2015, 12(6): 1219-1235. doi: 10.3934/mbe.2015.12.1219

An integrated cellular and sub-cellular model of cancer chemotherapy and therapies that target cell survival

1. 

Department of Applied Mathematics, Brown University, 182 George Street, Providence, RI 02906, United States

2. 

Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, United States, United States

3. 

Department of Mathematics, University of Michigan, 530 Church Street, Ann Arbor, MI 48109-1043, United States

Received  October 2014 Revised  April 2015 Published  August 2015

Apoptosis resistance is a hallmark of human cancer, and tumor cells often become resistant due to defects in the programmed cell death machinery. Targeting key apoptosis regulators to overcome apoptotic resistance and promote rapid death of tumor cells is an exciting new strategy for cancer treatment, either alone or in combination with traditionally used anti-cancer drugs that target cell division. Here we present a multiscale modeling framework for investigating the synergism between traditional chemotherapy and targeted therapies aimed at critical regulators of apoptosis.
Citation: Alexis B. Cook, Daniel R. Ziazadeh, Jianfeng Lu, Trachette L. Jackson. An integrated cellular and sub-cellular model of cancer chemotherapy and therapies that target cell survival. Mathematical Biosciences & Engineering, 2015, 12 (6) : 1219-1235. doi: 10.3934/mbe.2015.12.1219
References:
[1]

J. M. Adams and S. Cory, The Bcl-2 protein family: Arbiters of cell survival,, Science, 281 (1998), 1322.  doi: 10.1126/science.281.5381.1322.  Google Scholar

[2]

L. Bai, J. Chen, D. McEachern, L. Liu and H. Zhou et al., BM-1197: A novel and specific bcl-2/bcl-xl inhibitor inducing complete and long-lasting tumor regression in vivo,, PLoS One, 9 (2014).  doi: 10.1371/journal.pone.0099404.  Google Scholar

[3]

A. Basu and S. Krishnamurthy, BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes,, Nature, 415 (2002), 922.   Google Scholar

[4]

P. bouillet, J. F. Purton, D. I. Godfrey et al., BH3-only proteins and their roles in programmed cell death,, Oncogene, 27 (2009).   Google Scholar

[5]

D. T. Chao and S. J. Korsmeyer, Bcl-2 family: Regulators of cell death,, Annu. Rev. Immunol., 16 (1998), 395.  doi: 10.1146/annurev.immunol.16.1.395.  Google Scholar

[6]

G. Chu, Cellular responses to cisplatin: The roles of dna-binding proteins an DNA repair,, J. Biol. Chem., 269 (1994), 787.   Google Scholar

[7]

A. W. El-Kareh and T. W. Secomb, A mathematical model for cisplatin cellular pharmacodynamics,, Neoplasia, 5 (2003), 161.  doi: 10.1016/S1476-5586(03)80008-8.  Google Scholar

[8]

A. Florea and D. Busselberg, Cisplatin As An Anti-Tumor Drug: Cellular mechanisms of activity, drug resistance and induced side effects,, Cancers, 3 (2011), 1351.  doi: 10.3390/cancers3011351.  Google Scholar

[9]

K. V. Floros, H. Thomadaki, G. Lallas, N. Katsaros, M. Talieri and A. Scorilas, Cisplatin-induced apoptosis in HL-60 human promyelocytic leukemia cells: differential expression of BCL2 and novel apoptosis-related gene BCL2L12,, Ann NY Acad Sci, 1010 (2003), 153.  doi: 10.1196/annals.1299.025.  Google Scholar

[10]

V. M. Gonzalez, M. A. Fuertes, C. Alonso and J. M. Perez, Is Cisplatin-Induced Cell Death Always Produced by Apoptosis?,, Mol. Pharmacol., 59 (2001), 657.   Google Scholar

[11]

H. V. Jain, A. Richardson, M. Meyer-Hermann and H. M. Byrne, Exploiting the synergy between carboplatin and ABT-737 in the treatment of ovarian carcinomas,, PLoS One, 9 (2014).  doi: 10.1371/journal.pone.0081582.  Google Scholar

[12]

H. V. Jain and M. Meyer-Hermann, The molecular basis of synergism between carboplatin and ABT-737 therapy targeting ovarian carcinomas,, Cancer Res., 71 (2011), 705.  doi: 10.1158/0008-5472.CAN-10-3174.  Google Scholar

