The human Flap Endonuclease 1 (a.k.a. hFEN1) is a structure-specific nuclease involved in DNA replication and repair. This nuclease is thought to be a potential therapeutic target for treating cancers (e.g. chemosensitization, synthetic lethality) hence, the need for discovering and characterizing new hFEN1 inhibitors.
In December 2014, the European commission approved the first drug directed against a member of the PARP familiy (Poly ADP-Ribose Polymerases). Olaparib, a drug against ovarian cancer, has been developed by AstraZeneca and might become an important medicine very soon. Olaparib blocks PARP1 (see the Figure below showing the inhibitory effect of Olaparib on PARP1 measured with the PARP1 Chemiluminescent Activity Assay), an enzyme involved in cell repair, and is designed for ovarian cancer patients with certain hereditary gene mutations. It also has promise in treating other cancers, including breast and gastric tumors, opening up a substantial market opportunity. Olaparib is able to stop cancer cell growth in patients carrying inherited faults in the BRCA1 or BRCA2 genes (BReast CAncer 1 and 2 genes). [Read more…]
The synergistic combination of Poly(ADP-ribose) polymerases (PARP) and Topoisomerase I (Top1) inhibitors most beneficial on endonuclease-deficient cancer cells in cancer therapies ?
This is one of the elements discussed in the recent publication by Dr Benu Brata (National Institutes of Health (USA) and Indian Association for the Cultivation of Science (India) in Nucleic Acids Research. (1)
Hypoxia has important effects on chemosensitivity of cancer cells and the synthetic lethal effects of drugs.
In a recent work presented during the “Experimental and Molecular Therapeutics” sessions at the AACR 2014, Claudine Kiéda’s and Nadia Normand’s teams showed that PARP inhibitors are less synthetically lethal in hypoxic conditions with increased IC50 and survival percentage at higher concentrations.
Synthetic Lethality (SL) is defined as when loss of two genes independently has no effect on viability, but simultaneous loss of both genes causes cell death.
In cancer research and drug discovery, SL is observed when the cancer mutation and the drug simultaneously inhibit two otherwise independent pathways, leading to cell death. The best known SL relationship is between BRCA1/2 mutation (tumors deficient in Homologous Recombination (HR) DNA Repair pathway) and PARP inhibitors (affecting the Base Excision Repair (BER) DNA Repair pathway).
In their work, Dr Kiéda and Dr Normand used already published in vitro stable BRCA1- and BRCA2-KD cell lines (SilenciX® technology) to measure the synthetic lethal efficiency of PARP inhibitors (Olaparib, Veliparib and Rucaparib) in both normoxic and hypoxic conditions. They demonstrate that the BRCA-KD SilenciX® cell lines are effective and convenient in vitro cellular models to design new cancer drug candidates through the SL approach in oxygen-controlled conditions to better mimick physioxia seen in solid tumors.