• 1
    El-Serag HB. Hepatocellular carcinoma. N Engl J Med 2011; 365: 1118-1127.
  • 2
    Llovet JM, Bruix J. Molecular targeted therapies in hepatocellular carcinoma. HEPATOLOGY 2008; 48: 1312-1327.
  • 3
    Schulze-Osthoff K, Ferrari D, Los M, Wesselborg S, Peter ME. Apoptosis signaling by death receptors. Eur J Biochem 1998; 254: 439-459.
  • 4
    Falschlehner C, Ganten TM, Koschny R, Schaefer U, Walczak H. TRAIL and other TRAIL receptor agonists as novel cancer therapeutics. Adv Exp Med Biol 2009; 647: 195-206.
  • 5
    Guicciardi ME, Gores GJ. Life and death by death receptors. FASEB J 2009; 23: 1625-1637.
  • 6
    Gonzalvez F, Ashkenazi A. New insights into apoptosis signaling by Apo2L/TRAIL. Oncogene 2010; 29: 4752-4765.
  • 7
    Yin XM, Wang K, Gross A, Zhao Y, Zinkel S, Klocke B, et al. Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosis. Nature 1999; 400: 886-891.
  • 8
    Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA, Marsters SA, et al. Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin Invest 1999; 104: 155-162.
  • 9
    Walzcak H, Miller RE, Ariail K, Gliniak B, Griffith TS, Kubin M, et al. Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat Med 1999; 5: 157-163.
  • 10
    Ashkenazi A, Herbst RS. To kill a tumor cell: the potential of proapoptotic receptor agonists. J Clin Invest 2008; 118: 1979-1990.
  • 11
    Cretney E, Takeda K, Yagita H, Glaccum M, Peschon JJ, Smyth MJ. Increased susceptibility to tumor initiation and metastasis in TNF-related apoptosis-inducing ligand-deficient mice. J Immunol 2002; 168: 1356-1361.
  • 12
    Takeda K, Smyth MJ, Cretney E, Hayakawa Y, Kayagaki N, Yagita H, et al. Critical role for tumor necrosis factor-related apoptosis-inducing ligand in immune surveillance against tumor development. J Exp Med 2002; 195: 161-169.
  • 13
    Zerafa N, Westwood JA, Cretney E, Mitchell S, Waring P, Iezzi M, et al. Cutting edge: TRAIL deficiency accelerates hematological malignancies. J Immunol 2005; 175: 5586-5590.
  • 14
    Ganten TM, Koschny R, Sykora J, Schulze-Bergkamen H, Büchler P, Haas TL, et al. Preclinical differentiation between apparently safe and potentially hepatotoxic applications of TRAIL either alone or in combination with chemotherapeutic drugs. Clin Cancer Res 2006; 12: 2640-2646.
  • 15
    Ichikawa K, Liu W, Zhao L, Wang Z, Liu D, Ohtsuka T, et al. Tumoricidal activity of a novel anti-human DR5 monoclonal antibody without hepatocyte cytotoxicity. Nat Med 2001; 7: 954-960.
  • 16
    Hao C, Song JH, Hsi B, Lewis J, Song DK, Petruk KC, et al. TRAIL inhibits tumor growth but is nontoxic to human hepatocytes in chimeric mice. Cancer Res 2004; 64: 8502-8506.
  • 17
    Rowinsky EK. Targeted induction of apoptosis in cancer management: the emerging role of tumor necrosis factor-related apoptosis-inducing ligand receptor activating agents. J Clin Oncol 2005; 23: 9394-9407.
  • 18
    Yamanaka T, Shiraki K, Sugimoto K, Ito T, Fujikawa K, Ito M, et al. Chemotherapeutic agents augment TRAIL-induced apoptosis in human hepatocellular carcinoma cell lines. HEPATOLOGY 2000; 32: 482-490.
  • 19
    Daniels RA, Turley H, Kimberley FC, Liu XS, Mongkolsapaya J, Ch'En P, et al. Expression of TRAIL and TRAIL receptors in normal and malignant tissues. Cell Res 2005; 15: 430-438.
  • 20
    Chen XP, He SQ, Wang HP, Zhao YZ, Zhang WG. Expression of TNF-related apoptosis-inducing ligand receptors and antitumor tumor effects of TNF-related apoptosis-inducing ligand in human hepatocellular carcinoma. World J Gastroenterol 2003; 9: 2433-2440.
  • 21
    Dyer MJ, MacFarlane M, Cohen GM. Barriers to effective TRAIL-targeted therapy of malignancy. J Clin Oncol 2007; 25: 4505-4506.
  • 22
    Rajkumar SV, Richardson PG, Hideshima T, Anderson KC. Proteasome inhibition as a novel therapeutic target in human cancer. J Clin Oncol 2005; 23: 630-639.
  • 23
    Ganten TM, Koschny R, Haas TL, Sykora J, Li-Weber M, Herzer K, et al. Proteasome inhibition sensitizes hepatocellular carcinoma cells, but not human hepatocytes, to TRAIL. HEPATOLOGY 2005; 42: 588-597.
  • 24
    Koschny R, Ganten TM, Sykora J, Haas TL, Sprick MR, Kolb A, et al. TRAIL/bortezomib cotreatment is potentially hepatotoxic but induces cancer-specific apoptosis within a therapeutic window. HEPATOLOGY 2007; 45: 649-658.
