Cell Signaling and Resistance to Immunotoxins

Part of the Resistance to Targeted Anti-Cancer Therapeutics book series (RTACT, volume 6)


The use of toxic plant or microbial proteins or polypeptides as immunotoxins has been a long-pursued strategy to increase the efficacy of targeted anti-cancer therapeutics. However, although these toxins can be highly potent, resistance has repeatedly been observed. Resistance to immunotoxin scan occur because of neutralizing antibodies or limited tumor cell access but also because of protective cellular signaling events in cancer cells. An increasing number of preclinical studies indicate that the latter form of resistance can be caused by a variety of mechanisms that either pre-exist because of genetic or epigenetic alterations or are induced by the immunotoxin itself, including modulation of cell surface expression of target antigens, altered trafficking or cleavage of toxin molecules, reduced synthesis of modified amino acid residues that are required for the toxin’s inhibition of protein synthesis, inhibited caspase activation or activation of other pro-survival pathways, and perhaps activation of drug transporter proteins. While the clinical relevance of these potential resistance mechanisms remains to be demonstrated in future studies, they provide a conceptual framework for cellular resistance to immunotoxins, and may form the basis for the development of rational strategies aimed at improving immunotoxin-based cancer therapy.


Antibody Cancer Cellular Immunotherapy Immunotoxin Resistance Targeted Therapeutic Toxin 



B-cell lymphoma-2


Cyclic AMP


Cellular apoptosis susceptibility gene


Diphtheria toxin


Elongation factor-1


Elongation factor-2


Inhibitor of apoptosis protein


Interferon gamma


Insulin like growth factor


Interleukin:1 alpha






C-Jun NH2-terminal kinase


Nicotinamide adenine dinucleotide


Neuregulin:1 beta1


Poly (ADP) ribose polymerase


Protein kinase A


Protein kinase C


Pseudomonas exotoxin A


Phosphatidylinositol 3-kinase


Ribosomal RNA


Tumor necrosis factor alpha


TNF related apoptosis-inducing ligand


TNF like weak inducer of apoptosis


X-linked inhibitor of apoptosis protein



The author is a recipient of an ‘A’ Award from the Alex’s Lemonade Stand Foundation and is a Leukemia & Lymphoma Society Scholar in Clinical Research.


