Abstract
Despite adequately expressing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors DR4/DR5, malignant cells are frequently refractory to the cytotoxic effect of this apoptosis-inducing ligand. The susceptibility of cancer cells to TRAIL can be potentiated by cisplatin (CDDP). This study was designed to evaluate the ability of cisplatin to enhance the cytotoxic effect of TRAIL gene therapy using the recombinant adenovirus-mediated tumor-selective expression of membrane-bound green fluorescence protein (GFP)-TRAIL fusion protein (AdVgTRAIL) on thoracic cancer cells and to elucidate the putative mechanisms responsible for this synergistic combination effect. While causing little death of cultured thoracic cancer cells by itself, AdVgTRAIL in combination with CDDP, on the other hand, mediated profound supra-additive cytotoxicity and apoptosis via a strong bystander effect. CDDP/AdVgTRAIL-induced cytotoxicity was completely abrogated either by the pancaspase inhibitor zVAD-fmk or by the selective caspase 9 inhibitor or by transient knockdown of caspase 9 by siRNA, indicating that this process was caspase-mediated and mitochondria-dependent. This was confirmed by the observation that Bcl2 overexpression protected the cells from combination-induced cytotoxicity. Robust activation of caspase 8 activity in combination-treated cells was blocked by overexpression of Bcl2, indicating that caspase 8 activation was secondary to the mitochondria-mediated amplification feedback loop. Combining CDDP with AdVgTRAIL greatly enhances its tumoricidal efficacy in cultured thoracic cancer cells in vitro. The two agents interact to mediate profound activation of caspase cascade via recruitment of the mitochondria and positive feedback loop. The CDDP/AdVgTRAIL combination also exhibits a strong antitumor effect in in vivo animal model of human cancer xenografts.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Abbreviations
- AdVgTRAIL:
-
replication-defective adenovirus expressing GFP-TRAIL gene under hTERT promoter
- GFP:
-
green fluorescence protein
- TRAIL:
-
tumor necrosis factor-related apoptosis-inducing ligand
- CMV:
-
cytomegalovirus
- LacZ:
-
β-galactosidase gene
- MTT:
-
(4,5-dimethylthiazo-2-yl)-2,5-diphenyl tetrazolium bromide
References
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.
Pukac L, Kanakaraj P, Humphreys R, Alderson R, Bloom M, Sung C et al. HGS-ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivo. Br J Cancer 2005; 92: 1430–1441.
Ashkenazi A, Dixit VM . Apoptosis control by death and decoy receptors. Curr Opin Cell Biol 1999; 11: 255–260.
LeBlanc HN, Ashkenazi A . Apo2L/TRAIL and its death and decoy receptors. Cell Death Differ 2003; 10: 66–75.
Kelley SK, Ashkenazi A . Targeting death receptors in cancer with Apo2L/TRAIL. Curr Opin Pharmacol 2004; 4: 333–339.
Nicholson DW . Caspase structure, proteolytic substrates, and function during apoptotic cell death. Cell Death Differ 1999; 6: 1028–1042.
Salvesen GS, Dixit VM . Caspase activation: the induced-proximity model. Proc Natl Acad Sci USA 1999; 96: 10964–10967.
Boatright KM, Renatus M, Scott FL, Sperandio S, Shin H, Pedersen IM et al. A unified model for apical caspase activation. Mol Cell 2003; 11: 529–541.
Kroemer G, Dallaporta B, Resche-Rigon M . The mitochondrial death/life regulator in apoptosis and necrosis. Annu Rev Physiol 1998; 60: 619–642.
van Loo G, Saelens X, van Gurp M, MacFarlane M, Martin SJ, Vandenabeele P . The role of mitochondrial factors in apoptosis: a Russian roulette with more than one bullet. Cell Death Differ 2002; 9: 1031–1042.
Korsmeyer SJ, Wei MC, Saito M, Weiler S, Oh KJ, Schlesinger PH . Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c. Cell Death Differ 2000; 7: 1166–1173.
Scorrano L, Korsmeyer SJ . Mechanisms of cytochrome c release by proapoptotic BCL-2 family members. Biochem Biophys Res Commun 2003; 304: 437–444.
