Checkpoint Signaling, Base Excision Repair, and PARP Promote Survival of Colon Cancer Cells Treated with 5-Fluorodeoxyuridine but Not 5-Fluorouracil

The fluoropyrimidines 5-fluorouracil (5-FU) and FdUrd (5-fluorodeoxyuridine; floxuridine) are the backbone of chemotherapy regimens for colon cancer and other tumors. Despite their widespread use, it remains unclear how these agents kill tumor cells. Here, we have analyzed the checkpoint and DNA repair pathways that affect colon tumor responses to 5-FU and FdUrd. These studies demonstrate that both FdUrd and 5-FU activate the ATR and ATM checkpoint signaling pathways, indicating that they cause genotoxic damage. Notably, however, depletion of ATM or ATR does not sensitize colon cancer cells to 5-FU, whereas these checkpoint pathways promote the survival of cells treated with FdUrd, suggesting that FdUrd exerts cytotoxicity by disrupting DNA replication and/or inducing DNA damage, whereas 5-FU does not. We also found that disabling the base excision (BER) repair pathway by depleting XRCC1 or APE1 sensitized colon cancer cells to FdUrd but not 5-FU. Consistent with a role for the BER pathway, we show that small molecule poly(ADP-ribose) polymerase 1/2 (PARP) inhibitors, AZD2281 and ABT-888, remarkably sensitized both mismatch repair (MMR)-proficient and -deficient colon cancer cell lines to FdUrd but not to 5-FU. Taken together, these studies demonstrate that the roles of genotoxin-induced checkpoint signaling and DNA repair differ significantly for these agents and also suggest a novel approach to colon cancer therapy in which FdUrd is combined with a small molecule PARP inhibitor

Piezoresistive effect in spin-coated polyaniline thin films

Polymeric materials have been replacing other materials in various applications, from structural to electronic components. In particular, since the discovery of conducting polymers, the use of these materials is growing up in the manufacture of electronic components, such as organic light-emitting diodes, organic electrodes, energy storage devices and artificial muscles, among many others. On the other hand, examples of sensors of conductive polymers based on the piezoresistive effect with large potential for applications are not sufficiently investigated. This investigation reports on the piezoresistive effect of an intrinsically conductive polymer, polyaniline, which was prepared in the form of thin films by spin coating on polyethylene terephthalate substrates. The relationship between the electrical response and mechanical solicitations is presented for different preparation conditions. The values of the gauge factor ranges from 10 to 22 for different samples and demonstrates the viability of these materials as piezoresistive sensors.This work is funded by FEDER funds through the "Programa Operacional Factores de Competitividade - COMPETE" and by national funds by FCT-Fundacao para a Ciencia e a Tecnologia, project references PTDC/CTM/69316/2006, PTDC/CTMNAN/112574/2009, and NANO/NMed-SD/0156/2007. J.N.P, A. F. and J. G. R. thank the FCT for Grants SFRH/BD/66930/2009, SFRH/BD/69796/2010 and SFRH/BSAB/1014/2010, respectively. The authors also than the support of the COST Action MP1003, 2010: The 'European Scientific Network for Artificial Muscles' (ESNAM)