Skip to main content

Advertisement

SpringerLink
Log in

Promoting effect of Antrodia camphorata as an immunomodulating adjuvant on the antitumor efficacy of HER-2/neu DNA vaccine

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

It is well known that DNA vaccines induce protective humoral and cell-mediated immune responses in several animal models. Antrodia camphorata (AC) is a unique basidiomycete fungus of the Polyporaceae family that only grows on the aromatic tree Cinnamomum kanehirai Hayata (Lauraceae) endemic to Taiwan. Importantly, AC has been shown to be highly beneficial in the treatment and prevention of cancer. The goal of this study was to investigate whether AC is able to augment the antitumor immune properties of a HER-2/neu DNA vaccine in a mouse model in which p185neu is overexpressed in MBT-2 tumor cells. Compared with the mice that received the HER-2/neu DNA vaccine alone, co-treatment with AC suppressed tumor growth and extended the survival rate. This increase in the antitumor efficacy was attributed to the enhancement of the Th1-like cellular immune response by the HER-2/neu DNA vaccine–AC combination. Evidence for this came from the marked increase in the IFN-γ mRNA expression in CD4+ T cells in the draining inguinal lymph nodes, an increase in the number of functional HER-2/neu-specific CTLs, and the increased tumor infiltration of both CD4+ and CD8+ T cells, depletion of which abolishes the antitumor effect of the HER-2/neu DNA vaccine–AC therapy. Our results further indicate that the treatment of mice with AC enhanced DC activation and production of Th1-activating cytokines (e.g. IL-12, and IFN-α) in the draining lymph nodes, which were sufficient to directly stimulate T cell proliferation and higher IFN-γ production in response to ErbB2. Overall, these results clearly demonstrate that AC represents a promising immunomodulatory adjuvant that could enhance the therapeutic potency of HER-2/neu DNA vaccines in cancer therapy.

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.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Choo AY, Choo DK, Kim JJ, Weiner DB (2005) DNA vaccination in immunotherapy of cancer. Cancer Treat Res 123:137–156 Review

    Article  CAS  PubMed  Google Scholar 

  2. Cavallo F, Offringa R, van der Burg SH, Forni G, Melief CJ (2006) Vaccination for treatment and prevention of cancer in animal models. Adv Immunol 90:175–213 Review

    Article  CAS  PubMed  Google Scholar 

  3. Quaglino E, Iezzi M, Mastini C, Amici A, Pericle F, Di Carlo E, Pupa SM, De Giovanni C, Spadaro M, Curcio C, Lollini PL, Musiani P, Forni G, Cavallo F (2004) Electroporated DNA vaccine clears away multifocal mammary carcinomas in her-2/neu transgenic mice. Cancer Res 64:2858–2864

    Article  CAS  PubMed  Google Scholar 

  4. Lu Y, Wei YQ, Tian L, Zhao X, Yang L, Hu B, Kan B, Wen YJ, Liu F, Deng HX, Li J, Mao YQ, Lei S, Huang MJ, Peng F, Jiang Y, Zhou H, Zhou LQ, Luo F (2003) Immunogene therapy of tumors with vaccine based on xenogeneic epidermal growth factor receptor. J Immunol 170:3162–3170

    CAS  PubMed  Google Scholar 

  5. Kim D, Hoory T, Wu TC, Hung CF (2007) Enhancing DNA vaccine potency by combining a strategy to prolong dendritic cell life and intracellular targeting strategies with a strategy to boost CD4+ T cell. Hum Gene Ther 18:1129–1139

    Article  PubMed  Google Scholar 

  6. Wu SH, Ryvarden L, Chang TT (1997) Antrodia camphorata (“niu-chang-chih”), new combination of a medicinal fungus in Taiwan. Bot Bull Acad Sin 38:273–275

    Google Scholar 

  7. Hseu YC, Chang WC, Hseu YT, Lee CY, Yech YJ, Chen PC, Chen JY, Yang HL (2002) Protection of oxidative damage by aqueous extract from Antrodia camphorata mycelia in normal human erythrocytes. Life Sci 71:469–482

    Article  CAS  PubMed  Google Scholar 

  8. Song TY, Yen GC (2002) Antioxidant properties of Antrodia camphorata in submerged culture. J Agric Food Chem 50:3322–3327

    Article  CAS  PubMed  Google Scholar 

  9. Hsiao G, Shen MY, Lin KH, Lan MH, Wu LY, Chou DS, Lin CH, Su CH, Sheu JR (2003) Antioxidant and hepatoprotective effective of Antrodia camphorata extract. J Agric Food Chem 51:3302–3308

    Article  CAS  PubMed  Google Scholar 

  10. Wang GJ, Tseng HW, Chou CJ, Tsai TH, Chen CT, Lu MK (2003) The vasorelaxation of Antrodia camphorata mycelia: involvement of endothelial Ca2+–NO–cGMP pathway. Life Sci 73:2769–2783

