Activity of novel Cdc25 inhibitors and preliminary evaluation of their potentiation of chemotherapeutic drugs in human breast cancer cells

Life Sciences
Laurent Brault, Denyse Bagrel

Abstract

Dual-specific phosphatases Cdc25 play a critical role in the cell cycle regulation by activating kinases of Cdk/cyclin complexes. Three Cdc25 isoforms (A, B and C) have been identified in mammalians. Cdc25A and B display oncogenic properties and are over-expressed in different tumors. Cdc25 phosphatases are therefore attractive targets for therapeutic strategies. Novel maleic anhydride derivatives bearing a fatty acid chain of variable size have been synthesized and tested for their Cdc25 inhibitory potential using an in vitro assay. We report biological activity of ineffective, moderate, and efficient inhibitors on breast cancer cells (MCF7) and its counterpart resistant to vincristine (Vcr-R). The most potent compounds induced Cdk2 inhibition and accumulation in G0/G1 phase of the cell cycle. Moreover, apoptosis was triggered within 48-h treatment, without oxidative burst and modulation of the Bax to Bcl-2 ratio. When used as pre-treatments, these derivatives were also able to potentiate adriamycin and cisplatin toxicity in both cell lines. Thus, maleic anhydride derivatives may mediate apoptosis through a cell cycle blockage via inhibition of Cdc25. This class of inhibitors may present potential interest in therapeutic strat...Continue Reading

References

Sep 9, 1992·International Journal of Cancer. Journal International Du Cancer·R D WhelanB T Hill
Aug 8, 1996·Nature·K GalaktionovD Beach
Sep 21, 2000·The Journal of Clinical Investigation·M G CangiM Loda
Jan 24, 2002·The Journal of Biological Chemistry·Daniel F McCainZhong-Yin Zhang
Dec 4, 2002·Nature Reviews. Drug Discovery·Michael A LyonJohn S Lazo
Sep 6, 2003·The Journal of Pharmacy and Pharmacology·Kadriye CiftciPeter B Trovitch
May 6, 2004·Cancer Research·Marie-Christine BrezakBernard Ducommun
May 20, 2004·Bioorganic & Medicinal Chemistry Letters·Rumiko ShimazawaRyuichi Shirai
Aug 25, 2004·Chemistry & Biology·K Kristjánsdóttir, J Rudolph
Apr 1, 2006·Biochimica Et Biophysica Acta·Hannah M Heath-Engel, Gordon C Shore
Jun 10, 2006·Biochimica Et Biophysica Acta·Philippe A Parone, Jean-Claude Martinou
Jun 15, 2007·Nature Reviews. Cancer·Rose BoutrosBernard Ducommun

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Citations

Apr 25, 2012·Journal of Medicinal Chemistry·Antonio LavecchiaEttore Novellino
May 5, 2009·Current Opinion in Chemical Biology·Viktor V VintonyakHerbert Waldmann
Mar 16, 2012·Biochemical and Biophysical Research Communications·Hey-Young HongByung-Chul Kim
Oct 25, 2016·Journal of Enzyme Inhibition and Medicinal Chemistry·Emilie Evain-BanaMattia Mori

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