Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.30 (PARP)
 13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor growth is often associated with insufficient apoptosis. The Tumor Necrosis Factor (TNF)-Related Apoptosis-Inducing Ligand (TRAIL) and its proapoptotic receptors death receptor 4 (DR4) and DR5 agonistic monoclonal antibodies are being developed as targeted therapeutics because they kill cancer cells while sparing normal cells. A challenge to targeted therapeutics is the selection of patients who are most likely to benefit from targeted drugs because of the heterogeneity of cancer. Molecular imaging may be useful in targeted drug development by assessing the target expression and drug-target interaction, and for predicting therapeutic response. We hypothesized that the cell surface expression level of DR4/5 may predict the proapoptotic targeted therapeutic response if the signaling pathway downstream is intact. The goal of this proof-of-concept study was to develop a molecular imaging strategy to predict proapoptotic anti-cancer therapy response at an early stage of treatment. TRAIL and the DR5 agonistic monoclonal antibody HGS-ETR2 (Lexatumumab, TRM-2) were labeled with a near-infrared dye and these were used to image the TRAIL receptors on cultured TRAIL sensitive and TRAIL resistant human tumor cells as well as tumor xenografts. Imaging of cells and tumor-bearing animals was conducted with near infrared fluorescence imagers and apoptosis in cells was assessed by western blots of PARP-cleavage and flow cytometry of sub-G1 content. Apoptosis in tumors was evaluated by imaging near-infrared dye-labeled Annexin V and tumor tissue activated caspase-3 staining. Both in vitro and in vivo studies showed that imaging of death inducing ligand-receptor interaction was consistent with the apoptosis readout. Thus TRAIL sensitive tumors that express TRAIL receptors underwent cell death following treatment whereas tumors lacking TRAIL receptor expression were shown to be TRAIL resistant. In vivo molecular imaging of TRAIL receptor expression correlated with response to TRAIL therapy and an apoptotic response in vivo.
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PMID:Prediction of proapoptotic anticancer therapeutic response in vivo based on cell death visualization and TRAIL death ligand-receptor interaction. 2178 70

The acquisition of tamoxifen resistance is a major therapeutic problem in breast cancer. We developed a tamoxifen-resistant MCF-7 (TRM-7) cell line to elucidate the molecular mechanisms and factors associated with acquisition of such resistance. We showed that phosphorylation of STAT3 at tyrosine 705 (Y705) and RANTES expression are increased in response to tamoxifen in human breast cancer cells. On the basis of these results, we hypothesize that upregulated STAT3 phosphorylation and RANTES may be correlated with the development of drug resistance. Here, we showed that STAT3 and RANTES contribute to the maintenance of drug resistance. STAT3 phosphorylation is constitutively retained via a RANTES autocrine loop, which in turn upregulates anti-apoptotic signals in TRM-7 cells. STAT3-RANTES autocrine signaling affected expression of anti-apoptotic BCL-2 family genes and prevented TRM-7 cells from undergoing programmed cell death by inhibiting PARP and caspase-9 cleavage. Subsequently, blockade of STAT3 and RANTES in TRM-7 cells resulted in reduction of anti-apoptotic signals, which was rescued by exogenous RANTES treatment; drug resistance was also restored. Taken together, our results suggested that STAT3-RANTES autocrine signaling is essential for maintenance of drug resistance and inhibition of programmed cell death. These mechanisms of STAT3-RANTES autocrine signaling suggest a novel strategy for management of patients with tamoxifen-resistant tumors.
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PMID:STAT3-RANTES autocrine signaling is essential for tamoxifen resistance in human breast cancer cells. 2307 71