    Article  CAS  PubMed  Google Scholar 

  11. Shen YC, Wang YH, Chou YC, Chen CF, Lin LC, Chang TT, Tien JH, Chou CJ (2004) Evaluation of the anti-inflammatory activity of zhankuic acids isolated from the fruiting bodies of Antrodia camphorata. Planta Med 70:310–314

    Article  CAS  PubMed  Google Scholar 

  12. Lee IH, Huang RL, Chen CT, Chen HC, Hsu WC, Lu MK (2002) Antrodia camphorata polysaccharides exhibit anti-hepatitis B virus effects. FEMS Microbiol Lett 209:63–67

    Article  CAS  PubMed  Google Scholar 

  13. Liu DZ, Liang YC, Lin SY, Lin YS, Wu WC, Hou WC, Su CH (2007) Antihypertensive activities of a solid-state culture of Taiwanofungus camphorates (Chang-Chih) in spontaneously hypertensive rats. Biosci Biotechnol Biochem 71:23–30

    Article  CAS  PubMed  Google Scholar 

  14. Kuo MC, Chang CY, Cheng TL, Wu MJ (2008) Immunomodulatory effect of Antrodia camphorata mycelia and culture filtrate. J Ethnopharmacol 120:196–203

    Article  PubMed  Google Scholar 

  15. Chen KC, Peng CC, Peng RY, Su CH, Chiang HS, Yan JH, Hsieh-Li HM (2007) Unique formosan mushroom Antrodia camphorata differentially inhibits androgen-responsive LNCaP and -independent PC-3 prostate cancer cells. Nutr Cancer 57:111–121

    CAS  PubMed  Google Scholar 

  16. Hsu YL, Kuo PL, Cho CY, Ni WC, Tzeng TF, Ng LT, Kuo YH, Lin CC (2007) Antrodia cinnamomea fruiting bodies extract suppresses the invasive potential of human liver cancer cell line PLC/PRF/5 through inhibition of nuclear factor kB pathway. Food Chem Toxicol 45:1249–1257

    Article  CAS  PubMed  Google Scholar 

  17. Peng CC, Chen KC, Peng RY, Chyau CC, Su CH, Hsieh-Li HM (2007) Antrodia camphorata extract induces replicative senescence in superficial TCC, and inhibits the absolute migration capability in invasive bladder carcinoma cells. J Ethnopharmacol 109:93–103

    Article  PubMed  Google Scholar 

  18. Song TY, Hsu SL, Yeh CT, Yen GC (2005) Mycelia from Antrodia camphorata in submerged culture induced apoptosis of human heptoma HepG2 cells possibility through regulation of Fas pathway. J Agric Food Chem 53:5559–5564

    Article  CAS  PubMed  Google Scholar 

  19. Wu H, Pan CL, Yao YC, Chang SS, Li SL, Wu TF (2006) Proteomic analysis of the effect of Antrodia camphorata extract on human lung cancer A549 cell. Proteomics 6:826–835

    Article  CAS  PubMed  Google Scholar 

  20. Nakamura N, Hirakawa A, Gao JJ, Kakuda H, Shiro M, Komatsu Y, Sheu CC, Hattori M (2004) Five new maleic and succinic acid derivatives from the mycelium of Antrodia camphorata and their cytotoxic effects on LLC tumor cell line. J Nat Prod 67:46–48

    Article  CAS  PubMed  Google Scholar 

  21. Lu MC, Du YC, Chuu JJ, Hwang SL, Hsieh PC, Hung CS, Chang FR, Wu YC (2008) Active extracts of wild fruiting bodies of Antrodia camphorata (EEAC) induce leukemia HL 60 cells apoptosis partially through histone hypoacetylation and synergistically promote anticancer effect of trichostatin A. Arch Toxicol 83:1–9

    Google Scholar 

  22. Liu JJ, Huang TS, Hsu ML, Chen CC, Lin WS, Lu FJ, Chang WH (2004) Antitumor effects of the partially purified polysaccharides from Antrodia camphorata and the mechanism of its action. Toxicol Appl Pharmacol 201:186–193

    Article  CAS  PubMed  Google Scholar 

  23. Bargmann CI, Hung MC, Weinberg RA (1986) The neu oncogene encodes an epidermal growth factor-related protein. Nature 319:226–230

    Article  CAS  PubMed  Google Scholar 

  24. Ardizzoni A, Cafferata MA, Paganuzzi M, Filiberti R, Marroni P, Neri M, Fontana V, Nicoló G, Perdelli L, Stampino CG, Rosso R, Puntoni R (2001) Study of pretreatment serum levels of HER-2/neu oncoprotein as a prognostic and predictive factor in patients with advanced nonsmall cell lung carcinoma. Cancer 92:1896–1904