  1. 1.
    Thorpe PE, Ross WC, Cumber AJ, Hinson CA, Edwards DC, Davies AJ. Toxicity of diphtheria toxin for lymphoblastoid cells is increased by conjugation to antilymphocytic globulin. Nature. 1978;271:752–5.PubMedCrossRefGoogle Scholar
  2. 2.
    Blythman HE, Casellas P, Gros O, Gros P, Jansen FK, Paolucci F, Pau B, Vidal H. Immunotoxins: hybrid molecules of monoclonal antibodies and a toxin subunit specifically kill tumour cells. Nature. 1981;290:145–6.PubMedCrossRefGoogle Scholar
  3. 3.
    Shapira A, Benhar I. Toxin-based therapeutic approaches. Toxins (Basel). 2010;2:2519–83.CrossRefGoogle Scholar
  4. 4.
    Antignani A, Fitzgerald D. Immunotoxins: the role of the toxin. Toxins (Basel). 2013;5:1486–502.CrossRefGoogle Scholar
  5. 5.
    Dosio F, Stella B, Cerioni S, Gastaldi D, Arpicco S. Advances in anticancer antibody-drug conjugates and immunotoxins. Recent Pat Anticancer Drug Discov. 2014;9:35–65.PubMedGoogle Scholar
  6. 6.
    Kreitman RJ. Immunotoxins in cancer therapy. Curr Opin Immunol. 1999;11:570–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Deng Q, Barbieri JT. Molecular mechanisms of the cytotoxicity of ADP-ribosylating toxins. Annu Rev Microbiol. 2008;62:271–88.PubMedCrossRefGoogle Scholar
  8. 8.
    Choudhary S, Mathew M, Verma RS. Therapeutic potential of anticancer immunotoxins. Drug Discov Today. 2011;16:495–503.PubMedCrossRefGoogle Scholar
  9. 9.
    Madhumathi J, Verma RS. Therapeutic targets and recent advances in protein immunotoxins. Curr Opin Microbiol. 2012;15:300–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Polito L, Bortolotti M, Mercatelli D, Battelli MG, Bolognesi A. Saporin-S6: a useful tool in cancer therapy. Toxins (Basel). 2013;5:1698–722.CrossRefGoogle Scholar
  11. 11.
    Yamaizumi M, Mekada E, Uchida T, Okada Y. One molecule of diphtheria toxin fragment A introduced into a cell can kill the cell. Cell. 1978;15:245–50.PubMedCrossRefGoogle Scholar
  12. 12.
    Keppler-Hafkemeyer A, Brinkmann U, Pastan I. Role of caspases in immunotoxin-induced apoptosis of cancer cells. Biochemistry. 1998;37:16934–42.PubMedCrossRefGoogle Scholar
  13. 13.
    Keppler-Hafkemeyer A, Kreitman RJ, Pastan I. Apoptosis induced by immunotoxins used in the treatment of hematologic malignancies. Int J Cancer. 2000;87:86–94.PubMedCrossRefGoogle Scholar
  14. 14.
    Risberg K, Fodstad O, Andersson Y. Anti-melanoma activity of the 9.2.27PE immunotoxin in dacarbazine resistant cells. J Immunother. 2010;33:272–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Chang MP, Bramhall J, Graves S, Bonavida B, Wisnieski BJ. Internucleosomal DNA cleavage precedes diphtheria toxin-induced cytolysis. Evidence that cell lysis is not a simple consequence of translation inhibition. J Biol Chem. 1989;264:15261–7.PubMedGoogle Scholar
  16. 16.
    Morimoto H, Bonavida B. Diphtheria toxin- and Pseudomonas A toxin-mediated apoptosis. ADP ribosylation of elongation factor-2 is required for DNA fragmentation and cell lysis and synergy with tumor necrosis factor-alpha. J Immunol. 1992;149:2089–94.PubMedGoogle Scholar
  17. 17.
    Morimoto H, Bonavida B. Ricin-mediated cell-lysis and apoptosis of drug sensitive and resistant tumor-cells. Int J Oncol. 1993;2:363–71.PubMedGoogle Scholar
  18. 18.
    Kochi SK, Collier RJ. DNA fragmentation and cytolysis in U937 cells treated with diphtheria toxin or other inhibitors of protein synthesis. Exp Cell Res. 1993;208:296–302.PubMedCrossRefGoogle Scholar
  19. 19.
    Decker T, Oelsner M, Kreitman RJ, Salvatore G, Wang QC, Pastan I, Peschel C, Licht T. Induction of caspase-dependent programmed cell death in B-cell chronic lymphocytic leukemia by anti-CD22 immunotoxins. Blood. 2004;103:2718–26.PubMedCrossRefGoogle Scholar
  20. 20.
    Andersson Y, Juell S, Fodstad O. Downregulation of the antiapoptotic MCL-1 protein and apoptosis in MA-11 breast cancer cells induced by an anti-epidermal growth factor receptor-Pseudomonas exotoxin a immunotoxin. Int J Cancer. 2004;112:475–83.PubMedCrossRefGoogle Scholar
