Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Apoptosis

Enhanced antitumor activity by a selective conditionally replicating adenovirus combining with MDA-7/interleukin-24 for B-lymphoblastic leukemia via induction of apoptosis

Leukemia volume 22, pages 361–369 (2008)Cite this article

Abstract

Conditionally replicating adenoviruses (CRAds) represent a promising new platform for anticancer therapy. However, CRAds have been evaluated little in hematopoietic malignancies because of the lack of expression of coxsackie adenovirus receptor (CAR) on their cell surface. In this study, we showed that CAR was expressed on two types of lymphoblastic leukemia cell lines and primary leukemia cells, and that ZD55, a CRAd, exerted a potent antileukemia effect in vitro and in vivo. Furthermore, ZD55 expressing melanoma differentiation-associated gene-7/interleukin-24 (ZD55-IL-24) elicited significant enhanced antileukemia activity comparing with ZD55, concomitant with upregulation of RNA-dependent protein kinase R (PKR), increased phosphorylation of p38 mitogen-activated protein kinase (MAPK), and induction of endoplasmic reticulum (ER) stress. These data for the first time indicate that MDA-7/IL-24 exerts its antitumor effect on leukemia cells via multiple pathways, and suggest that oncolytic adenoviruses, ZD55 and ZD55-IL-24 could potentially be used against CAR-expressing hematological malignancies such as B-lymphoblastic leukemia/lymphoma and some myeloid leukemia.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Kirn D, Martuza RL, Zwiebel J . Replication-selective virotherapy for cancer: biological principles, risk management and future directions. Nat Med 2001; 7: 781–787.

    Article  CAS  Google Scholar 

  2. Bischoff JR, Kirn DH, Williams A, Heise C, Horn S, Muna M et al. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 1996; 274: 373–376.

    Article  CAS  Google Scholar 

  3. Nemunaitis J, Khuri F, Ganly I, Arseneau J, Posner M, Vokes E et al. Phase II trial of intratumoral administration of ONYX-015, a replication selective adenovirus, in patients with refractory head and neck cancer. J Clin Oncol 2001; 19: 289–298.

    Article  CAS  Google Scholar 

  4. Reid T, Galanis E, Abbruzzese J, Sze D, Andrews J, Romel L et al. Intra-arterial administration of a replication-selective adenovirus (dl1520) in patients with colorectal carcinoma metastatic to the liver: a phase I trial. Gene Therapy 2001; 8: 1618–1626.

    Article  CAS  Google Scholar 

  5. Reid T, Galanis E, Abbruzzese J, Sze D, Wein LM, Andrews J et al. Hepatic arterial infusion of a replication-selective oncolytic adenovirus (dl1520): phase II viral, immunologic, and clinical endpoints. Cancer Res 2002; 62: 6070–6079.

    CAS  Google Scholar 

  6. Makower D, Rozenblit A, Kaufman H, Edelman M, Lane ME, Zwiebel J et al. Phase II clinical trial of intralesional administration of the oncolytic adenovirus ONYX-015 in patients with hepatobiliary tumors with correlative p53 studies. Clin Cancer Res 2003; 9: 693–702.

    Google Scholar 

  7. Mulvihill S, Warren R, Venook A, Adler A, Randlev B, Heise C et al. Safety and feasibility of injection with an E1B-55 kDa gene-deleted, replication-selective adenovirus (ONYX-015) into primary carcinomas of the pancreas: a phase I trial. Gene Therapy 2001; 8: 308–315.

    Article  CAS  Google Scholar 

  8. Vasey PA, Shulman LN, Campos S, Davis J, Gore M, Johnston S et al. Phase I trial of intraperitoneal injection of the E1B-55-kd-gene-deleted adenovirus ONYX-015 (dl1520) given on days 1 through 5 every 3 weeks in patients with recurrent/refractory epithelial ovarian cancer. J Clin Oncol 2002; 20: 1562–1569.

    CAS  Google Scholar 

  9. Nemunaitis J, Cunningham C, Buchanan A, Bluckburn A, Edelman G, Maples P et al. Intravenous infusion of a replication-selective adenovirus (ONYX-015) in cancer patients: safety, feasibility and biological activity. Gene Therapy 2001; 8: 746–759.

    Article  CAS  Google Scholar 

  10. Liu X, Qiu S, Zou W, Pei Z, Gu J, Luo C et al. Effective gene-virotherapy for complete eradication of tumor mediated by the combination of hTRAIL (TNFsF10) and plasminogen k5. Mol Ther 2005; 11: 531–541.

