PARP inhibitors are less synthetically lethal in hypoxic conditions – AACR 2014

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.

Sources:

SilenciX®, novel stable knock-down cellular models to screen new molecular targets through the synthetic lethality approach  (“Experimental and Molecular Therapeutics” poster session – AACR 2014, San Diego) Abstract n° 3733
Eric Mennesson1, Anne-Marie Renault1, Isabelle Fixe1, Catherine Grillon2, Claudine Kiéda2, Nadia Normand1  (1/ tebu-bio – 2/ Centre de Biophysique Moléculaire CNRS UPR 4301 (France)).

Comments

  1. Joost Boex says:

    So, the SilenciX cells were cultured in hypoxic conditions? How? And how is that connected to the SL?

  2. Philippe Fixe says:

    Joost,
    SL is an experimental approach used in Drug discovery. Solid tumors (central sections) are highly hypoxic. This hypoxia contributes to drug resistance or at least strongly influences drug efficiency.
    Researchers are developing in vitro experimental conditions aiming at mimicking tumor hypoxic conditions to better evaluate therapeutic drugs.
    In this work, cells were incubated at 1% O2 in a C-chamber (Biospherix) in which gas level was controlled by ProOx 110 oxygen controller.
    I hope this clarifies.
    Philippe

  3. Joost Boex says:

    Hi Philippe,
    Thanks for your explanation.
    So the SilenciX also work under hypoxic conditions. That’s good to know but also expectable since they’re most often HeLa cells coming from tumours.
    I expected that for the hypoxic culturing the Petaka systems would have been used, I was surprised that there was no specific mentioning if this in the publication.
    Regards & good luck, Joost

  4. Philippe Fixe says:

    Celartia’s Petaka chambers are a plastic labware device that enable the cells themselves to auto-regulate the levels of oxygen & CO2 in the media. These alternative does not need any external instrumentation as seen in the experimental procedure described here.

Trackbacks

  1. […] HeLa cell lines). This shRNA technology has already been used in Drug Discovery approaches (ex. PARP inhibitors efficiency by Synthetic Lethality in Hypoxic conditions). […]

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