[13]

H. V. Jain, J. E. Nor and T. L. Jackson, Quantification of endothelial cell-targeted anti-Bcl-2 therapy and its suppression of tumor growth and vascularization,, Mol. Cancer There., 8 (2009), 2926.  doi: 10.1158/1535-7163.MCT-08-1223.  Google Scholar

[14]

H. V. Jain, J. E. Nor and T. L. Jackson, Modeling the VEGF-Bcl-2-CXCL8 pathway in intratumoral agiogenesis,, Bull. Math. Biol., 70 (2008), 89.  doi: 10.1007/s11538-007-9242-9.  Google Scholar

[15]

Z. Jiang, X. Zheng and K. M. Rich, Down-regulation of Bcl-2 and Bcl-xL expression with bispecific antisense treatment in glioblastoma cell lines induce cell death,, J Neurochem, 84 (2003), 273.  doi: 10.1046/j.1471-4159.2003.01522.x.  Google Scholar

[16]

Y. Jung and S. J. Lippard, Direct Cellular Responses to Platinum-Induced DNA Damage,, Chem. Rev., 107 (2007), 1387.   Google Scholar

[17]

A. Kothandapani, V. S. Dangeti and A. R. Brown, et al., Novel role of base excision repair (BER) in mediating cisplatin cytotoxicity,, J. Biol. Chem., 286 (2011), 14564.   Google Scholar

[18]

Q. T. Le and A. J. Giaccia, Therapeutic exploitation of the physiological and molecular genetic alterations in head and neck cancer,, Clin. Cancer Res., 9 (2003), 4287.   Google Scholar

[19]

J. Y. Li, Y. Y. Li, W. Jin, Q. Yang, Z. M. Shao and X. S. Tian, ABT-737 reverses the acquired radioresistance of breast cancer cells by targeting Bcl-2 and Bcl-xL,, J. Exp Clin. Cancer Res., 31 (2012).  doi: 10.1186/1756-9966-31-102.  Google Scholar

[20]

T. Lindsten, A. J. Ross and A. King et al., The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues,, Mol. Cell., 6 (2000), 1389.  doi: 10.1016/S1097-2765(00)00136-2.  Google Scholar

[21]

S. R. McWhinney, R. M. Goldberg and H. L. McLeod, Platinum neurotoxicity pharmacogenetics,, Mol. Cancer Ther., 8 (2009), 10.  doi: 10.1158/1535-7163.MCT-08-0840.  Google Scholar

[22]

D. Mitra, S. P. Malkoski and X. Wang, Cancer stem cells in head and neck cancer,, Cancers, 3 (2011), 415.  doi: 10.3390/cancers3010415.  Google Scholar

[23]

M. J. Mokhtari, A. Akbarzadeh and M. Hashemi et al., Cisplatin induces down regulation of BCL2 in T47D breast cancer cell line,, Adv Studies in Biol, 4 (2012), 19.   Google Scholar

[24]

S. Mueller, M. Schittenhelm and F. Honecker, et al., Cell-cycle progression and response of germ cell tumors to cisplatin in vitro,, Int. J. Oncol., 29 (2006), 471.  doi: 10.3892/ijo.29.2.471.  Google Scholar

[25]

D. W. Nicholson, From bench to clinic with apoptosis-based therapeutic agents,, Nature, 407 (2000), 810.   Google Scholar

[26]

D. Park, A. T. Magis and R. Li et al., Novel small-molecule inhibitors of Bcl-XL to treat lung cancer,, Cancer Res., 73 (2013), 5485.  doi: 10.1158/0008-5472.CAN-12-2272.  Google Scholar

[27]

D. Pulte and H. Brennera, Changes in survival in head and neck cancers in the late 20th and early 21st century: A period analysis,, Oncologist, 15 (2010), 994.  doi: 10.1634/theoncologist.2009-0289.  Google Scholar

[28]

J. C. Reed, Apoptosis-based therapies,, Nat. Rev. Drug Discov., 1 (2002), 111.  doi: 10.1038/nrd726.  Google Scholar

[29]

J. C. Reed, Bcl-2 family proteins: Strategies for overcoming chemoresistance in cancer,, Adv. in Pharm., 41 (1997), 501.  doi: 10.1016/S1054-3589(08)61070-4.  Google Scholar

