NFκB Pathway Modeling for Optimal Drug Combination Therapy on Multiple Myeloma
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.
[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.
[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.
@article{"International Journal of Medical, Medicine and Health Sciences:54034", author = "Huiming Peng and Jianguo Wen and Hongwei Li and Jeff Chang and Xiaobo Zhou", title = "NFκB Pathway Modeling for Optimal Drug Combination Therapy on Multiple Myeloma", 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.", volume = "4", number = "5", pages = "190-7", }
