In silico simulation of inhibitor drug effects on nuclear factor-kappaB pathway dynamics.
NF-kappaB is a transcription factor family that activates numerous genes that are related to cell survival, apoptosis, and cell migration. Its persistent activity is associated with tumor formation, growth, metastasis, and drug resistance in many cancer types, including lymphoma, colon cancer, and breast cancer. Current therapeutic efforts for inhibiting this central "switch" include using small molecules to block a selected target in this pathway. Recognizing the regulatory network structure of the NF-kappaB pathway, we examine in silico the effects of inhibitors targeting various network components, using a kinetic model of the pathway. By simulating the corresponding perturbed system dynamics, we show the resulting time course of inhibition has distinct target-specific profiles. In particular, greater oscillatory potential exists for inhibition of upstream events than for direct inhibition of NF-kappaB, at low drug concentrations. This phenomenon is observed also when we examine the dynamic effects of the recently approved proteasome inhibitor, bortezomib (PS-341), and compare it with other inhibitors, taking its pharmacokinetics into consideration. Such kinetic analyses of the "drugged" molecular system will facilitate optimal drug target selection and the development of treatment protocols for a molecularly targeted therapy.
Sung
Myong-Hee
MH
Biometric Research Branch, National Cancer Institute, National Institutes of Health, 6130 Executive Blvd. EPN 8146, MSC 7434, Bethesda, MD 20892, USA. sungm@mail.nih.gov
Simon
Richard
R
D003198:Computer Simulation; D006801:Humans; D051550:I-kappa B Kinase; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human