Ruffolo SC, Breckenridge DG, Nguyen M, Goping IS, Gross A, Korsmeyer SJ et al. BID-dependent and BID-independent pathways for BAX insertion into mitochondria. Cell Death Differ 2000; 7: 1101–1108.
Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ et al. Two CD95 (APO-1/Fas) signaling pathways. EMBO J 1998; 17: 1675–1687.
Saelens X, Festjens N, Vande WL, van Gurp M, van Loo G, Vandenabeele P . Toxic proteins released from mitochondria in cell death. Oncogene 2004; 23: 2861–2874.
Fulda S, Meyer E, Debatin KM . Inhibition of TRAIL-induced apoptosis by Bcl-2 overexpression. Oncogene 2002; 21: 2283–2294.
Izeradjene K, Douglas L, Tillman DM, Delaney AB, Houghton JA . Reactive oxygen species regulate caspase activation in tumor necrosis factor-related apoptosis-inducing ligand-resistant human colon carcinoma cell lines. Cancer Res 2005; 65: 7436–7445.
Slee EA, Harte MT, Kluck RM, Wolf BB, Casiano CA, Newmeyer DD et al. Ordering the cytochrome c-initiated caspase cascade: hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in a caspase-9-dependent manner. J Cell Biol 1999; 144: 281–292.
Ozoren N, el Deiry WS . Defining characteristics of Types I and II apoptotic cells in response to TRAIL. Neoplasia 2002; 4: 551–557.
Nguyen DM, Yeow WS, Ziauddin MF, Baras A, Tsai W, Reddy RM et al. The essential role of the mitochondria-dependent death-signaling cascade in chemotherapy-induced potentiation of Apo2L/TRAIL cytotoxicity in cultured thoracic cancer cells: amplified caspase 8 is indispensable for combination-mediated massive cell death. Cancer J 2006; 12: 257–273.
Ziauddin MF, Yeow WS, Maxhimer JB, Baras A, Chua A, Reddy RM et al. Valproic acid, an antiepileptic drug with histone deacetylase inhibitory activity, potentiates the cytotoxic effect of Apo2L/TRAIL on cultured thoracic cancer cells through mitochondria-dependent caspase activation. Neoplasia 2006; 8: 446–457.
Reddy RM, Yeow WS, Chua A, Nguyen DM, Baras A, Ziauddin MF et al. Rapid and profound potentiation of Apo2L/TRAIL-mediated cytotoxicity and apoptosis in thoracic cancer cells by the histone deacetylase inhibitor Trichostatin A: the essential role of the mitochondria-mediated caspase activation cascade. Apoptosis 2007; 12: 55–71.
Tsai WS, Yeow WS, Chua A, Reddy RM, Nguyen DM, Schrump DS et al. Enhancement of Apo2L/TRAIL-mediated cytotoxicity in esophageal cancer cells by cisplatin. Mol Cancer Ther 2006; 5: 2977–2990.
Muhlethaler-Mottet A, Bourloud KB, Auderset K, Joseph JM, Gross N . Drug-mediated sensitization to TRAIL-induced apoptosis in caspase-8-complemented neuroblastoma cells proceeds via activation of intrinsic and extrinsic pathways and caspase-dependent cleavage of XIAP, Bcl-xL and RIP. Oncogene 2004; 23: 5415–5425.
Lacour S, Micheau O, Hammann A, Drouineaud V, Tschopp J, Solary E et al. Chemotherapy enhances TNF-related apoptosis-inducing ligand DISC assembly in HT29 human colon cancer cells. Oncogene 2003; 22: 1807–1816.
Kondo K, Yamasaki S, Sugie T, Teratani N, Kan T, Imamura M et al. Cisplatin-dependent upregulation of death receptors 4 and 5 augments induction of apoptosis by TNF-related apoptosis-inducing ligand against esophageal squamous cell carcinoma. Int J Cancer 2005; 118: 230–242.
Evdokiou A, Bouralexis S, Atkins GJ, Chai F, Hay S, Clayer M et al. Chemotherapeutic agents sensitize osteogenic sarcoma cells, but not normal human bone cells, to Apo2L/TRAIL-induced apoptosis. Int J Cancer 2002; 99: 491–504.