    Article  CAS  PubMed  Google Scholar 

  25. Underwood M, Bartlett J, Reeves J, Gardiner DS, Scott R, Cooke T (1995) C-erbB-2 gene amplification: a molecular marker in recurrent bladder tumors? Cancer Res 55:2422–2430

    CAS  PubMed  Google Scholar 

  26. Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A et al (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244:707–712

    Article  CAS  PubMed  Google Scholar 

  27. Lin CC, Chou CW, Shiau AL, Tu CF, Ko TM, Chen YL, Yang BC, Tao MH, Lai MD (2004) Therapeutic HER2/Neu DNA vaccine inhibits mouse tumor naturally overexpressing endogenous neu. Mol Ther 10:290–301

    Article  CAS  PubMed  Google Scholar 

  28. Lin CC, Yen MC, Lin CM, Huang SS, Yang HJ, Chow NH, Lai MD (2008) Delivery of noncarrier naked DNA vaccine into the skin by supersonic flow induces a polarized T helper type 1 immune response to cancer. J Gene Med 10:679–689

    Article  CAS  PubMed  Google Scholar 

  29. Lai MD, Yen MC, Lin CM, Tu CF, Wang CC, Lin PS, Yang HJ, Lin CC (2009) The effects of DNA formulation and administration route on cancer therapeutic efficacy with xenogenic EGFR DNA vaccine in a lung cancer animal model. Genet Vaccines Ther 7:2

    Article  PubMed  Google Scholar 

  30. Guiducci C, Vicari AP, Sangaletti S, Trinchieri G, Colombo MP (2005) Redirecting in vivo elicited tumor infiltrating macrophages and dendritic cells towards tumor rejection. Cancer Res 65:3437–3446

    CAS  PubMed  Google Scholar 

  31. Hsiao G, Shen MY, Lin KH, Lan MH, Wu LY, Chou DS, Lin CH, Su CH, Sheu JR (2003) Antioxidative and hepatoprotective effects of Antrodia camphorata extract. J Agric Food Chem 51:3302–3308

    Article  CAS  PubMed  Google Scholar 

  32. Li YH, Chung HC, Liu SL, Chao TH, Chen JC (2009) A novel inhibitory effect of Antrodia camphorata extract on vascular smooth muscle cell migration and neointima formation in mice. Int Heart J 50:207–220

    Article  PubMed  Google Scholar 

  33. Tu CF, Lin CC, Chen MC, Ko TM, Lin CM, Wang YC, Lai MD (2007) Autologous neu DNA vaccine can be as effective as xenogenic neu DNA vaccine by altering administration route. Vaccine 25:719–728

    Article  CAS  PubMed  Google Scholar 

  34. Cheng PC, Hsu CY, Chen CC, Lee KM (2008) In vivo immunomodulatory effects of Antrodia camphorata polysaccharides in a T1/T2 doubly transgenic mouse model for inhibiting infection of Schistosoma mansoni. Toxicol Appl Pharmacol 227:291–298

    Article  CAS  PubMed  Google Scholar 

  35. Singh A, Nie H, Ghosn B, Qin H, Kwak LW, Roy K (2008) Efficient modulation of T-cell response by dual-mode, single-carrier delivery of cytokine-targeted siRNA and DNA vaccine to antigen-presenting cells. Mol Ther 16:2011–2021

    Article  CAS  PubMed  Google Scholar 

  36. Haynes JR (2004) Particle-mediated DNA vaccine delivery to the skin. Expert Opin Biol Ther 4:889–900 Review

    Article  CAS  PubMed  Google Scholar 

  37. Lin CC, Tu CF, Yen MC, Chen MC, Hsieh WJ, Chang WC, Chang WT, Lai MD (2007) Inhibitor of heat-shock protein 90 enhances the antitumor effect of DNA vaccine targeting clients of heat-shock protein. Mol Ther 15:404–410

    Article  CAS  PubMed  Google Scholar 

  38. Robinson HL, Torres CA (1997) DNA vaccine. Semin Immunol 9:271–283

    Article  CAS  PubMed  Google Scholar 

  39. Condon C, Watkins SC, Celluzzi CM, Thompson K, Falo LD Jr (1996) DNA-based immunization by in vivo transfection of dendritic cells. Nat Med 2:1122–1128

    Article  CAS  PubMed  Google Scholar 

  40. Boyle CM, Morin M, Webster RG, Robinson HL (1996) Role of different lymphoid tissues in the initiation and maintenance of DNA. J Virol 70:9074–9078

    CAS  PubMed  Google Scholar 

  41. Winegar RA, Monforte JA, Suing KD, O’Loughlin KG, Rudd CJ, Mac-Gregor JT (1996) Determination of tissue distribution of an intramuscular plasmid vaccine using PCR and in situ DNA hybridization. Hum Gene Ther 7:2185–2194