    Article  CAS  Google Scholar 

  11. Zhang Z, Zou W, Luo C, Li B, Wang J, Sun L et al. An armed oncolytic adenovirus system, ZD55-gene, demonstrating potent antitumoral efficacy. Cell Res 2003; 13: 481–489.

    Article  CAS  Google Scholar 

  12. Pei Z, Chu L, Zou W, Zhang Z, Qiu S, Qi R et al. An oncolytic adenoviral vector of Smac increases antitumor activity of TRAIL against HCC in human cells and in mice. Hepatology 2004; 39: 1371–1381.

    Article  CAS  Google Scholar 

  13. Zhao L, Gu J, Dong A, Zhang Y, Zhong L, He Y et al. Potent antitumor activity of oncolytic adenovirus expressing mda-7/IL-24 for colorectal cancer. Hum Gene Ther 2005; 16: 845–858.

    Article  CAS  Google Scholar 

  14. Fisher PB . Is mda7/IL24 a ‘magic bullet’ for cancer? Cancer Res 2005; 65: 10128–10138.

    Article  CAS  Google Scholar 

  15. Su ZZ, Madireddi MT, Lin JJ, Young CS, Kitada S, Reed JC et al. The cancer growth suppressor gene mda-7 selectively induces apoptosis in human breast cancer cells and inhibits tumor growth in nude mice. Proc Natl Acad Sci USA 1998; 95: 14400–14405.

    Article  CAS  Google Scholar 

  16. Gopalan B, Shanker M, Chada S, Ramesh R . MDA-7/IL-24 suppresses human ovarian carcinoma growth in vitro and in vivo. Mol Cancer 2007; 6: 11.

    Article  Google Scholar 

  17. Saeki T, Mhashilkar A, Chada S, Branch C, Roth JA, Ramesh R . Tumor suppressive effects by adenovirus-mediated mda-7 gene transfer in nonsmall cell lung cancer in vitro. Gene Therapy 2000; 7: 2051–2057.

    Article  CAS  Google Scholar 

  18. Saeki T, Mhashilkar A, Swanson X, Zou-Yang X, Sieqer K, Kawabe S et al. Inhibition of human lung cancer growth following adenovirus mediated mda-7 gene expression in vivo. Oncogene 2002; 21: 4558–4566.

    Article  CAS  Google Scholar 

  19. Zhao L, Dong A, Gu J, Liu Z, Zhang Y, Zhang W et al. The antitumor activity of TRAIL and IL-24 with replicating oncolytic adenovirus in colorectal cancer. Cancer Gene Ther 2006; 13: 1011–1022.

    Article  CAS  Google Scholar 

  20. Cunningham CC, Chada S, Merritt JA, Tong A, Senzer N, Zhang Y et al. Clinical and local biological effects of an intratumoral injection of mda-7 (IL24; INGN 241) in patients with advanced carcinoma: a phase I study. Mol Ther 2005; 11: 149–159.

    Article  CAS  Google Scholar 

  21. Tong AW, Nemunaitis J, Su D, Zhang Y, Cunningham C, Senzer N et al. Intratumoral injection of INGN 241, a nonreplicating adenovector expressing the melanoma-differentiation associated gene-7 (mda-7/IL24): biologic outcome in advanced cancer patients. Mol Ther 2005; 11: 160–172.

    Article  CAS  Google Scholar 

  22. Pataer A, Vorburger SA, Barber GN, Chada S, Mahshilkar AM, Zou-Yang H et al. Adenoviral transfer of the melanoma differentiation-associated gene 7 (mad7) induces apoptosis of lung cancer cells via up-regulation of the double-stranded RNA-dependent protein kinase (PKR). Cancer Res 2002; 62: 2239–2243.

    CAS  Google Scholar 

  23. Sarkar D, Su ZZ, Lebedeva IV, Sauane M, Gopalkrishnan RV, Valerie K et al. Mda-7 (IL-24) mediates selective apoptosis in human melanoma cells by inducing the coordinated overexpression of the GADD family of genes by means of p38 MAPK. Proc Natl Acad Sci USA 2002; 99: 10054–10059.

    Article  CAS  Google Scholar 

  24. Mhashilkar AM, Schrock RD, Hindi M, Liao J, Sieqer K, Kourouma F et al. Melanoma-differentiation associated gene-7 (mda-7): a novel anti-tumor gene for cancer gene therapy. Mol Med 2001; 7: 271–282.