Liu W, Bodle E, Chen JY, Gao M, Rosen GD, Broaddus VC . Tumor necrosis factor-related apoptosis-inducing ligand and chemotherapy cooperate to induce apoptosis in mesothelioma cell lines. Am J Respir Cell Mol Biol 2001; 25: 111–118.
Sayers TJ, Brooks AD, Koh CY, Ma W, Seki N, Raziuddin A et al. The proteasome inhibitor PS-341 sensitizes neoplastic cells to TRAIL-mediated apoptosis by reducing levels of c-FLIP. Blood 2003; 102: 303–310.
Inoue S, MacFarlane M, Harper N, Wheat LM, Dyer MJ, Cohen GM . Histone deacetylase inhibitors potentiate TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in lymphoid malignancies. Cell Death Differ 2004; 11 (Suppl 2): S193–S206.
Guo F, Sigua C, Tao J, Bali P, George P, Li Y et al. Cotreatment with histone deacetylase inhibitor LAQ824 enhances Apo-2L/tumor necrosis factor-related apoptosis inducing ligand-induced death inducing signaling complex activity and apoptosis of human acute leukemia cells. Cancer Res 2004; 64: 2580–2589.
Fulda S, Debatin KM . Resveratrol-mediated sensitisation to TRAIL-induced apoptosis depends on death receptor and mitochondrial signalling. Eur J Cancer 2005; 41: 786–798.
Shankar S, Srivastava RK . Enhancement of therapeutic potential of TRAIL by cancer chemotherapy and irradiation: mechanisms and clinical implications. Drug Resist Updat 2004; 7: 139–156.
LeBlanc H, Lawrence D, Varfolomeev E, Totpal K, Morlan J, Schow P et al. Tumor-cell resistance to death receptor-induced apoptosis through mutational inactivation of the proapoptotic Bcl-2 homolog Bax. Nat Med 2002; 8: 274–281.
Ganten TM, Haas TL, Sykora J, Stahl H, Sprick MR, Fas SC et al. Enhanced caspase-8 recruitment to and activation at the DISC is critical for sensitization of human hepatocellular carcinoma cells to TRAIL-induced apoptosis by chemotherapeutic drugs. Cell Death Differ 2004; 11: S86–96.
Arizono Y, Yoshikawa H, Naganuma H, Hamada Y, Nakajima Y, Tasaka K . A mechanism of resistance to TRAIL/Apo2L-induced apoptosis of newly established glioma cell line and sensitisation to TRAIL by genotoxic agents. Br J Cancer 2003; 88: 298–306.
Kagawa S, He C, Gu J, Koch P, Rha SJ, Roth JA et al. Antitumor activity and bystander effects of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene. Cancer Res 2001; 61: 3330–3338.
Jacob D, Davis JJ, Zhang L, Zhu H, Teraishi F, Fang B . Suppression of pancreatic tumor growth in the liver by systemic administration of the TRAIL gene driven by the hTERT promoter. Cancer Gene Ther 2005; 12: 109–115.
Lin T, Huang X, Gu J, Zhang L, Roth JA, Xiong M et al. Long-term tumor-free survival from treatment with the GFP-TRAIL fusion gene expressed from the hTERT promoter in breast cancer cells. Oncogene 2002; 21: 8020–8028.
Lin T, Gu J, Zhang L, Huang X, Stephens LC, Curley SA et al. Targeted expression of green fluorescent protein/tumor necrosis factor-related apoptosis-inducing ligand fusion protein from human telomerase reverse transcriptase promoter elicits antitumor activity without toxic effects on primary human hepatocytes. Cancer Res 2002; 62: 3620–3625.
Reddy RM, Tsai WS, Ziauddin MF, Zuo J, Cole Jr GW, Maxhimer JB et al. Cisplatin enhances apoptosis induced by a tumor-selective adenovirus expressing tumor necrosis factor-related apoptosis-inducing ligand. J Thorac Cardiovasc Surg 2004; 128: 883–891.
Chang JY, Zhang X, Komaki R, Cheung R, Fang B . Tumor-specific apoptotic gene targeting overcomes radiation resistance in esophageal adenocarcinoma. Int J Radiat Oncol Biol Phys 2006; 64: 1482–1494.
