INVESTIGATION OF SOME MOLECULAR MECHANISMS OF CYTOTOXIC 1,5-DIARYL-3-OXO-1,4-PENTADIENES

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Date
2012-08-31Author
Helal, Muath
Type
ThesisDegree Level
MastersMetadata
Show full item recordAbstract
Glutathione S-transferase GSTπ has been one of the significant targets for cancer treatment in the
past several years. The reason behind that is 1) its overexpression in some cancer cells compared
to normal ones 2) its ability to cause resistance against cancer chemotherapeutics and 3) its
protective role against reactive oxygen species (ROS). We have synthesized a large number of
compounds which have strong potency against different cancer cell lines. These compounds
possess a 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore. In the present study some
investigations as to the way in which cytotoxicity is mediated was undertaken. Our results have
demonstrated that the analogs NC 2067 and NC 2081 behaved as substrates for GSTπ and
reduced the level of GSH. This was apparent by the decrease in the concentrations of both
compounds after the addition of GSTπ and GSH. In addition, both agents caused about 3-7 folds
increase in ROS levels. The dichlorodihydrofluorescein dye was used for this purpose due to its fluorescence characteristic after being oxidized by ROS. High levels of these species cause a
drop in the mitochondrial membrane potential. This phenomenon was detected when the monomeric form of JC-1 levels were increased after treatment. The reduction of 2-3 folds was
seen when the cells were treated with the IC₅₀ values of both compounds. In addition, both
agents inhibited oxygen consumption implicating their ability to inhibit oxidative
phosphorylation. We also evaluated the effect of both agents on mitochondrial swelling. NC
2081 caused swelling using concentrations of 10 μM and 50 μM. This was apparent when the
absorption of an isolated rat liver mitochondrial solution decreased after the addition of the
compound. The addition of the higher concentration caused about 2 fold greater effect than the
lower one. On the other hand, compound NC 2067 produced minimal swelling only at a
concentration of 50 μM.
Degree
Master of Science (M.Sc.)Department
Pharmacy and NutritionProgram
PharmacySupervisor
Dimmock, Jonathan; Nazarali, AdilCommittee
Alcorn, Jane; Bandy, BrianCopyright Date
July 2012Subject
Glutathione S-transferase, Glutathione, Mitochondria, Mitochondrial membrane potential, Reactive oxygen species.