  21. 21.
    Jenkins CE, Swiatoniowski A, Issekutz AC, Lin TJ. Pseudomonas aeruginosa exotoxin A induces human mast cell apoptosis by a caspase-8 and—3-dependent mechanism. J Biol Chem. 2004;279:37201–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Du X, Youle RJ, Fitzgerald DJ, Pastan I. Pseudomonas exotoxin A-mediated apoptosis is Bak dependent and preceded by the degradation of Mcl-1. Mol Cell Biol. 2010;30:3444–52.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Liu Z, Feng Z, Zhu X, Xu W, Zhu J, Zhang X, Fan Z, Ji G. Construction, expression, and characterization of an anti-tumor immunotoxin containing the human anti-c-Met single-chain antibody and PE38KDEL. Immunol Lett. 2013;149:30–40.PubMedCrossRefGoogle Scholar
  24. 24.
    Thorburn J, Frankel AE, Thorburn A. Apoptosis by leukemia cell-targeted diphtheria toxin occurs via receptor-independent activation of Fas-associated death domain protein. Clin Cancer Res. 2003;9:861–5.PubMedGoogle Scholar
  25. 25.
    Lanotte M, Riviere JB, Hermouet S, Houge G, Vintermyr OK, Gjertsen BT, Doskeland SO. Programmed cell death (apoptosis) is induced rapidly and with positive cooperativity by activation of cyclic adenosine monophosphate-kinase I in a myeloid leukemia cell line. J Cell Physiol. 1991;146:73–80.PubMedCrossRefGoogle Scholar
  26. 26.
    Yankelevich B, Soldatenkov VA, Hodgson J, Polotsky AJ, Creswell K, Mazumder A. Differential induction of programmed cell death in CD8 + and CD4 + T cells by the B subunit of cholera toxin. Cell Immunol. 1996;168:229–34.PubMedCrossRefGoogle Scholar
  27. 27.
    Allam M, Bertrand R, Zhang-Sun G, Pappas J, Viallet J. Cholera toxin triggers apoptosis in human lung cancer cell lines. Cancer Res. 1997;57:2615–8.PubMedGoogle Scholar
  28. 28.
    Yan L, Herrmann V, Hofer JK, Insel PA. beta-adrenergic receptor/cAMP-mediated signaling and apoptosis of S49 lymphoma cells. Am J Physiol Cell Physiol. 2000;279:C1665–74.PubMedGoogle Scholar
  29. 29.
    Pessina A, Croera C, Savalli N, Bonomi A, Cavicchini L, Turlizzi E, Guizzardi F, Guido L, Daprai L, Neri MG. Bcl-2 down modulation in WEHI-3B/CTRES cells resistant to Cholera Toxin (CT)-induced apoptosis. Cell Res. 2006;16:306–12.PubMedCrossRefGoogle Scholar
  30. 30.
    Zheng X, Ou Y, Shu M, Wang Y, Zhou Y, Su X, Zhu W, Yin W, Li S, Qiu P, Yan G, Zhang J, Hu J, Xu D. Cholera toxin, a typical protein kinase A activator, induces G1 phase growth arrest in human bladder transitional cell carcinoma cells via inhibiting the c-Raf/MEK/ERK signaling pathway. Mol Med Rep. 2014;9:1773–9.PubMedGoogle Scholar
  31. 31.
    Andersson Y, Le H, Juell S, Fodstad O. AMP-activated protein kinase protects against anti-epidermal growth factor receptor-Pseudomonas exotoxin A immunotoxin-induced MA11 breast cancer cell death. Mol Cancer Ther. 2006;5:1050–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Nishihara H, Kizaka-Kondoh S, Insel PA, Eckmann L. Inhibition of apoptosis in normal and transformed intestinal epithelial cells by cAMP through induction of inhibitor of apoptosis protein (IAP)-2. Proc Natl Acad Sci U S A. 2003;100:8921–6.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Taylor RC, Cullen SP, Martin SJ. Apoptosis: controlled demolition at the cellular level. Nat Rev Mol Cell Biol. 2008;9:231–41.PubMedCrossRefGoogle Scholar
  34. 34.
    Evan GI, Vousden KH. Proliferation, cell cycle and apoptosis in cancer. Nature. 2001;411:342–8.PubMedCrossRefGoogle Scholar
  35. 35.
    Green DR, Kroemer G. The pathophysiology of mitochondrial cell death. Science. 2004;305:626–9.PubMedCrossRefGoogle Scholar
  36. 36.
    Fesik SW. Promoting apoptosis as a strategy for cancer drug discovery. Nat Rev Cancer. 2005;5:876–85.PubMedCrossRefGoogle Scholar
  37. 37.