    Article  CAS  Google Scholar 

  25. Douglas JT, Kim M, Sumerel LA, Carey DE, Curiel DT . Efficient oncolysis by a replicating adenovirus (ad) in vivo is critically dependent on tumor expression of primary ad receptors. Cancer Res 2001; 61: 813–817.

    CAS  Google Scholar 

  26. Wickham TJ, Mathias P, Cheresh DA, Nemerow GR . Interins αvβ3 and αvβ5 promote adenovirus internalization but not virus attachment. Cell 1993; 73: 309–319.

    Article  CAS  Google Scholar 

  27. Mentel R, Dopping G, Wegner U, Seidel W, Liebermann H, Dohner L . Adenovirus-receptor interaction with human lymphocytes. J Med Virol 1997; 51: 252–257.

    Article  CAS  Google Scholar 

  28. Rebel VI, Hartnett S, Denham J, Chan M, Finberg R, Sieff CA . Maturation and lineage-specific expression of the coxsackie and adenovirus receptor in hematopoietic cells. Stem cells 2000; 18: 176–182.

    Article  CAS  Google Scholar 

  29. Li Y, Pong RC, Bergelson JM, Hall MC, Sagalowsky AI, Tseng CP et al. Loss of adenoviral receptor expression in human bladder cancer cells: a potential impact on the efficacy of gene therapy. Cancer Res 1999; 59: 325–330.

    CAS  Google Scholar 

  30. Hemmi S, Geertsen R, Mezzacasa A, Peter I, Dummer R . The presence of human coxsackie virus and adenovirus receptor is associated with efficient adenovirus-mediated transgene expression in human melanoma cell cultures. Hum Gene Ther 1998; 9: 2363–2373.

    Article  CAS  Google Scholar 

  31. Rao Q, Zhang G, Lin Y, Wu K . Production of matrix metalloproteinase-9 by cord blood CD34+ cells and its role in migration. Ann Hematol 2004; 83: 409–413.

    Article  CAS  Google Scholar 

  32. Qian W, Liu J, Jin J, Ni W, Xu W . Arsenic trioxide induces not only apoptosis but also autophagic cell death in leukemia cell lines via up-regulation of Beclin-1. Leuk Res 2007; 31: 329–339.

    Article  Google Scholar 

  33. Sauane M, Lebedeva IV, Su ZZ, Choo HT, Randolph A, Valerie K et al. Melanoma differentiation associated gene-7/interleukin-24 promotes tumor cell-specific apoptosis through both secretory and nonsecretory pathways. Cancer Res 2004; 64: 2988–2993.

    Article  CAS  Google Scholar 

  34. Sieger KA, Mhashilkar AM, Stewart A, Sutton RB, Strube RW, Chen SY et al. The tumor suppressor activity of MDA-7/IL-24 is mediated by intracellular protein expression in NSCLC cells. Mol Ther 2004; 9: 355–367.

    Article  CAS  Google Scholar 

  35. Gopalan B, Litvak A, Sharma S, Mhashilkar AM, Chada S, Ramesh R . Activation of the Fas–FasL signaling pathway by MDA-7/IL-24 kills human ovarian cancer cells. Cancer Res 2005; 65: 3017–3024.

    Article  CAS  Google Scholar 

  36. Peng KW, Donovan KA, Schneider U, Cattaneo R, Lust JA, Russell SJ . Oncolytic measles viruses displaying a single-chain antibody against CD38, a myeloma cell marker. Blood 2003; 101: 2557–2562.

    Article  CAS  Google Scholar 

  37. Suter SE, Chein MB, von Messling V, Yip B, Cattaneo R, Vernau W et al. In vitro canine distemper virus infection of canine lymphoid cells: a prelude to oncolytic therapy for lymphoma. Clin Cancer Res 2005; 11: 1579–1587.

    Article  CAS  Google Scholar 

  38. Mentel R, Dopping G, Wegner U, Seidel W, Lieber-mann H, Dohner L . Adenovirus-receptor interaction with human lymphocytes. J Med Virol 1997; 51: 252–257.

    Article  CAS  Google Scholar 

  39. Medina D, Sheay W, Goodell L, Kidd P, White E, Rabson AB et al. Adenovirus mediated cytotoxicity of chronic lymphocytic leukemia cells. Blood 1999; 94: 3499–3508.

