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Research and Reviews: A Journal of Pharmacology

Mechanistic Studies on Aziridinyl-Benzoquinones in Cultured Tumour Cells

  1. Fatma M. Ben Rabha
  2. Mabruka S. Elashheb
  3. Samia A. Hassan
  4. Lamees A. Ben Saad
  5. 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.

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