    Plati J, Bucur O, Khosravi-Far R. Dysregulation of apoptotic signaling in cancer: molecular mechanisms and therapeutic opportunities. J Cell Biochem. 2008;104:1124–49.PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Du X, Xiang L, Mackall C, Pastan I. Killing of resistant cancer cells with low Bak by a combination of an antimesothelin immunotoxin and a TRAIL Receptor 2 agonist antibody. Clin Cancer Res. 2011;17:5926–34.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Brinkmann U, Mansfield E, Pastan I. Effects of BCL-2 overexpression on the sensitivity of MCF-7 breast cancer cells to ricin, diphtheria and Pseudomonas toxin and immunotoxins. Apoptosis. 1997;2:192–8.PubMedCrossRefGoogle Scholar
  40. 40.
    Bogner C, Dechow T, Ringshausen I, Wagner M, Oelsner M, Lutzny G, Licht T, Peschel C, Pastan I, Kreitman RJ, Decker T. Immunotoxin BL22 induces apoptosis in mantle cell lymphoma (MCL) cells dependent on Bcl-2 expression. Br J Haematol. 2010;148:99–109.PubMedCrossRefGoogle Scholar
  41. 41.
    Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ, Kunzer AR, Letai A, Li C, Mitten MJ, Nettesheim DG, Ng S, Nimmer PM, O'connor JM, Oleksijew A, Petros AM, Reed JC, Shen W, Tahir SK, Thompson CB, Tomaselli KJ, Wang B, Wendt MD, Zhang H, Fesik SW, Rosenberg SH. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005;435:677–81.PubMedCrossRefGoogle Scholar
  42. 42.
    Tse C, Shoemaker AR, Adickes J, Anderson MG, Chen J, Jin S, Johnson EF, Marsh KC, Mitten MJ, Nimmer P, Roberts L, Tahir SK, Xiao Y, Yang X, Zhang H, Fesik S, Rosenberg SH, Elmore SW. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008;68:3421–8.PubMedCrossRefGoogle Scholar
  43. 43.
    Traini R, Ben-Josef G, Pastrana DV, Moskatel E, Sharma AK, Antignani A, Fitzgerald DJ. ABT-737 overcomes resistance to immunotoxin-mediated apoptosis and enhances the delivery of pseudomonas exotoxin-based proteins to the cell cytosol. Mol Cancer Ther. 2010;9:2007–15.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Fitzgerald DJ, Moskatel E, Ben-Josef G, Traini R, Tendler T, Sharma A, Antignani A, Mussai F, Wayne A, Kreitman RJ, Pastan I. Enhancing immunotoxin cell-killing activity via combination therapy with ABT-737. Leuk Lymphoma. 2011;52(Suppl 2):79–81.PubMedCrossRefGoogle Scholar
  45. 45.
    Mattoo AR, Fitzgerald DJ. Combination treatments with ABT-263 and an immunotoxin produce synergistic killing of ABT-263-resistant small cell lung cancer cell lines. Int J Cancer. 2013;132:978–87.PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Antignani A, Sarnovsky R, Fitzgerald DJ. ABT-737 promotes the dislocation of ER luminal proteins to the cytosol, including pseudomonas exotoxin. Mol Cancer Ther. 2014;13:1655–63.PubMedCrossRefGoogle Scholar
  47. 47.
    Hollevoet K, Antignani A, Fitzgerald DJ, Pastan I. Combining the antimesothelin immunotoxin SS1P with the BH3-mimetic ABT-737 induces cell death in SS1P-resistant pancreatic cancer cells. J Immunother. 2014;37:8–15.PubMedCrossRefGoogle Scholar
  48. 48.
    Morimoto H, Safrit JT, Bonavida B. Synergistic effect of tumor necrosis factor-alpha- and diphtheria toxin-mediated cytotoxicity in sensitive and resistant human ovarian tumor cell lines. J Immunol. 1991;147:2609–16.PubMedGoogle Scholar
  49. 49.
    Morimoto H, Yonehara S, Bonavida B. Overcoming tumor necrosis factor and drug resistance of human tumor cell lines by combination treatment with anti-Fas antibody and drugs or toxins. Cancer Res. 1993;53:2591–6.PubMedGoogle Scholar
  50. 50.
    Horita H, Frankel AE, Thorburn A. Acute-myeloid-leukemia-targeted toxins kill tumor cells by cell-type-specific mechanisms and synergize with TRAIL to allow manipulation of the extent and mechanism of tumor cell death. Leukemia. 2008;22:652–5.PubMedCrossRefGoogle Scholar
  51. 51.