Zhang X, Cheung RM, Komaki R, Fang B, Chang JY . Radiotherapy sensitization by tumor-specific TRAIL gene targeting improves survival of mice bearing human non-small cell lung cancer. Clin Cancer Res 2005; 11: 6657–6668.
Voelkel-Johnson C, King DL, Norris JS . Resistance of prostate cancer cells to soluble TNF-related apoptosis-inducing ligand (TRAIL/Apo2L) can be overcome by doxorubicin or adenoviral delivery of full-length TRAIL. Cancer Gene Ther 2002; 9: 164–172.
Nguyen DM, Spitz FR, Yen N, Cristiano RJ, Roth JA . Gene therapy for lung cancer: enhancement of tumor suppression by a combination of sequential systemic cisplatin and adenovirus-mediated p53 gene transfer. J Thorac Cardiovasc Surg 1996; 112: 1372–1376.
Jin H, Yang R, Fong S, Totpal K, Lawrence D, Zheng Z et al. Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand cooperates with chemotherapy to inhibit orthotopic lung tumor growth and improve survival. Cancer Res 2004; 64: 4900–4905.
Charo J, Finkelstein SE, Grewal N, Restifo NP, Robbins PF, Rosenberg SA . Bcl-2 overexpression enhances tumor-specific T-cell survival. Cancer Res 2005; 65: 2001–2008.
He C, Lao WF, Hu XT, Xu XM, Xu J, Fang BL . Anti-liver cancer activity of TNF-related apoptosis-inducing ligand gene and its bystander effects. World J Gastroenterol 2004; 10: 654–659.
Reid T, Warren R, Kirn D . Intravascular adenoviral agents in cancer patients: lessons from clinical trials. Cancer Gene Ther 2002; 9: 979–986.
Merritt JA, Roth JA, Logothetis CJ . Clinical evaluation of adenoviral-mediated p53 gene transfer: review of INGN 201 studies. Semin Oncol 2001; 28: 105–114.
Takeuchi H, Kanzawa T, Kondo Y, Komata T, Hirohata S, Kyo S et al. Combination of caspase transfer using the human telomerase reverse transcriptase promoter and conventional therapies for malignant glioma cells. Int J Oncol 2004; 25: 57–63.
Faraoni I, Turriziani M, Masci G, De Vecchis L, Shay JW, Bonmassar E et al. Decline in telomerase activity as a measure of tumor cell killing by antineoplastic agents in vitro. Clin Cancer Res 1997; 3: 579–585.
Acknowledgements
This work was support by the Intramural Research Program of the National Cancer Institute of The National Institutes of Health and the start-up funds of the DeWitt Daughter Family Department of Surgery and the Sylvester Comprehensive Cancer Center, University of Miami. We acknowledge the contributions of Mr Arnold Mixon and Mr Shawn Farid of the Flow Cytometry Core Facility, Surgery Branch, Center for Cancer Research, NCI/NIH.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Shamimi-Noori, S., Yeow, WS., Ziauddin, M. et al. Cisplatin enhances the antitumor effect of tumor necrosis factor-related apoptosis-inducing ligand gene therapy via recruitment of the mitochondria-dependent death signaling pathway. Cancer Gene Ther 15, 356–370 (2008). https://doi.org/10.1038/sj.cgt.7701120
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.cgt.7701120
Keywords
This article is cited by
-
Acetyl-11-keto-β-boswellic acid enhances the cisplatin sensitivity of non-small cell lung cancer cells through cell cycle arrest, apoptosis induction, and autophagy suppression via p21-dependent signaling pathway
Cell Biology and Toxicology (2021)
-
Guiding TRAIL to cancer cells through Kv10.1 potassium channel overcomes resistance to doxorubicin
European Biophysics Journal (2016)
-
Hypoxia-induced autophagy mediates cisplatin resistance in lung cancer cells
Scientific Reports (2015)
-
Synergistic antitumor effect of AAV-mediated TRAIL expression combined with cisplatin on head and neck squamous cell carcinoma
BMC Cancer (2011)
-
Doxorubicin and etoposide sensitize small cell lung carcinoma cells expressing caspase-8 to TRAIL
Molecular Cancer (2010)