Skip to main content
SpringerLink
Log in

Dichloroacetate (DCA) enhances tumor cell death in combination with oncolytic adenovirus armed with MDA-7/IL-24

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Dichloroacetate (DCA) is a metabolic modulator for the treatment of lactic acidosis and inherited mitochondrial diseases. A recent study showed that DCA treatment could induce apoptosis in many kinds of tumor cell lines via mitochondrial apoptotic pathway while sparing normal cells. ONYX-015 (dl 1520) is one of the oncolytic adenoviruses developed by the deletion of E1B-55kD gene of type 5 adenoviral DNA, and it replicates efficiently and selectively in tumor cells. ZD55-IL-24, an E1B-55kD deleted oncolytic adenovirus carrying interleukin-24 (IL-24, also called melanoma differentiation associated gene-7), had showed potent antitumor efficacy in a variety of tumor cells and exerted no apparent toxicity on normal cells. Given both the good therapeutic effect and low toxicity of these agents, here we investigated whether DCA in combination with ZD55-IL-24 or ONYX-015 could have more efficient antitumor activity in vitro experiments. Therefore, we tested the cytotoxicity of combination therapy in normal hepatic cells L-02 and QSG-7701 using the MTT assay. Our results showed that DCA combined with ONYX-015 or ZD55-IL-24 exhibited more potent antitumor activity than DCA or virus alone, and the combination treatment did not have superimposed toxicities in normal cells. Thus, a novel combination therapy associating oncolytic adenoviruses with relatively low toxic drug without severe side effects was proposed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R et al (2007) A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11:37–51

    Article  CAS  PubMed  Google Scholar 

  2. Michelakis ED, Webster L, Mackey JR (2008) Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Br J Cancer 99:989–994

    Article  CAS  PubMed  Google Scholar 

  3. Cao W, Yacoub S, Shiverick KT, Namiki K, Sakai Y, Porvasnik S et al (2008) Dichloroacetate (DCA) sensitizes both wild-type and over expressing Bcl-2 prostate cancer cells in vitro to radiation. Prostate 68:1223–1231

    Article  CAS  PubMed  Google Scholar 

  4. Wong JY, Huggins GS, Debidda M, Munshi NC, De Vivo I (2008) Dichloroacetate induces apoptosis in endometrial cancer cells. Gynecol Oncol 109:394–402

    Article  CAS  PubMed  Google Scholar 

  5. Pan JG, Mak TW (2007) Metabolic targeting as an anticancer strategy: dawn of a new era? Sci STKE 2007: pe14

  6. Ganly I, Kirn D, Eckhardt G, Rodriguez GI, Soutar DS, Otto R et al (2000) A phase I study of Onyx-015, an E1B attenuated adenovirus, administered intratumorally to patients with recurrent head and neck cancer. Clin Cancer Res 6:798–806

    CAS  PubMed  Google Scholar 

  7. Kirn D, Hermiston T, McCormick F (1998) ONYX-015: clinical data are encouraging. Nat Med 4:1341–1342

    Article  CAS  PubMed  Google Scholar 

  8. Heise C, Sampson-Johannes A, Williams A, McCormick F, Von Hoff DD, Kirn DH (1997) ONYX-015, an E1B gene-attenuated adenovirus, causes tumor-specific cytolysis and antitumoral efficacy that can be augmented by standard chemotherapeutic agents. Nat Med 3:639–645

    Article  CAS  PubMed  Google Scholar 

  9. Khuri FR, Nemunaitis J, Ganly I, Arseneau J, Tannock IF, Romel L et al (2000) a controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer. Nat Med 6:879–885

    Article  CAS  PubMed  Google Scholar 

  10. You L, Yang CT, Jablons DM (2000) ONYX-015 works synergistically with chemotherapy in lung cancer cell lines and primary cultures freshly made from lung cancer patients. Cancer Res 60:1009–1013

    CAS  PubMed  Google Scholar 

  11. Liu XY (2006) Targeting gene-virotherapy of cancer and its prosperity. Cell Res 16:879–886

    Article  CAS  PubMed  Google Scholar 

  12. Liu XY, Gu JF (2006) Targeting gene-virotherapy of cancer. Cell Res 16:25–30

    Article  PubMed  Google Scholar 

  13. Zhang ZL, Zou WG, Luo CX, Li BH, Wang JH, Sun LY et al (2003) An armed oncolytic adenovirus system, ZD55-gene, demonstrating potent antitumoral efficacy. Cell Res 13:481–489

    Article  CAS  PubMed  Google Scholar 

  14. Yang M, Cao X, Yu MC, Gu JF, Shen ZH, Ding M et al (2008) Potent antitumor efficacy of ST13 for colorectal cancer mediated by oncolytic adenovirus via mitochondrial apoptotic cell death. Hum Gene Ther 19:343–353

    Article  CAS  PubMed  Google Scholar 

  15. Zhang Y, Gu J, Zhao L, He L, Qian W, Wang J et al (2006) Complete elimination of colorectal tumor xenograft by combined manganese superoxide dismutase with tumor necrosis factor-related apoptosis-inducing ligand gene virotherapy. Cancer Res 66:4291–4298

    Article  CAS  PubMed  Google Scholar 

  16. Zhang Y, Qin X, Zhang Y, Zhao L, Wang Y, Liu X et al (2008) Combination of ZD55-MnSOD therapy with 5-FU enhances antitumor efficacy in colorectal cancer. J Cancer Res Clin Oncol 134:219–226