[30]

A. W. Roberts, J. F. Seymour and J. R. Brown et al., Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: Results of a phase I study of navitoclax in patients with relapsed or refractory disease,, J. Clin. Oncol., 30 (2012), 488.  doi: 10.1200/JCO.2011.34.7898.  Google Scholar

[31]

S. Y. Sharp, P. M. Rogers and L. R. Kelland, Transport of cisplatin and bis-acetato-ammine-dichlorocyclohexylamine Platinum(IV) (JM216) in human ovarian carcinoma cell lines: identification of a plasma membrane protein associated with cisplatin resistance,, Clin. Cancer Res., 1 (1995), 981.   Google Scholar

[32]

C. M. Sorenson, M. A. Barry and A. Eastman, Analysis of events associated with cell cycle arrest at G2 phase and cell death induced by cisplatin,, JNCI., 82 (1990), 749.  doi: 10.1093/jnci/82.9.749.  Google Scholar

[33]

J. Smith, L. M. Tho, N. Xu and D. A. Gillespie, The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer,, Adv. Cancer Res., 108 (2010), 73.  doi: 10.1016/B978-0-12-380888-2.00003-0.  Google Scholar

[34]

G. C. Shore and J. Viallet, Modeling the bcl-2 family of apoptosis suppressors for potential herapeutic benefit in cancer,, Hemotol., 1 (2005), 226.   Google Scholar

[35]

V. Sresht, J. R. Bellare and S. K. Gupta, Modeling the cytotoxicity of cisplatin,, Ind. Eng. Chem. Res., 50 (2011), 12872.  doi: 10.1021/ie102360e.  Google Scholar

[36]

K. A. Tacka, D. Szalda, A. K. Souid, J. Goodisman and J. C. Dabrowiak, Experimental and theoretical studies on the pharmacodynamics of cisplatin in jurkat cells,, Chem. Res. Toxicol., 17 (2004), 1434.  doi: 10.1021/tx0498760.  Google Scholar

[37]

V. Troger, J. L. Fischel and P. Formento et al., Effects of prolonged exposure to cisplatin on cytotoxicity and intracellular drug concentration,, Eur. J. Cancer, 28 (1992), 82.   Google Scholar

[38]

C. Tse, A. R. Shoemaker and J. Adickes et al., ABT-263: A potent and orally bioavailable Bcl-2 family inhibitor,, Cancer Res., 68 (2008), 3421.  doi: 10.1158/0008-5472.CAN-07-5836.  Google Scholar

[39]

M. C. Wei, W. X. Zong and E. H. Cheng et al., Proapoptotic BAX and BAK: A requisite gateway to mitochondrial dysfunction and death,, Scient, 292 (2001), 727.  doi: 10.1126/science.1059108.  Google Scholar

show all references

References:
[1]

J. M. Adams and S. Cory, The Bcl-2 protein family: Arbiters of cell survival,, Science, 281 (1998), 1322.  doi: 10.1126/science.281.5381.1322.  Google Scholar

[2]

L. Bai, J. Chen, D. McEachern, L. Liu and H. Zhou et al., BM-1197: A novel and specific bcl-2/bcl-xl inhibitor inducing complete and long-lasting tumor regression in vivo,, PLoS One, 9 (2014).  doi: 10.1371/journal.pone.0099404.  Google Scholar

[3]

A. Basu and S. Krishnamurthy, BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes,, Nature, 415 (2002), 922.   Google Scholar

[4]

P. bouillet, J. F. Purton, D. I. Godfrey et al., BH3-only proteins and their roles in programmed cell death,, Oncogene, 27 (2009).   Google Scholar

[5]

D. T. Chao and S. J. Korsmeyer, Bcl-2 family: Regulators of cell death,, Annu. Rev. Immunol., 16 (1998), 395.  doi: 10.1146/annurev.immunol.16.1.395.  Google Scholar

[6]

G. Chu, Cellular responses to cisplatin: The roles of dna-binding proteins an DNA repair,, J. Biol. Chem., 269 (1994), 787.   Google Scholar

[7]

A. W. El-Kareh and T. W. Secomb, A mathematical model for cisplatin cellular pharmacodynamics,, Neoplasia, 5 (2003), 161.  doi: 10.1016/S1476-5586(03)80008-8.  Google Scholar