    Tai CJ, Hsu CH, Shen SC, Lee WR, Jiang MC. Cellular apoptosis susceptibility (CSE1 L/CAS) protein in cancer metastasis and chemotherapeutic drug-induced apoptosis. J Exp Clin Cancer Res. 2010;29:110.PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Brinkmann U, Brinkmann E, Gallo M, Pastan I. Cloning and characterization of a cellular apoptosis susceptibility gene, the human homologue to the yeast chromosome segregation gene CSE1. Proc Natl Acad Sci U S A. 1995;92:10427–31.PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Brinkmann U, Brinkmann E, Gallo M, Scherf U, Pastan I. Role of CAS, a human homologue to the yeast chromosome segregation gene CSE1, in toxin and tumor necrosis factor mediated apoptosis. Biochemistry. 1996;35:6891–9.PubMedCrossRefGoogle Scholar
  54. 54.
    Pollak MN, Schernhammer ES, Hankinson SE. Insulin-like growth factors and neoplasia. Nat Rev Cancer. 2004;4:505–18.PubMedCrossRefGoogle Scholar
  55. 55.
    Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer. 2008;8:915–28.PubMedCrossRefGoogle Scholar
  56. 56.
    Pollak M. The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat Rev Cancer. 2012;12:159–69.PubMedGoogle Scholar
  57. 57.
    Weroha SJ, Haluska P. The insulin-like growth factor system in cancer. Endocrinol Metab Clin North Am. 2012;41:335–50, vi.PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Singh P, Alex JM, Bast F. Insulin receptor (IR) and insulin-like growth factor receptor 1 (IGF-1R) signaling systems: novel treatment strategies for cancer. Med Oncol. 2014;31:805.PubMedCrossRefGoogle Scholar
  59. 59.
    Malaguarnera R, Belfiore A. The emerging role of insulin and insulin-like growth factor signaling in cancer stem cells. Front Endocrinol (Lausanne). 2014;5:10.Google Scholar
  60. 60.
    Liu XF, Fitzgerald DJ, Pastan I. The insulin receptor negatively regulates the action of Pseudomonas toxin-based immunotoxins and native Pseudomonas toxin. Cancer Res. 2013;73:2281–8.PubMedCentralPubMedCrossRefGoogle Scholar
  61. 61.
    Greganova E, Altmann M, Butikofer P. Unique modifications of translation elongation factors. FEBS J. 2011;278:2613–24.PubMedCrossRefGoogle Scholar
  62. 62.
    Wei H, Xiang L, Wayne AS, Chertov O, Fitzgerald DJ, Bera TK, Pastan I. Immunotoxin resistance via reversible methylation of the DPH4 promoter is a unique survival strategy. Proc Natl Acad Sci U S A. 2012;109:6898–903.PubMedCentralPubMedCrossRefGoogle Scholar
  63. 63.
    Hu X, Wei H, Xiang L, Chertov O, Wayne AS, Bera TK, Pastan I. Methylation of the DPH1 promoter causes immunotoxin resistance in acute lymphoblastic leukemia cell line KOPN-8. Leuk Res. 2013;37:1551–6.PubMedCrossRefGoogle Scholar
  64. 64.
    Roy V, Ghani K, Caruso M. A dominant-negative approach that prevents diphthamide formation confers resistance to Pseudomonas exotoxin A and diphtheria toxin. PLoS ONE. 2010;5:e15753.PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    Wei H, Bera TK, Wayne AS, Xiang L, Colantonio S, Chertov O, Pastan I. A modified form of diphthamide causes immunotoxin resistance in a lymphoma cell line with a deletion of the WDR85 gene. J Biol Chem. 2013;288:12305–12.PubMedCentralPubMedCrossRefGoogle Scholar
  66. 66.
    Cantley LC. The phosphoinositide 3-kinase pathway. Science. 2002;296:1655–7.PubMedCrossRefGoogle Scholar
  67. 67.
    Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov. 2005;4:988–1004.PubMedCrossRefGoogle Scholar
  68. 68.
    Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129:1261–74.PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Porta C, Paglino C, Mosca A. Targeting PI3K/Akt/mTOR signaling in cancer. Front Oncol. 2014;4:64.PubMedCentralPubMedCrossRefGoogle Scholar
  70. 70.
    Baiz D, Hassan S, Choi YA, Flores A, Karpova Y, Yancey D, Pullikuth A, Sui G, Sadelain M, Debinski W, Kulik G. Combination of the PI3K inhibitor ZSTK474 with a PSMA-targeted immunotoxin accelerates apoptosis and regression of prostate cancer. Neoplasia. 2013;15:1172–83.PubMedCentralPubMedCrossRefGoogle Scholar
  71. 71.