  • 25
    Chen KF, Yeh PY, Hsu C, Hsu CH, Lu YS, Hsieh HP, et al. Bortezomib overcomes tumor necrosis factor-related apoptosis-inducing ligand resistance in hepatocellular carcinoma cells in part through the inhibition of the phosphatidylinositol 3-kinase/Akt pathway. J Biol Chem 2009; 284: 11121-11133.
  • 26
    Breuhan K, Longerich T, Schirmacher P. Dysregulation of growth factor signaling in human hepatocellular carcinoma. Oncogene 2006; 25: 3787-3800.
  • 27
    Buckley AF, Burgart LJ, Sahai V, Kakar S. Epidermal growth factor receptor expression and gene copy number in conventional hepatocellular carcinoma. Am J Clin Pathol 2008; 129: 245-251.
  • 28
    Schneider B, Münkel S, Krippner-Heidenreich A, Grunwald I, Wels WS, Wajant H, et al. Potent antitumoral activity of TRAIL through generation of tumor-targeted single-chain fusion proteins. Cell Death Dis 2010; 1: e68.
  • 29
    Siegemund M, Pollak N, Seifert O, Wahl K, Hanak K, Vogel A, et al. Superior antitumoral activity of dimerized targeted single-chain TRAIL fusion proteins under retention of tumor selectivity. Cell Death Dis 2012; 3: e295.
  • 30
    Nussler AK, Nussler NC, Merk V, Brulport M, Schormann W, Hengstler JG. The holy grail of hepatocyte culturing and therapeutic use. In: Santin M, ed. Regenerative Medicine Today. Berlin, Germany: Springer International; 2009: 283-320.
  • 31
    Seidel N, Volkmann X, Länger F, Flemming P, Manns MP, Schulze-Osthoff K, et al. The extent of liver steatosis in chronic hepatitis C virus infection is mirrored by caspase activity in serum. HEPATOLOGY. 2005; 42: 113- 120.
  • 32
    Volkmann X, Fischer U, Bahr MJ, Ott M, Lehner F, MacFarlane M, et al. Increased hepatotoxicity of tumor necrosis factor-related apoptosis-inducing ligand in diseased human liver. HEPATOLOGY 2007; 46: 1498-1508.
  • 33
    Ishimura N, Isomoto H, Bronk SF, Gores GJ. Trail induces cell migration and invasion in apoptosis-resistant cholangiocarcinoma cells. Am J Physiol Gastrointest Liver Physiol 2006; 290: G129-G136.
  • 34
    Trauzold A, Siegmund D, Schniewind B, Sipos B, Egberts J, Zorenkov D, et al. TRAIL promotes metastasis of human pancreatic ductal adenocarcinoma. Oncogene 2006; 25: 7434-7439.
  • 35
    Schattenberg JM, Schuchmann M, Galle PR. Cell death and hepatocarcinogenesis: Dysregulation of apoptosis signaling pathways. J Gastroenterol Hepatol 2011; 26(Suppl 1): 213-219.
  • 36
    Fabregat I, Roncero C, Fernández M. Survival and apoptosis: a dysregulated balance in liver cancer. Liver Int 2007; 27: 155-162.
  • 37
    Dimberg LY, Anderson CK, Camidge R, Behbakht K, Thorburn A, Ford HL. On the TRAIL to successful cancer therapy? Predicting and counteracting resistance against TRAIL-based therapeutics. Oncogene 2012 May 14. doi: 10. 1038/onc. 2012.164.
  • 38
    Naumann I, Kappler R, von Schweinitz D, Debatin KM, Fulda S. Bortezomib primes neuroblastoma cells for TRAIL-induced apoptosis by linking the death receptor to the mitochondrial pathway. Clin Cancer Res 2011; 17: 3204-3218.
  • 39
    Adams A, Palombella VJ, Sausville EA, Johnson J, Destree A, Lazarus DD, et al. Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 1999; 59: 2615-2622.
  • 40
    Kelley SK, Harris LA, Xie D, Deforge L, Totpal K, Bussiere J, et al. Preclinical studies to predict the disposition of Apo2L/tumor necrosis factor-related apoptosis-inducing ligand in humans: characterization of in vivo efficacy, pharmacokinetics, and safety. J Pharmacol Exp Ther 2001; 299: 31-38.
  • 41
    Xiang H, Nguyen CB, Kelley SK, Dybdal N, Escandón E. Tissue distribution, stability, and pharmacokinetics of Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand in human colon carcinoma COLO205 tumor-bearing nude mice. Drug Metab Dispos 2004; 32: 1230-1238.
  • 42
    Wajant H, Moosmayer D, Wüest T, Bartke T, Gerlach E, Schönherr U, et al. Differential activation of TRAIL-R1 and -2 by soluble and membrane TRAIL allows selective surface antigen-directed activation of TRAIL-R2 by a soluble TRAIL derivative. Oncogene 2001; 20: 4101-4106.
  • 43
    van der Sloot AM, Tur V, Szegezdi E, Mullally MM, Cool RH, Samali A, et al. Designed tumor necrosis factor-related apoptosis-inducing ligand variants initiating apoptosis exclusively via the DR5 receptor. Proc Natl Acad Sci U S A 2006; 103: 8634-8639.