    Article  CAS  PubMed  Google Scholar 

  17. Cunningham CC, Chada S, Merritt JA, Tong A, Senzer N, Zhang Y et al (2005) 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 11:149–159

    Article  CAS  PubMed  Google Scholar 

  18. Eager R, Harle L, Nemunaitis J (2008) Ad-MDA-7; INGN 241: a review of preclinical and clinical experience. Expert Opin Biol Ther 8:1633–1643

    Article  CAS  PubMed  Google Scholar 

  19. Fisher PB (2005) Is mda-7/IL-24 a “magic bullet” for cancer? Cancer Res 65:10128–10138

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  22. Wu YM, Zhang KJ, Yue XT, Wang YQ, Yang Y, Li GC et al (2009) Enhancement of tumor cell death by combining cisplatin with an oncolytic adenovirus carrying MDA-7/IL-24. Acta Pharmacol Sin 30:467–477

    Article  CAS  PubMed  Google Scholar 

  23. Zhong S, Yu D, Wang Y, Qiu S, Wu S, Liu X (2010) An armed oncolytic adenovirus ZD55-IL-24 combined with ADM or DDP demonstrated enhanced antitumor effect in lung cancer. Acta Oncol 49:91–99

    Article  CAS  PubMed  Google Scholar 

  24. Hassoun EA, Ray S (2003) The induction of oxidative stress and cellular death by the drinking water disinfection by-products, dichloroacetate and trichloroacetate in J774.A1 cells. Comp Biochem Physiol C Toxicol Pharmacol 135:119–128

    Article  PubMed  Google Scholar 

  25. Pan Q, Liu B, Liu J, Cai R, Wang Y, Qian C (2007) Synergistic induction of tumor cell death by combining cisplatin with an oncolytic adenovirus carrying TRAIL. Mol Cell Biochem 304:315–323

    Article  CAS  PubMed  Google Scholar 

  26. Kreisberg RA (1980) Lactate homeostasis and lactic acidosis. Ann Intern Med 92:227–237

    CAS  PubMed  Google Scholar 

  27. Stacpoole PW, Felts JM (1970) Diisopropylammonium dichloroacetate (DIPA) and sodium dichloracetate (DCA): effect on glucose and fat metabolism in normal and diabetic tissue. Metabolism 19:71–78

    Article  CAS  PubMed  Google Scholar 

  28. Inoue S, Shanker M, Miyahara R, Gopalan B, Patel S, Oida Y et al (2006) MDA-7/IL-24-based cancer gene therapy: translation from the laboratory to the clinic. Curr Gene Ther 6:73–91

    Article  CAS  PubMed  Google Scholar 

  29. Sauane M, Su ZZ, Gupta P, Lebedeva IV, Dent P, Sarkar D et al (2008) Autocrine regulation of mda-7/IL-24 mediates cancer-specific apoptosis. Proc Natl Acad Sci USA 105:9763–9768

    Article  CAS  PubMed  Google Scholar 

  30. Su Z, Emdad L, Sauane M, Lebedeva IV, Sarkar D, Gupta P et al (2005) Unique aspects of mda-7/IL-24 antitumor bystander activity: establishing a role for secretion of MDA-7/IL-24 protein by normal cells. Oncogene 24:7552–7566

    Article  CAS  PubMed  Google Scholar 

  31. Sauane M, Gupta P, Lebedeva IV, Su ZZ, Sarkar D, Randolph A et al (2006) N-glycosylation of MDA-7/IL-24 is dispensable for tumor cell-specific apoptosis and “bystander” antitumor activity. Cancer Res 66:11869–11877

    Article  CAS  PubMed  Google Scholar 

  32. McMurtry MS, Bonnet S, Wu X, Dyck JR, Haromy A, Hashimoto K et al (2004) Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ Res 95:830–840

    Article  CAS  PubMed  Google Scholar 

  33. Stacpoole PW, Kerr DS, Barnes C, Bunch ST, Carney PR, Fennell EM et al (2006) Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children. Pediatrics 117:1519–1531

    Article  PubMed  Google Scholar 

  34. Stacpoole PW, Gilbert LR, Neiberger RE, Carney PR, Valenstein E, Theriaque DW et al (2008) Evaluation of long-term treatment of children with congenital lactic acidosis with dichloroacetate. Pediatrics 121:e1223–e1228

    Article  PubMed  Google Scholar 

  35. Stacpoole PW, Kurtz TL, Han Z, Langaee T (2008) Role of dichloroacetate in the treatment of genetic mitochondrial diseases. Adv Drug Deliv Rev 60:1478–1487

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Prof. Qijun Qian for kindly providing ONYX-015. This work was supported by Natural Science Foundation of Zhejiang Province (No. Y205282), the National Nature Science Foundation of China (nos. 30623003 and 30800093) and by Zhejiang Sci-Tech University grant 0616033 to Prof. Xin Yuan Liu.

Author information

Authors and Affiliations

  1. Xin Yuan Institute of Medicine and Biotechnology, School of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, Zhejiang, China

    Lianli Xiao, Xin Li, Na Niu, Jing Qian, Guoliang Xie & Yigang Wang

Authors
  1. Lianli Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Na Niu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jing Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Guoliang Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yigang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lianli Xiao.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Xiao, L., Li, X., Niu, N. et al. Dichloroacetate (DCA) enhances tumor cell death in combination with oncolytic adenovirus armed with MDA-7/IL-24. Mol Cell Biochem 340, 31–40 (2010). https://doi.org/10.1007/s11010-010-0397-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-010-0397-6

Keywords

Search

Navigation