title: Basis of a FTIR spectroscopy methodology for automated evaluation of Akt kinase inhibitor on leukemic cell lines used as model.
abstract: The PI3K/Akt-signaling pathway, associated with cancer development and disease progression, is recognized to be an anti-tumor drug target that could present important therapeutic benefit. However, no targeted Akt medicines have been commercialized yet, reflecting that drug selection procedures requires significant improvement from early research to clinical trials. Thus, new methods permitting both the evaluation of cytotoxic and proliferation inhibition effect on cancer cells but also to provide a global fingerprint of the drug action mechanism of new Akt inhibitor candidates are of major interest. Because it can detect very subtle molecular changes and could provide a global fingerprint of drug effects on cells, Fourier-transform infrared (FTIR) spectroscopy appears to be a promising method to develop new time- and cost-saving tools for chemical library screening improvements. In this study, we combine FTIR spectroscopy, advanced chemometrics analysis and cross-validation by standard biological assays to establish a basis of a mid-throughput methodology for rapid and automated assessment of cell response to Akt inhibitors and quantitative evaluation of their anti-proliferative effects. Our results shows that our methodology is able (1) to detect cell response to an Akt inhibitor exposure even for very low doses, (2) to provide biochemical information of interest about its effects on the cell metabolism, lipidome, and proteome, (3) to predict accurately resulting cell proliferation inhibition rate. Thus, further based on a large spectral data base, our methodology could contribute to facilitate preliminary screening of chemical libraries and improving the selection procedure of drug candidates in laboratory routine.
authors.affiliation: University Bordeaux, Pharmacochimie, FRE 3396, Bordeaux, France.
authors.forename: Adrian
authors.initials: A
authors.lastname: Travo
authors.forename: Vanessa
authors.initials: V
authors.lastname: Desplat
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Barron
authors.forename: Emilie
authors.initials: E
authors.lastname: Poychicot-Coustau
authors.forename: Jean
authors.initials: J
authors.lastname: Guillon
authors.forename: Gérard
authors.initials: G
authors.lastname: Déléris
authors.forename: Isabelle
authors.initials: I
authors.lastname: Forfar
mesh_terms: D001331:Automation; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor / Q000295:instrumentation / Q000379:methods*; D057166:High-Throughput Screening Assays / Q000295:instrumentation / Q000379:methods; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D008954:Models, Biological; D047428:Protein Kinase Inhibitors / Q000032:analysis / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D017550:Spectroscopy, Fourier Transform Infrared / Q000379:methods*
chemical_list: D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt