E-MTAB-1353 - Transcription profiling by array of H. sapeins NSCLC A549 cell line to investigate two distinct poly(ADP-ribose) polymerase (PARP) inhibitors as a hyperadditive combination effect with CDDP
Last updated on 12 November 2012, released on 31 October 2013
Non-small cell lung cancer (NSCLC) is often treated with cisplatin (CDDP). Here, we report that two distinct poly(ADP-ribose) polymerase (PARP) inhibitors exhibited a hyperadditive combination effect with CDDP to kill NSCLC cells. A majority of CDDP-resistant cell lines and clones exhibited constitutively increased PARP expression and enzymatic activity. Cells with hyperactivated PARP initiated a DNA damage response and the intrinsic pathway of apoptosis in response to pharmacological PARP inhibition or PARP1-targeting siRNAs. Transcriptome analysis depicted an unsupervised hierarchical clustering of NSCLC cells and CDDP resistant counterparts regarding to their response to PARP inhibitors. PARP-overexpressing tumors displayed elevated levels of intracellular poly(ADP-ribose) (PAR), which predicted the response to PARP inhibitors in vitro and in vivo more accurately than PARP expression itself. Thus, CDDP-resistant cancer cells develop a dependency to PARP, becoming susceptible to PARP inhibitor-induced apoptosis.
transcription profiling by array, in vitro, individual genetic characteristics
PARP dependency as a frequent byproduct of cisplatin resistance. Judith Michels, Ilio Vitale, Lorenzo Galluzzi, Julien Adam, Ken André Olaussen, Oliver Kepp, Laura Senovilla, Ibtissam Talhaoui, Justine Guegan, Aïcha Goubar, David Enot, Monique Talbot, Angélique Robin, Philippe Girard, Cédric Oréar, Delphine Lissa, Abdul Qader Sukkurwala, Parviz Behnam Motlagh, Kimitoshi Kohno, Gen Sheng Wu, Catherine Brenner, Philippe Dessen, Murat Saparbaev, Jean-Charles Soria, Maria Castedo, Guido Kroemer.