[8]

A. Florea and D. Busselberg, Cisplatin As An Anti-Tumor Drug: Cellular mechanisms of activity, drug resistance and induced side effects,, Cancers, 3 (2011), 1351.  doi: 10.3390/cancers3011351.  Google Scholar

[9]

K. V. Floros, H. Thomadaki, G. Lallas, N. Katsaros, M. Talieri and A. Scorilas, Cisplatin-induced apoptosis in HL-60 human promyelocytic leukemia cells: differential expression of BCL2 and novel apoptosis-related gene BCL2L12,, Ann NY Acad Sci, 1010 (2003), 153.  doi: 10.1196/annals.1299.025.  Google Scholar

[10]

V. M. Gonzalez, M. A. Fuertes, C. Alonso and J. M. Perez, Is Cisplatin-Induced Cell Death Always Produced by Apoptosis?,, Mol. Pharmacol., 59 (2001), 657.   Google Scholar

[11]

H. V. Jain, A. Richardson, M. Meyer-Hermann and H. M. Byrne, Exploiting the synergy between carboplatin and ABT-737 in the treatment of ovarian carcinomas,, PLoS One, 9 (2014).  doi: 10.1371/journal.pone.0081582.  Google Scholar

[12]

H. V. Jain and M. Meyer-Hermann, The molecular basis of synergism between carboplatin and ABT-737 therapy targeting ovarian carcinomas,, Cancer Res., 71 (2011), 705.  doi: 10.1158/0008-5472.CAN-10-3174.  Google Scholar

[13]

H. V. Jain, J. E. Nor and T. L. Jackson, Quantification of endothelial cell-targeted anti-Bcl-2 therapy and its suppression of tumor growth and vascularization,, Mol. Cancer There., 8 (2009), 2926.  doi: 10.1158/1535-7163.MCT-08-1223.  Google Scholar

[14]

H. V. Jain, J. E. Nor and T. L. Jackson, Modeling the VEGF-Bcl-2-CXCL8 pathway in intratumoral agiogenesis,, Bull. Math. Biol., 70 (2008), 89.  doi: 10.1007/s11538-007-9242-9.  Google Scholar

[15]

Z. Jiang, X. Zheng and K. M. Rich, Down-regulation of Bcl-2 and Bcl-xL expression with bispecific antisense treatment in glioblastoma cell lines induce cell death,, J Neurochem, 84 (2003), 273.  doi: 10.1046/j.1471-4159.2003.01522.x.  Google Scholar

[16]

Y. Jung and S. J. Lippard, Direct Cellular Responses to Platinum-Induced DNA Damage,, Chem. Rev., 107 (2007), 1387.   Google Scholar

[17]

A. Kothandapani, V. S. Dangeti and A. R. Brown, et al., Novel role of base excision repair (BER) in mediating cisplatin cytotoxicity,, J. Biol. Chem., 286 (2011), 14564.   Google Scholar

[18]

Q. T. Le and A. J. Giaccia, Therapeutic exploitation of the physiological and molecular genetic alterations in head and neck cancer,, Clin. Cancer Res., 9 (2003), 4287.   Google Scholar

[19]

J. Y. Li, Y. Y. Li, W. Jin, Q. Yang, Z. M. Shao and X. S. Tian, ABT-737 reverses the acquired radioresistance of breast cancer cells by targeting Bcl-2 and Bcl-xL,, J. Exp Clin. Cancer Res., 31 (2012).  doi: 10.1186/1756-9966-31-102.  Google Scholar

[20]

T. Lindsten, A. J. Ross and A. King et al., The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues,, Mol. Cell., 6 (2000), 1389.  doi: 10.1016/S1097-2765(00)00136-2.  Google Scholar

[21]

S. R. McWhinney, R. M. Goldberg and H. L. McLeod, Platinum neurotoxicity pharmacogenetics,, Mol. Cancer Ther., 8 (2009), 10.  doi: 10.1158/1535-7163.MCT-08-0840.  Google Scholar

[22]

D. Mitra, S. P. Malkoski and X. Wang, Cancer stem cells in head and neck cancer,, Cancers, 3 (2011), 415.  doi: 10.3390/cancers3010415.  Google Scholar

[23]