    Article  CAS  PubMed  Google Scholar 

  42. Vicari AP, Caux C, Trinchieri G (2002) Tumour escape from immune surveillance through dendritic cell inactivation. Semin Cancer Biol 12:33–42

    Article  CAS  PubMed  Google Scholar 

  43. Vicari AP, Chiodoni C, Vaure C, Aït-Yahia S, Dercamp C, Matsos F, Reynard O, Taverne C, Merle P, Colombo MP, O’Garra A, Trinchieri G, Caux C (2002) Reversal of tumor-induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and anti-interleukin 10 receptor antibody. J Exp Med 196:541–549

    Article  CAS  PubMed  Google Scholar 

  44. Tzai TS, Lin CI, Shiau AL, Wu CL (1998) Antisense oligonucleotide specific for transforming growth factor-beta 1 inhibit both in vitro and in vivo growth of MBT-2 murine bladder cancer. Anticancer Res 18:1585–1589

    CAS  PubMed  Google Scholar 

  45. Chen CH, Wang TL, Hung CF, Yang Y, Young RA, Pardoll DM, Wu TC (2000) Enhancement of DNA vaccine potency by linkage of antigen gene to an HSP70 gene. Cancer Res 60:1035–1042

    CAS  PubMed  Google Scholar 

  46. Orlandi F, Venanzi FM, Concetti A, Yamauchi H, Tiwari S, Norton L, Wolchok JD, Houghton AN, Gregor PD (2007) Antibody and CD8+ T cell responses against HER2/neu required for tumor eradication after DNA immunization with a Flt-3 ligand fusion Vaccine. Clin Cancer Res 13:6195–6203

    Article  CAS  PubMed  Google Scholar 

  47. Spadaro M, Ambrosino E, Iezzi M, Di Carlo E, Sacchetti P, Curcio C, Amici A, Wei W-Z, Musiani P, Lollini P-L, Cavallo F, Forni G (2005) Cure of mammary carcinomas in Her-2 transgenic mice through sequential stimulation of innate (neoadjuvant interleukin-12) and adaptive (DNA vaccine electroporation) immunity. Clin Cancer Res 11:1941–1952

    Article  CAS  PubMed  Google Scholar 

  48. Tseng CW, Trimble C, Zeng Q, Monie A, Alvarez RD, Huh WK, Hoory T, Wang MC, Hung CF, Wu TC (2009) Low-dose radiation enhances therapeutic HPV DNA vaccination in tumor-bearing hosts. Cancer Immunol Immunother 58:737–748

    Article  CAS  PubMed  Google Scholar 

  49. Tseng CW, Hung CF, Alvarez RD, Trimble C, Huh WK, Kim D, Chuang CM, Lin CT, Tsai YC, He L, Monie A, Wu TC (2008) Pretreatment with cisplatin enhances E7-specific CD8+ T-cell-mediated antitumor immunity induced by DNA vaccination. Clin Cancer Res 14:3185–3192

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by grants from the Taichung Veterans General Hospital and National Chung Hsing University(TCVGH-NCHU-987614) Taichung, Taiwan, and in part by the Ministry of Education, Taiwan, ROC under the ATU plan.

Conflict of interest statement

None.

Author information

Authors and Affiliations

  1. Institute of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan, ROC

    Chia-Hsin Huang, Min-Tze Wu & Hsien-Chang Chang

  2. Agricultural Research Institute, Council of Agriculture, Executive Yuan, Taipei, Taiwan, ROC

    Chia-Hsin Huang

  3. Institute of Biomedical Sciences, College of Life Science, National Chung Hsing University, Taichung, Taiwan, ROC

    Chia-Che Chang, Sin-Ting Wang & Chi-Chen Lin

  4. Institute of Biotechnology, National Ilan University, Ilan, Taiwan, ROC

    Chiu-Mei Lin

  5. Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC

    Eric I. C. Li

  6. Department of Medical Education and Research, Taichung-Veterans General Hospital, Taichung, Taiwan, ROC

    Chi-Chen Lin

  7. Institute of Medical Technology, College of Life Science, National Chung Hsing University, Taichung, Taiwan, ROC

    Chi-Chen Lin

Authors
  1. Chia-Hsin Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chia-Che Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chiu-Mei Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sin-Ting Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Min-Tze Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eric I. C. Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hsien-Chang Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chi-Chen Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chi-Chen Lin.

Additional information

H.-C. Chang and C.-C Lin contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Huang, CH., Chang, CC., Lin, CM. et al. Promoting effect of Antrodia camphorata as an immunomodulating adjuvant on the antitumor efficacy of HER-2/neu DNA vaccine. Cancer Immunol Immunother 59, 1259–1272 (2010). https://doi.org/10.1007/s00262-010-0852-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-010-0852-y

Keywords

Search

Navigation