Mechanistic Studies on Aziridinyl-Benzoquinones in Cultured Tumour Cells

Authors

  • Fatma M. Ben Rabha Associate Professor Department of Pharmacology, Faculty of Medicine, University of Tripoli, Tripoli, Libya
  • Mabruka S. Elashheb Associate Professor Department of Pharmacology, Faculty of Medicine, University of Tripoli, Tripoli, Libya
  • Samia A. Hassan Assistant Professor, Department of Pharmacology, Faculty of Medicine, University of Tripoli, Tripoli, Libya
  • Lamees A. Ben Saad Assistant Professor, Department of Pharmacology, Faculty of Medicine, University of Tripoli, Tripoli, Libya
  • Mahmud H. Arhima Associate Professor Department of Pharmacology, Faculty of Medicine, University of Tripoli, Tripoli, Libya

Keywords:

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

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.

References

Winski SL, Hargreaves RH, Butler J, Ross DA. (1998). A new screening system for NAD(P)H:quinone oxidoreductase (NQO1)-directed antitumor quinones: Identification of a new aziridinylbenzoquinone, RH1, as a NQO1-directed antitumor agent. Clinical Cancer Research, 4 (12): 3083-3088.

Winski SL, Swann E, Hargreaves RH, Dehn DL, Butler J, Moody CJ, Ross, D. 2001. Relationship between NAD (P) H: quinone oxidoreductase 1 (NQO1) levels in a series of stably transfected cell lines and susceptibility to antitumor quinones. Biochemical Pharmacology. 61(12), 1509-1516.

Danson S, Ward TH, Butler J, Ranson M. 2004. DT-diaphorase: a target for new anticancer drugs. Cancer Treatment Reviews. 30(5): 437-449.

Abraham I, Joshi R, Pardasani P, Pardasani RT. 2011. Recent advances in 1,4- benzoquinone chemistry. Journal of the Brazillian chemical Socity. J, Braz, Chem. Soc, 22(3):385-421.

Danson SJ, Johnson P, Ward TH, Halbert G, Dive C, Ranson M. 2011. Phase l pharmacokinetic and pharmacodynamic study of bioreductive drug RH1 Annals of Oncology, 22(7), 1653-1660.

Vale Miliukiene, Henrikas Nivinskas, Narmantas Cenas. Cytotoxicity of anticancer aziridinyl- substuted benzoquinones in primary mice splenocytes. The Jorunal of the Polish Biochemical Society and the Polish Academy of Sciences. 2014:61:(4):833-836

Jonas Sarlausakas, Ausra Nemeikaite- Ceniene, Henrikas Nivinskas, Vale Miliukiene, Rasa Jarasiene, Milda Peciukaityte, Daiva Baltriukiene, Virginija Bukelskiene, Kastis Krikstopaitis, Narimantas Cenas. 2015. Redox reactions and cytotoxicity mechanisms of anticancer aziridinyl- substituted- 1, 4- benzoquinones: a minireview CHEMIJA. 26(3); 208-217.

Nemeikaite- Ceniene, Ausra; Jarasiene, Rasa; Nivinskas, Henrikas; Sarlausakas, Jonas, Narimantas. 2015. Cytotoxicity of anticancer aziridinyl- benzoquinone in murine hepatome MH22a cells: the properties of RH1- resistant subline. Chemija; 26 (1); 46-50.

Hargreaves RH, Mayalarp SP, Butler J, McAdam SR, O'Hare CC, Hartley JA.1997. Cross-linking and sequence specific alkylation of DNA by aziridinyl quinones. 2. Structure requirements for sequence selectivity. Journal of Medicinal Chemistry, 40(3): 357-361.

Francesco AM Di, Ward TH, Butler J. 2004. Diaziridinylbenzoquinones. In: Methods in Enzymology. Academic Press. 174-193

Di Francesco A, Hargreaves R, Wallace T, Mayalarp S, Hazarti A, Hartley JA, Butler J. 2000. The abnormal cytotoxicity of 2,5-diaziridinyl-1,4-benzoquinone-3-phenyl esters. Anticancer Drug Design. 15, 347-359.

Dandawate PR, Vyas AC, Padhye SB, Singh MW, Baruah JB. 2010. Perspectives on medicinal properties of benzoquinone compounds Mini-Review in Medicinal Chemistry, 10(5); 436-54.

Kim JY, Kim CH, Straford IJ, Patterson AV, Heddry JH. 2004. The bio-reductive agent RH1 and [gamma]-irradiation both cause G2/M cell cycle phase arrest and polyploidy in a p53-mutated human breast cancer cell line. International Journal of Radiation Oncology Biology Physics 58,376-385.

Dehn DL, Inayat-Hussain SH, Ross D. 2005. RH1 induces cellular damage in an NAD(P)H:quinone oxidoreductase 1-dependent manner: relationship between DNA cross-linking, cell cycle perturbations, and apoptosis. J Pharmacol Exp Ther, 313(2): 771-779.

Downloads

Published

2021-09-20

Issue

Vol. 11 No. 2 (2021)

Section

Research Article

License

Declaration and Copyright Transfer Form

(to be completed by authors)

I/ We, the undersigned author(s) of the submitted manuscript, hereby declare, that the above manuscript which is submitted for publication in the STM Journals(s), is not published already in part or whole (except in the form of abstract) in any journal or magazine for private or public circulation, and, is not under consideration of publication elsewhere.

  • I/We will not withdraw the manuscript after 1 week of submission as I have read the Author Guidelines and will adhere to the guidelines.
  • I/We Author(s ) have niether given nor will give this manuscript elsewhere for publishing after submitting in STM Journal(s).
  • I/ We have read the original version of the manuscript and am/ are responsible for the thought contents embodied in it. The work dealt in the manuscript is my/ our own, and my/ our individual contribution to this work is significant enough to qualify for authorship.
  •  I/We also agree to the authorship of the article in the following order:

Author’s name                                    

 

1. ________________

2. ________________

3. ________________

4. ________________

 

We  Author(s) tick this box and would request you to consider it as our signature as we agree to the terms of this Copyright Notice, which will apply to this submission if and when it is published by this journal.