Inhaltszusammenfassung

Curcumin has been shown to be active against various cancers and it has also been seen to exhibit good synergism with other nutraceutical for example resveratrol, piperine and genistein. In this study we have investigated nineteen new synthetic derivatives of curcumin for their anticancer activity and further assessed the effect on cancer cells of a combination of curcumin and ascorbic acid (AA). The first part of this work focused on overcoming multidrug resistance and the nineteen syntheti...Curcumin has been shown to be active against various cancers and it has also been seen to exhibit good synergism with other nutraceutical for example resveratrol, piperine and genistein. In this study we have investigated nineteen new synthetic derivatives of curcumin for their anticancer activity and further assessed the effect on cancer cells of a combination of curcumin and ascorbic acid (AA). The first part of this work focused on overcoming multidrug resistance and the nineteen synthetic derivatives of curcumin were tested on acute lymphoblastic CCRF-CEM leukemia cells and the P-gp overexpressing subline CEM/ADR5000. The cytotoxicity of the new synthetic derivatives was established using the resazurin assay. Ability to inhibit P-gp function was also assessed by the doxorubicin uptake assay and in silico studies of the same have been carried out using molecular docking tools and QSAR studies. The compounds displayed varied levels of cytotoxicity with some of them exhibiting lower IC50 values in comparison to the parent compound curcumin. The new synthetic derivatives also showed ability to inhibit P-gp function of extrusion of doxorubicin from the cells and some of them inhibited P-gp better than the control drug verapamil. These derivatives can be used to design novel and better P-gp inhibitors. The second part of our study focused on the cytotoxic effect of a combination of curcumin with AA on varied cancer cell lines. Here we carried out the chemoprofiling of three different members of the curcuma species and observed that curcumin was present in all curcuma species while AA was only available in C. longa. The combination of curcumin and AA was tested for cytotoxicity on human cancer cell lines including CCRF-CEM and CEM/ADR5000 leukemia, HCT116p53+/+ and HCT116p53-/- colon cancer, and U87MG and U87MG.∆EGRF glioblastoma. The drug combination exhibited additive cytotoxicity in leukemia and colon cancer cell lines while in the glioblastoma cell lines additive to supra additive cytotoxicity was recorded. Further we assessed the pharmacogenomics of curcumin and AA by microarray- based mRNA expression, COMPARE analysis and hierarchical cluster analysis. Gene profiles were obtained and they were used to predict sensitivity and resistance of the tumor cells to curcumin and AA. From these gene profiles we also established the gene functions that our compounds affected by assessing up and down regulation patterns as exhibited by the color coded heat map analysis. Both curcumin and AA affected varied groups of genes and varied functions in the cell lines. The pharmacogenomics results further supports the cytotoxicity results of additive effects.» weiterlesen» einklappen

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DDC Sachgruppe:
Naturwissenschaften