American Institute of Mathematical Sciences

Advanced
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

Alexis B. Cook 1, , Daniel R. Ziazadeh 2, , Jianfeng Lu 2, and  Trachette L. Jackson 3,

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.
Keywords: cisplatin., Multiscale model, cancer therapy.
Mathematics Subject Classification: Primary: 92C37, 92C50; Secondary: 92C4.
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), 1322-1326. doi: 10.1126/science.281.5381.1322.

[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), e99404. doi: 10.1371/journal.pone.0099404.

[3]

A. Basu and S. Krishnamurthy, BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes, Nature, 415 (2002), 922-926.

[4]

P. bouillet, J. F. Purton, D. I. Godfrey et al., BH3-only proteins and their roles in programmed cell death, Oncogene, 27 (2009), S128-S136.

[5]

D. T. Chao and S. J. Korsmeyer, Bcl-2 family: Regulators of cell death, Annu. Rev. Immunol., 16 (1998), 395-419. doi: 10.1146/annurev.immunol.16.1.395.

[6]

G. Chu, Cellular responses to cisplatin: The roles of dna-binding proteins an DNA repair, J. Biol. Chem., 269 (1994), 787-790.

[7]

A. W. El-Kareh and T. W. Secomb, A mathematical model for cisplatin cellular pharmacodynamics, Neoplasia, 5 (2003), 161-169. doi: 10.1016/S1476-5586(03)80008-8.

[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), 1351-1371. doi: 10.3390/cancers3011351.

[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), 153-158. doi: 10.1196/annals.1299.025.

[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), 657-663.

[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), e81582. doi: 10.1371/journal.pone.0081582.

[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), 705-715. doi: 10.1158/0008-5472.CAN-10-3174.

[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), 2926-2936. doi: 10.1158/1535-7163.MCT-08-1223.

[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), 89-117. doi: 10.1007/s11538-007-9242-9.

[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), 273-281. doi: 10.1046/j.1471-4159.2003.01522.x.

[16]

Y. Jung and S. J. Lippard, Direct Cellular Responses to Platinum-Induced DNA Damage, Chem. Rev., 107 (2007), 1387-1407.

[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), 14564-14574.

[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), 4287-4295.

[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), p102. doi: 10.1186/1756-9966-31-102.

[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), 1389-1399. doi: 10.1016/S1097-2765(00)00136-2.

[21]

S. R. McWhinney, R. M. Goldberg and H. L. McLeod, Platinum neurotoxicity pharmacogenetics, Mol. Cancer Ther., 8 (2009), 10-16. doi: 10.1158/1535-7163.MCT-08-0840.

[22]

D. Mitra, S. P. Malkoski and X. Wang, Cancer stem cells in head and neck cancer, Cancers, 3 (2011), 415-427. doi: 10.3390/cancers3010415.

[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), 19-25.

[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), 471-479. doi: 10.3892/ijo.29.2.471.

[25]

D. W. Nicholson, From bench to clinic with apoptosis-based therapeutic agents, Nature, 407 (2000), 810-816.

[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), 5485-5496. doi: 10.1158/0008-5472.CAN-12-2272.

[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), 994-1001. doi: 10.1634/theoncologist.2009-0289.

[28]

J. C. Reed, Apoptosis-based therapies, Nat. Rev. Drug Discov., 1 (2002), 111-121. doi: 10.1038/nrd726.

[29]

J. C. Reed, Bcl-2 family proteins: Strategies for overcoming chemoresistance in cancer, Adv. in Pharm., 41 (1997), 501-532. doi: 10.1016/S1054-3589(08)61070-4.

[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), 488-496. doi: 10.1200/JCO.2011.34.7898.

[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), 981-989.

[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), 749-755. doi: 10.1093/jnci/82.9.749.

[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), 73-112. doi: 10.1016/B978-0-12-380888-2.00003-0.

[34]

G. C. Shore and J. Viallet, Modeling the bcl-2 family of apoptosis suppressors for potential herapeutic benefit in cancer, Hemotol., 1 (2005), 226-230.

[35]

V. Sresht, J. R. Bellare and S. K. Gupta, Modeling the cytotoxicity of cisplatin, Ind. Eng. Chem. Res., 50 (2011), 12872-12880. doi: 10.1021/ie102360e.

[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), 1434-1444. doi: 10.1021/tx0498760.

[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), 82-86.

