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Mechanistic Studies on Aziridinyl-Benzoquinones in Cultured Tumour Cells

Fatma M. Ben Rabha, Mabruka S. Elashheb, Samia A. Hassan, Lamees A. Ben Saad, Mahmud H. Arhima

Abstract


This study compares the anti-tumour effects of NQO1 activated drug RH1 (2, 5-diaziridinyl-3 - hydoxymethyl-6-methyl-1, 4-benzoquinone) with a lipophilic ester derivative Es5 on the isogenic cell lines MDA 468 and MDA 468 NQO1 which differs only in expression of wtNQO1. A 39- fold enhancement of growth inhibitory activity was seen in NQO1 expressing cells compared the NQO1 null cells for the Es5 compared to the 25- fold increase seen for the parent drug, RH1. The kinetics of cell cycle arrest, apoptosis are different in the NQO1 expressing and null cell lines. This indicates a different mechanism of activations and/ or activity for these agents in the presence of active NQO1 protein. We show that Es5 has a higher partition coefficient than RH1 which may enable Es5 to enter the brain. Following cleavage of the ester group Es5 produces a quinone whose cytoxicity profile is comparable to RH1.

Keywords


anti-tumour, lipophilic, cytoxicity, inhibitory, ester group

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References


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