M. J. Mokhtari, A. Akbarzadeh and M. Hashemi et al., Cisplatin induces down regulation of BCL2 in T47D breast cancer cell line,, Adv Studies in Biol, 4 (2012), 19.   Google Scholar

[24]

S. Mueller, M. Schittenhelm and F. Honecker, et al., Cell-cycle progression and response of germ cell tumors to cisplatin in vitro,, Int. J. Oncol., 29 (2006), 471.  doi: 10.3892/ijo.29.2.471.  Google Scholar

[25]

D. W. Nicholson, From bench to clinic with apoptosis-based therapeutic agents,, Nature, 407 (2000), 810.   Google Scholar

[26]

D. Park, A. T. Magis and R. Li et al., Novel small-molecule inhibitors of Bcl-XL to treat lung cancer,, Cancer Res., 73 (2013), 5485.  doi: 10.1158/0008-5472.CAN-12-2272.  Google Scholar

[27]

D. Pulte and H. Brennera, Changes in survival in head and neck cancers in the late 20th and early 21st century: A period analysis,, Oncologist, 15 (2010), 994.  doi: 10.1634/theoncologist.2009-0289.  Google Scholar

[28]

J. C. Reed, Apoptosis-based therapies,, Nat. Rev. Drug Discov., 1 (2002), 111.  doi: 10.1038/nrd726.  Google Scholar

[29]

J. C. Reed, Bcl-2 family proteins: Strategies for overcoming chemoresistance in cancer,, Adv. in Pharm., 41 (1997), 501.  doi: 10.1016/S1054-3589(08)61070-4.  Google Scholar

[30]

A. W. Roberts, J. F. Seymour and J. R. Brown et al., Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: Results of a phase I study of navitoclax in patients with relapsed or refractory disease,, J. Clin. Oncol., 30 (2012), 488.  doi: 10.1200/JCO.2011.34.7898.  Google Scholar

[31]

S. Y. Sharp, P. M. Rogers and L. R. Kelland, Transport of cisplatin and bis-acetato-ammine-dichlorocyclohexylamine Platinum(IV) (JM216) in human ovarian carcinoma cell lines: identification of a plasma membrane protein associated with cisplatin resistance,, Clin. Cancer Res., 1 (1995), 981.   Google Scholar

[32]

C. M. Sorenson, M. A. Barry and A. Eastman, Analysis of events associated with cell cycle arrest at G2 phase and cell death induced by cisplatin,, JNCI., 82 (1990), 749.  doi: 10.1093/jnci/82.9.749.  Google Scholar

[33]

J. Smith, L. M. Tho, N. Xu and D. A. Gillespie, The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer,, Adv. Cancer Res., 108 (2010), 73.  doi: 10.1016/B978-0-12-380888-2.00003-0.  Google Scholar

[34]

G. C. Shore and J. Viallet, Modeling the bcl-2 family of apoptosis suppressors for potential herapeutic benefit in cancer,, Hemotol., 1 (2005), 226.   Google Scholar

[35]

V. Sresht, J. R. Bellare and S. K. Gupta, Modeling the cytotoxicity of cisplatin,, Ind. Eng. Chem. Res., 50 (2011), 12872.  doi: 10.1021/ie102360e.  Google Scholar

[36]

K. A. Tacka, D. Szalda, A. K. Souid, J. Goodisman and J. C. Dabrowiak, Experimental and theoretical studies on the pharmacodynamics of cisplatin in jurkat cells,, Chem. Res. Toxicol., 17 (2004), 1434.  doi: 10.1021/tx0498760.  Google Scholar

[37]

V. Troger, J. L. Fischel and P. Formento et al., Effects of prolonged exposure to cisplatin on cytotoxicity and intracellular drug concentration,, Eur. J. Cancer, 28 (1992), 82.   Google Scholar

[38]

C. Tse, A. R. Shoemaker and J. Adickes et al., ABT-263: A potent and orally bioavailable Bcl-2 family inhibitor,, Cancer Res., 68 (2008), 3421.  doi: 10.1158/0008-5472.CAN-07-5836.  Google Scholar

[39]

M. C. Wei, W. X. Zong and E. H. Cheng et al., Proapoptotic BAX and BAK: A requisite gateway to mitochondrial dysfunction and death,, Scient, 292 (2001), 727.  doi: 10.1126/science.1059108.  Google Scholar

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