[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), 3421-3428. doi: 10.1158/0008-5472.CAN-07-5836.

[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), 727-730. doi: 10.1126/science.1059108.

show all references

References:
[1]

J. M. Adams and S. Cory, The Bcl-2 protein family: Arbiters of cell survival, Science, 281 (1998), 1322-1326. doi: 10.1126/science.281.5381.1322.

[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), e99404. doi: 10.1371/journal.pone.0099404.

[3]

A. Basu and S. Krishnamurthy, BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes, Nature, 415 (2002), 922-926.

[4]

P. bouillet, J. F. Purton, D. I. Godfrey et al., BH3-only proteins and their roles in programmed cell death, Oncogene, 27 (2009), S128-S136.

[5]

D. T. Chao and S. J. Korsmeyer, Bcl-2 family: Regulators of cell death, Annu. Rev. Immunol., 16 (1998), 395-419. doi: 10.1146/annurev.immunol.16.1.395.

[6]

G. Chu, Cellular responses to cisplatin: The roles of dna-binding proteins an DNA repair, J. Biol. Chem., 269 (1994), 787-790.

[7]

A. W. El-Kareh and T. W. Secomb, A mathematical model for cisplatin cellular pharmacodynamics, Neoplasia, 5 (2003), 161-169. doi: 10.1016/S1476-5586(03)80008-8.

[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), 1351-1371. doi: 10.3390/cancers3011351.

[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), 153-158. doi: 10.1196/annals.1299.025.

[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), 657-663.

[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), e81582. doi: 10.1371/journal.pone.0081582.

[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), 705-715. doi: 10.1158/0008-5472.CAN-10-3174.

[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), 2926-2936. doi: 10.1158/1535-7163.MCT-08-1223.

[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), 89-117. doi: 10.1007/s11538-007-9242-9.

[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), 273-281. doi: 10.1046/j.1471-4159.2003.01522.x.

[16]

Y. Jung and S. J. Lippard, Direct Cellular Responses to Platinum-Induced DNA Damage, Chem. Rev., 107 (2007), 1387-1407.

[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), 14564-14574.

[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), 4287-4295.

[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), p102. doi: 10.1186/1756-9966-31-102.

[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), 1389-1399. doi: 10.1016/S1097-2765(00)00136-2.

[21]

S. R. McWhinney, R. M. Goldberg and H. L. McLeod, Platinum neurotoxicity pharmacogenetics, Mol. Cancer Ther., 8 (2009), 10-16. doi: 10.1158/1535-7163.MCT-08-0840.

[22]

D. Mitra, S. P. Malkoski and X. Wang, Cancer stem cells in head and neck cancer, Cancers, 3 (2011), 415-427. doi: 10.3390/cancers3010415.

[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), 19-25.

[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), 471-479. doi: 10.3892/ijo.29.2.471.

[25]

D. W. Nicholson, From bench to clinic with apoptosis-based therapeutic agents, Nature, 407 (2000), 810-816.

[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), 5485-5496. doi: 10.1158/0008-5472.CAN-12-2272.

[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), 994-1001. doi: 10.1634/theoncologist.2009-0289.

[28]

J. C. Reed, Apoptosis-based therapies, Nat. Rev. Drug Discov., 1 (2002), 111-121. doi: 10.1038/nrd726.

[29]

J. C. Reed, Bcl-2 family proteins: Strategies for overcoming chemoresistance in cancer, Adv. in Pharm., 41 (1997), 501-532. doi: 10.1016/S1054-3589(08)61070-4.

[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), 488-496. doi: 10.1200/JCO.2011.34.7898.

[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), 981-989.

[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), 749-755. doi: 10.1093/jnci/82.9.749.

[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), 73-112. doi: 10.1016/B978-0-12-380888-2.00003-0.

[34]

G. C. Shore and J. Viallet, Modeling the bcl-2 family of apoptosis suppressors for potential herapeutic benefit in cancer, Hemotol., 1 (2005), 226-230.

[35]

V. Sresht, J. R. Bellare and S. K. Gupta, Modeling the cytotoxicity of cisplatin, Ind. Eng. Chem. Res., 50 (2011), 12872-12880. doi: 10.1021/ie102360e.

[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), 1434-1444. doi: 10.1021/tx0498760.

[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), 82-86.

[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), 3421-3428. doi: 10.1158/0008-5472.CAN-07-5836.

[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), 727-730. doi: 10.1126/science.1059108.

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