PT - JOURNAL ARTICLE AU - Vidya Ramakrishnan AU - Donald E. Mager TI - Network-Based Analysis of Bortezomib Pharmacodynamic Heterogeneity in Multiple Myeloma Cells AID - 10.1124/jpet.118.247924 DP - 2018 Jan 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - jpet.118.247924 4099 - http://jpet.aspetjournals.org/content/early/2018/04/09/jpet.118.247924.short 4100 - http://jpet.aspetjournals.org/content/early/2018/04/09/jpet.118.247924.full AB - The objective of this study is to evaluate the heterogeneity in pharmacodynamic response in four in vitro multiple myeloma cell lines to treatment with bortezomib, and to assess whether such differences are associated with drug-induced intracellular signaling protein dynamics identified via a logic-based network modeling approach. The in vitro pharmacodynamic efficacy of bortezomib was evaluated through concentration-effect and cell proliferation dynamical studies in U266, RPMI8226, MM.1S, and NCI-H929 myeloma cell lines. A Boolean logic-based network model incorporating intracellular protein signaling pathways relevant to myeloma cell growth, proliferation, and apoptosis was developed based on information available in the literature and utilized to identify key proteins regulating bortezomib pharmacodynamics. The time-course of network-identified proteins were measured using the MAGPIX® protein assay system. Traditional pharmacodynamic modeling end-points (e.g., IC50, KC50, and Kmax) established variable responses of the cell lines to bortezomib treatment, classifying cell lines as more sensitive (MM.1S and NCI-H929) and less sensitive (U266 and RPMI8226). Network centrality and model reduction identified key proteins (e.g., pNFκB, pAKT, pmTOR, Bcl-2, pJNK, pp53, p21, pBAD, Caspase 8, and Caspase 9) that govern bortezomib pharmacodynamics. The corresponding relative expression (normalized to 0 h untreated-control cells) of proteins demonstrated a greater magnitude and earlier onset of stimulation/inhibition in cells more sensitive (MM.1S and NCI-H929) to bortezomib induced cell death at 20 nM, relative to the less sensitive cells (U266 and RPMI8226). Overall, differences in intracellular signaling appears to be associated with bortezomib pharmacodynamic heterogeneity, and key proteins may be potential biomarkers to evaluate bortezomib responses.