NFκB Pathway Modeling for Optimal Drug Combination Therapy on Multiple Myeloma
Commenced in January 2007
Frequency: Monthly
Edition: International
Paper Count: 32799
NFκB Pathway Modeling for Optimal Drug Combination Therapy on Multiple Myeloma

Authors: Huiming Peng, Jianguo Wen, Hongwei Li, Jeff Chang, Xiaobo Zhou

Abstract:

NFκB activation plays a crucial role in anti-apoptotic responses in response to the apoptotic signaling during tumor necrosis factor (TNFa) stimulation in Multiple Myeloma (MM). Although several drugs have been found effective for the treatment of MM by mainly inhibiting NFκB pathway, there are no any quantitative or qualitative results of comparison assessment on inhibition effect between different single drugs or drug combinations. Computational modeling is becoming increasingly indispensable for applied biological research mainly because it can provide strong quantitative predicting power. In this study, a novel computational pathway modeling approach is employed to comparably assess the inhibition effects of specific single drugs and drug combinations on the NFκB pathway in MM, especially the prediction of synergistic drug combinations.

Keywords: Computational modeling, drug combination, inhibition effect, multiple myeloma, NFkB pathway.

Digital Object Identifier (DOI): doi.org/10.5281/zenodo.1060114

Procedia APA BibTeX Chicago EndNote Harvard JSON MLA RIS XML ISO 690 PDF Downloads 2998

References:


[1] Younes, H., et al., "Targeting the phosphatidylinositol 3-kinase pathway in multiple myeloma," Clin Cancer Res, 2007. 13(13): p. 3771-5.
[2] Hideshima, T., Mitsiades, C., Tonon, G., Richardson, P.G., and K.C. Anderson, "Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets," Nat Rev Cancer, 2007. 7(8): p. 585-98.
[3] van de Donk, N.W., H.M. Lokhorst, and A.C. Bloem, "Growth factors and antiapoptotic signaling pathways in multiple myeloma," Leukemia, 2005. 19(12): p. 2177-85.
[4] Hideshima, T., T., Chauhan, D., Schlossman, R., Richardson, P., and K.C. Anderson, "The role of tumor necrosis factor alpha in the pathophysiology of human multiple myeloma: therapeutic applications," Oncogene, 2001. 20(33): p. 4519-27.
[5] Hideshima, T., et al., "NF-kappa B as a therapeutic target in multiple myeloma," J Biol Chem, 2002. 277(19): p. 16639-47.
[6] Li, Z.W., Chen, H., Campbell, R.A., Bonavida, B., and J.R. Berenson, "NF-kappaB in the pathogenesis and treatment of multiple myeloma," Curr Opin Hematol, 2008. 15(4): p. 391-9.
[7] Ghosh, S. and M. Karin, "Missing pieces in the NF-kappaB puzzle," Cell, 2002. 109 Suppl: p. S81-96.
[8] Sung, M.H. and R. Simon, "In silico simulation of inhibitor drug effects on nuclear factor-kappaB pathway dynamics," Mol Pharmacol, 2004. 66(1): p. 70-5.
[9] Hoffmann, A., Levchenko, A., Scott, M.L., and D. Baltimore, "The IkappaB-NF-kappaB signaling module: temporal control and selective gene activation," Science, 2002. 298(5596): p. 1241-5.
[10] Park, S.G., et al., "The influence of the signal dynamics of activated form of IKK on NF-kB and anti-apoptotic expressions: A systems biology approach," FEBS Letters, 2006. 580: p. 822-830.
[11] Faratian, D., et al., "Systems biology reveals new strategies for personalizing cancer medicine and confirms the role of PTEN in resistance to trastuzumab," Cancer Res, 2009. 69(16): p. 6713-20.
[12] Moehren, G., et al., "Temperature dependence of the epidermal growth factor receptor signaling network can be accounted for by a kinetic model," Biochemistry, 2002. 41(1): p. 306-20.
[13] Goryanin, O., F. Demin, and Tobin, "Applications of whole cell and large pathway mathematical models in the pharmaceutical industry," Metabolic Engineering in the Post Genomic Era, 2004: p. 321-56.
[14] Hook, R. and T.A. Jeeves, "Direct search solution of numerical and statistical problems," J. Assoc, Comp., 1961. 8(2): p. 221-9.
[15] CI, B., "The toxicity of poisons combined jointly," Ann Appl Biol, 1939. 26: p. 585-615.
[16] Wen, J., et al., "P38 MAPK inhibition enhancing ATO-induced cytotoxicity against multiple myeloma cells," Br J Haematol, 2008. 140(2): p. 169-80.
[17] Wen, J., et al., "Enhanced antimyeloma cytotoxicity by the combination of arsenic trioxide and bortezomib is further potentiated by p38 MAPK inhibition," Leuk Res, 2009.
[18] Loewe, S., "The problem of synergism and antagonism of combined drugs," Arzneimittelforschung, 1953. 3(6): p. 285-90.
[19] Peterson, J.J. and S.J. Novick, "Nonlinear blending: a useful general concept for the assessment of combination drug synergy," J Recept Signal Transduct Res, 2007. 27(2-3): p. 125-46.