytes; (iii) and to clarify the role of reactive oxygen species (ROS) in the induction of apoptosis by those combinations. The study covers 15 anticancer drugs - conventional and new-generation. The experiments were performed on Jurkat leukemia cell line and normal lymphocytes, isolated from clinically healthy blood donors. Four parameters were analyzed simultaneously in both cell suspensions treated by drug or 6-ANA (separately, and in combination): cell viability, induction of apoptosis, level of ROS, and level of protein-carbonyl products. Most combinations of drug plus 6-ANA were characterized by synergistic cytotoxic effects on Jurkat cells. The synergism increased with increasing incubation time. Upon combination of 6-ANA with conventional chemotherapeutic (e.g. doxorubicin), synergistic cytotoxic effects were also detected in normal lymphocytes. In both cell types, the cytotoxicity of the combination of doxorubicin plus 6-ANA was accompanied by increased induction of apoptosis, but by a slight reduction of ROS and protein-carbonyl products compared to cells treated with doxorubicin only. Upon combination of 6-ANA with new-generation anticancer drugs (e.g. everolimus or barasertib), the synergistic cytotoxic effect on leukemia lymphocytes was also accompanied by very strong induction of apoptosis through ROS-independent mechanism(s). Neither of these combinations exhibited any cytotoxicity towards normal lymphocytes. The data suggest that 6-ANA could be used as a supplementary component in anticancer chemotherapy, and would allows therapeutic doses of anticancer drugs to be reduced, thereby minimizing their side-effects

2-Deoxy-D-glucose Sensitizes Cancer Cells to Barasertib and Everolimus by ROS-independent Mechanism(s).

The aim of the present study was to investigate: (i) the possibility of sensitizing cancer cells to anticancer drugs using the redox modulator 2-deoxy-D-glucose (2-DDG); (ii) to find such combinations with synergistic cytotoxic effect; (iii) and to clarify the role of reactive oxygen species (ROS) for induction of apoptosis and cytotoxicity through these combinations. The study covers 15 anticancer drugs - both conventional and new-generation. Four parameters were analyzed simultaneously in Jurkat leukemia cells, treated by drugs or 2-DDG (separately or in combination): cell viability, induction of apoptosis, levels of ROS, and level of protein-carbonyl products. Very well-expressed synergistic cytotoxic effects were found after 48-h treatment of Jurkat cells with 2-DDG in combination with: palbociclib, everolimus, lonafarnib, bortezomib, and barasertib. The synergistic cytotoxic effect of everolimus with 2-DDG was accompanied by very strong induction of apoptosis in cells, but a very strong reduction of ROS level. Changes in the levels of protein-carbonyl products were not detected. The synergistic cytotoxic effect of barasertib with 2-DDG was accompanied by very strong induction of apoptosis in cells, without any increase of ROS levels, but with an enhancement of protein-carbonyl products

Resveratrol Modulates the Redox-status and Cytotoxicity of Anticancer Drugs by Sensitizing Leukemic Lymphocytes and Protecting Normal Lymphocytes

Aim: The study is directed to the effect of resveratrol on the redox-status and viability of leukemic and normal lymphocytes, as well as its ability to sensitize leukemic lymphocytes to anticancer drugs. Materials and Methods: Cytotoxicity was analyzed by trypan blue staining, apoptosis – by Annexin V test, and oxidative stress – by the intracellular levels of reactive oxygen species (ROS) and protein-carbonyl products. Results: Incubation of resveratrol in combination with the majority of anticancer drugs resulted in higher toxicity than resveratrol or drug alone. In the case of leukemic lymphocytes treated with barasertib and everolimus in the presence of resveratrol, synergistic cytotoxicity was accompanied by strong induction of apoptosis, increased levels of hydroperoxides and insignificant changes in protein-carbonyl products. None of these parameters changed in normal lymphocytes. Conclusion: Resveratrol is a promising supplementary compound for anticancer therapy, that may allow reduction of the therapeutic doses of barasertib and everolimus, minimizing their side-effects

Synergistic Cytotoxicity of Melatonin and New-generation Anticancer Drugs Against Leukemia Lymphocytes But Not Normal Lymphocytes.

The present study demonstrates specific sensitization of leukemia lymphocytes towards anticancer drugs using melatonin and clarifies the role of reactive oxygen species (ROS) for induction of apoptosis. The study covers four conventional and 11 new-generation anticancer drugs. Four parameters were analyzed simultaneously in leukemia and normal lymphocytes treated with drug, melatonin, or their combination: cell viability, induction of apoptosis, level of reactive oxygen species (ROS), and level of protein-carbonyl products. Almost all investigated combinations of melatonin with new-generation anticancer drugs were characterized by synergistic cytotoxicity towards leukemia lymphocytes, while the combinations with conventional drugs exhibited additive or antagonistic effects on cell viability. In leukemia lymphocytes, the additive cytotoxicity of doxorubicin plus melatonin was accompanied by low levels of ROS and protein-carbonyl products, as well as by suppression of apoptosis. In normal lymphocytes, none of the studied parameters changed significantly compared to cells treated with doxorubicin only. The combinations of everolimus plus melatonin and barasertib plus melatonin exhibited impressive synergistic cytotoxic effects on leukemia lymphocytes but did not affect the viability of normal lymphocytes. In leukemia cells, the synergistic cytotoxicity was accompanied by strong induction of apoptosis but a decrease of ROS to a level below that of the control. In normal lymphocytes, these combinations did not affect the level of ROS nor of protein-carbonyl products, and did not induce apoptosis. The data suggest that melatonin is a promising supplementary component in chemotherapy which allows the therapeutic doses of anticancer drugs to be reduced, minimizing their side-effects