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Prabhu, Saurabh
Languages: English
Types: Doctoral thesis
Subjects: B230
Substituted indoles (2-arylindoles) and related structures are known to exhibit potent anti-cancer activity against human breast cancer cell lines, and a range of other therapeutic targets. This activity, and other factors such as their biological activity, the fact that they are privileged structures, and the presence of the indole nucleus in various commercial anti-cancer drugs led to the choosing of indoles for the current study as a starting point for the development of new treatments against glioma. Investigation began on determining the anti-cancer activity of a variety of indoles against glioma cell lines (1321N1 and U87MG) using a number of different cell-based assays and also to compare them with conventional anti-cancer drugs. The aim was to find potent anti-cancer compound(s), amongst the compounds tested, and by studying its preliminary structure-activity-relationships (SAR), try to determine how the active compound(s) may be exerting their effects.\ud The SAR screening was divided into two main groups: indoles without a 2-aryl group and indoles with a 2-aryl group. The most potent compound identified, and its analogues, were further tested on the non-cancerous SVGp12 cell line to check for specificity of these indoles towards cancer cells, wherein it was found that these compounds were not specific to any particular cell type. Furthermore, activity was also observed for the best lead compound in the glioblastoma short-term culture, IN859, in which it gave a relatively low micromolar IC50 value (400 μM).\ud The results indicated that the anti-cancer activity of these compounds started within 2 h and therefore it was speculated that the mechanism of action of these compounds might work through the generation of reactive oxygen species (ROS). A ROS-detection kit was used to demonstrate this hypothesis, a result which was later corroborated using flow cytometry, and also provided quantitative analysis of the amount of ROS generated. It was further hypothesised that in the cells studied, autophagy was mediated due to excessive ROS generation. This was also confirmed over a similar time course by quantifying the amount of fluorescence generated in the 1321N1 and U87MG cell lines when labelled with acridine orange (a dye used to detect the formation of autophagosomes during autophagy) using flow cytometry. Moreover, the use of an autophagy inhibitor, 3-methyladenine, was shown to inhibit autophagy in these cell lines, again validating this hypothesis.\ud In conclusion, it has been demonstrated that the ability of certain substituted privileged indoles possessing a 2-aryl group and having an attached –OH group to it may have a rapid, deleterious effect on the viability of a primary short term culture (IN859) and glioma cell lines (1321N1 and U87MG). The mechanism of action of these indoles to cause cell death may be via the generation of ROS, leading to cell death initiated by autophagy.\ud Another short separate study was also performed in order to investigate the anti-cancer activity of an anionic host defence peptide, Cn-AMP2, on the above mentioned cell lines. This peptide was found to exhibit a modest cytostatic effect on both the cell lines but at higher concentrations (> 1 mM) and only when the serum concentrations were weaned down from 10 % to 2.5 %.

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