    CAS  Google Scholar 

  40. Wang Y, Xue A, Hallden G, Francis F, Yuan M, Griffin BE et al. Virus-associated RNA I-deleted adenovirus, a potential oncolytic agent targeting EBV-associated tumors. Cancer Res 2005; 65: 1523–1531.

    Article  CAS  Google Scholar 

  41. Rivera AA, Davydova J, Schierer S, Wang M, Krasnykh V, Yamamoto M et al. Combining high selectivity of replication with fiber chimerism for effective adenoviral oncolysis of CAR-negative melanoma cells. Gene Therapy 2004; 11: 1694–1702.

    Article  CAS  Google Scholar 

  42. Yotnda P, Zompeta C, Heslop HE, Andreeff M, Brenner MK, Marini F . Comparison of the efficiency of transduction of leukemic cells by fiber-modified adenoviruses. Hum Gene Ther 2004; 15: 1229–1242.

    Article  CAS  Google Scholar 

  43. Chen L, Pulsipher M, Chen D, Sieff C, Elias A, Fine HA et al. Selective transgene expression for detection and elimination of contaminating carcinoma cells in hematopoietic stem cell sources. J Clin Invest 1996; 98: 2539–2548.

    Article  CAS  Google Scholar 

  44. Dix BR, Edwards SJ, Braithwaite AW . Dose the antitumor adenovirus ONXY-015/dll1520 selectively target cells defective in the p53 pathway? J Virol 2001; 75: 5443–5447.

    Article  CAS  Google Scholar 

  45. Gupta P, Su ZZ, Lebedeva IV, Sarkar D, Sauane M, Emdad L et al. mda-7/IL-24: multifunctional cancer-specific apoptosis-inducing cytokine. Pharmacol Ther 2006; 111: 596–628.

    Article  CAS  Google Scholar 

  46. Mhashilkar AM, Stewart AL, Sieger K, Yang HY, Khimani AH, Ito I et al. MDA-7 negatively regulates the beta-catenin and PI3K signaling pathways in breast and lung tumor cells. Mol Ther 2003; 8: 207–219.

    Article  CAS  Google Scholar 

  47. Lebedeva IV, Sarkar D, Su ZZ, Kitada S, Dent P, Stein CA et al. Bcl-2 and Bcl-x(L) differentially protect human prostate cancer cells from induction of apoptosis by melanoma differentiation associated gene-7, mda-7/IL-24. Oncogene 2003; 22: 8758–8773.

    Article  CAS  Google Scholar 

  48. Yacoub A, Mitchell C, Lister A, Lebedeva IV, Sarkar D, Su ZZ et al. Melanoma differentiation-associated 7 (interleukin 24) inhibits growth and enhances radiosensitivity of glioma cells in vitro and in vivo. Clin Cancer Res 2003; 9: 3272–3281.

    CAS  Google Scholar 

  49. Gupta P, Walter MR, Su ZZ, Lebedeva IV, Emdad L, Randolph A et al. BiP/GRP78 is an intracellular target for MDA-7/IL-24 induction of cancer-specific apoptosis. Cancer Res 2006; 66: 8182–8191.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by National Natural Science Foundation of China grants 30470745 (W Qian); 30600257 (Y Tong, W Qian); the Key Social Development Project of Zhejiang Province grants 2004c23005 (W Qian); Chinese National ‘973’ Project Foundation grants 2003AA216031, 2002AA216021 and Natural Science Foundation of China grants 30120160823 (X Liu). We thank L Wang for her help with electron microscope.

Author information

Authors and Affiliations

  1. Department of hematology, Institute of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, PR, China

    W Qian, J Liu, Y Tong, S Yan, C Yang & M Yang

  2. Division of Gene therapy, Xinyuan Institute of Medicine and Biotechnology, School of Life Sciences, Zhejiang University of Technology and Sciences, Hangzhou, PR, China

    W Qian & X Liu

  3. Division of Gene therapy, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, PR, China

    X Liu

Authors
  1. W Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y Tong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. X Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to W Qian.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Qian, W., Liu, J., Tong, Y. et al. Enhanced antitumor activity by a selective conditionally replicating adenovirus combining with MDA-7/interleukin-24 for B-lymphoblastic leukemia via induction of apoptosis. Leukemia 22, 361–369 (2008). https://doi.org/10.1038/sj.leu.2405034

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2405034

Keywords

This article is cited by

Search

Advanced search

Quick links