    Davol PA, Bizuneh A, Frackelton AR, Jr. Wortmannin. a phosphoinositide 3-kinase inhibitor, selectively enhances cytotoxicity of receptor-directed-toxin chimeras in vitro and in vivo. Anticancer Res. 1999;19:1705–13.PubMedGoogle Scholar
  72. 72.
    Wu CP, Calcagno AM, Ambudkar SV. Reversal of ABC drug transporter-mediated multidrug resistance in cancer cells: evaluation of current strategies. Curr Mol Pharmacol. 2008;1:93–105.PubMedCentralPubMedCrossRefGoogle Scholar
  73. 73.
    Tiwari AK, Sodani K, Dai CL, Ashby CR, Jr., Chen ZS. Revisiting the ABCs of multidrug resistance in cancer chemotherapy. Curr Pharm Biotechnol. 2011;12:570–94.PubMedCrossRefGoogle Scholar
  74. 74.
    Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG. Cancer drug resistance: an evolving paradigm. Nat Rev Cancer. 2013;13:714–26.PubMedCrossRefGoogle Scholar
  75. 75.
    Chen KG, Sikic BI. Molecular pathways: regulation and therapeutic implications of multidrug resistance. Clin Cancer Res. 2012;18:1863–9.PubMedCentralPubMedCrossRefGoogle Scholar
  76. 76.
    Sui H, Fan ZZ, Li Q. Signal transduction pathways and transcriptional mechanisms of ABCB1/Pgp-mediated multiple drug resistance in human cancer cells. J Int Med Res. 2012;40:426–35.PubMedCrossRefGoogle Scholar
  77. 77.
    De Jong MC, Scheffer GL, Broxterman HJ, Hooijberg JH, Slootstra JW, Meloen RH, Kreitman RJ, Husain SR, Joshi BH, Puri RK, Scheper RJ. Multidrug-resistant tumor cells remain sensitive to a recombinant interleukin-4-Pseudomonas exotoxin, except when overexpressing the multidrug resistance protein MRP1. Clin Cancer Res. 2003;9:5009–17.PubMedGoogle Scholar
  78. 78.
    Mcgrath MS, Rosenblum MG, Philips MR, Scheinberg DA. Immunotoxin resistance in multidrug resistant cells. Cancer Res. 2003;63:72–9.PubMedGoogle Scholar
  79. 79.
    Zhou H, Hittelman WN, Yagita H, Cheung LH, Martin SS, Winkles JA, Rosenblum MG. Antitumor activity of a humanized, bivalent immunotoxin targeting fn14-positive solid tumors. Cancer Res. 2013;73:4439–50.PubMedCentralPubMedCrossRefGoogle Scholar
  80. 80.
    Francisco JA, Kiener PA, Moran-Davis P, Ledbetter JA, Siegall CB. Cytokine activation sensitizes human monocytic and endothelial cells to the cytotoxic effects of an anti-CD40 immunotoxin. J Immunol. 1996;157:1652–8.PubMedGoogle Scholar
  81. 81.
    Salard D, Kuzel TM, Samuelson E, Rosen S, Bakouche O. Interleukin-1 alpha increases the preferential cytotoxicity of an interleukin-2-diphtheria toxin fusion protein against neoplastic lymphocytes from patients with the Sezary syndrome compared to normal lymphocytes. J Clin Immunol. 1998;18:223–34.PubMedCrossRefGoogle Scholar
  82. 82.
    Podar K, Raab MS, Chauhan D, Anderson KC. The therapeutic role of targeting protein kinase C in solid and hematologic malignancies. Expert Opin Investig Drugs. 2007;16:1693–707.PubMedCrossRefGoogle Scholar
  83. 83.
    Newton AC. Protein kinase C: poised to signal. Am J Physiol Endocrinol Metab. 2010;298:E395–402.PubMedCentralPubMedCrossRefGoogle Scholar
  84. 84.
    Mattoo AR, Pastan I, Fitzgerald D. Combination treatments with the PKC inhibitor, enzastaurin, enhance the cytotoxicity of the anti-mesothelin immunotoxin, SS1P. PLoS ONE. 2013;8:e75576.PubMedCentralPubMedCrossRefGoogle Scholar
  85. 85.
    Biberacher V, Decker T, Oelsner M, Wagner M, Bogner C, Schmidt B, Kreitman RJ, Peschel C, Pastan I, Meyer Zum Buschenfelde C, Ringshausen I. The cytotoxicity of anti-CD22 immunotoxin is enhanced by bryostatin 1 in B-cell lymphomas through CD22 upregulation and PKC-betaII depletion. Haematologica. 2012;97:771–9.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Clinical Research DivisionFred Hutchinson Cancer Research CenterSeattleUSA
  2. 2.Department of Medicine/Division of HematologyUniversity of Washington School of MedicineSeattleUSA
  3. 3.Department of EpidemiologyUniversity of Washington School of Public HealthSeattleUSA

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