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Cancer Immunology, Immunotherapy

, Volume 61, Issue 11, pp 1989–2002 | Cite as

Shikonin induces immunogenic cell death in tumor cells and enhances dendritic cell-based cancer vaccine

  • Hui-Ming Chen
  • Pi-Hsueh Wang
  • Swey-Shen Chen
  • Chih-Chun Wen
  • Yun-Hsiang Chen
  • Wen-Chin Yang
  • Ning-Sun YangEmail author
Original article

Abstract

Immunogenic cell death is characterized by damage-associated molecular patterns, which can enhance the maturation and antigen uptake of dendritic cells. Shikonin, an anti-inflammatory and antitumor phytochemical, was exploited here as an adjuvant for dendritic cell-based cancer vaccines via induction of immunogenic cell death. Shikonin can effectively activate both receptor- and mitochondria-mediated apoptosis and increase the expression of all five tested damage-associated molecular patterns in the resultant tumor cell lysates. The combination treatment with damage-associated molecular patterns and LPS activates dendritic cells to a high maturation status and enhances the priming of Th1/Th17 effector cells. Shikonin-tumor cell lysate-loaded mature dendritic cells exhibit a high level of CD86 and MHC class II and activate Th1 cells. The shikonin-tumor cell lysate-loaded dendritic cell vaccines result in a strong induction of cytotoxic activity of splenocytes against target tumor cells, a retardation in tumor growth, and an increase in the survival of test mice. The much enhanced immunogenicity and efficacy of the current cancer vaccine formulation, that is, the use of shikonin-treated tumor cells as cell lysates for the pulse of dendritic cells in culture, may suggest a new ex vivo approach for developing individualized, dendritic cells-based anticancer vaccines.

Keywords

Immunogenic cell death Shikonin Damage-associated molecular pattern Dendritic cells Cancer vaccine 

Abbreviations

Bax

Bcl-2–associated X protein

Bcl-2

B-cell lymphoma 2

CRT

Calreticulin

DAMPs

Damage-associated molecular patterns

DC

Dendritic cell

DX

Doxorubicin

DX-TCL

Doxorubicin-treated tumor cells as cell lysates

ER

Endoplasmic reticulum

GM-CSF

Granulocyte/macrophage-colony stimulatory factor

GRP

Glucose-related protein

HMGB1

High-mobility group protein box 1

HSP

Heat shock protein

MHC

Major histocompatibility complex

MG

MG-132

MG-TCL

MG-132-treated tumor cells as cell lysates

RORγt

Retinoic acid receptor-related orphan nuclear receptor gamma t

SK

Shikonin

SK-TCL

Shikonin-treated tumor cells as cell lysates

Tbet

Th1-specific T box transcription factor

TCL

Tumor cell lysate

TLR4

Toll-like receptor 4

TNFα

Tumor necrosis factor alpha

TX

Paclitaxel

TX-TCL

Paclitaxel-treated tumor cells as cell lysates

XIAP

X-linked inhibitor of apoptosis protein

Notes

Acknowledgments

This present work was sponsored by the Grant (NSC-097-2320-B-001-012) from the National Science Council, Taiwan and the Grant (99-Academia Sinica Investigator Award-12) from Academia Sinica, Taiwan. We thank Heiko Kuhn, Miranda Jane Loney, and Ruth Giodan for manuscript editing.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

262_2012_1258_MOESM1_ESM.jpg (127 kb)
Supplementary material 1 (JPEG 126 kb)
262_2012_1258_MOESM2_ESM.jpg (52 kb)
Supplementary material 2 (JPEG 51 kb)

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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Hui-Ming Chen
    • 1
    • 2
  • Pi-Hsueh Wang
    • 2
  • Swey-Shen Chen
    • 2
    • 5
    • 6
  • Chih-Chun Wen
    • 2
  • Yun-Hsiang Chen
    • 2
  • Wen-Chin Yang
    • 1
    • 2
  • Ning-Sun Yang
    • 2
    • 3
    • 4
    • 7
    Email author
  1. 1.Department and Institute of PharmacologyNational Yang-Ming UniversityTaipeiTaiwan, ROC
  2. 2.Institute of Agricultural Biotechnology Research CenterAcademia SinicaTaipeiTaiwan, ROC
  3. 3.Institute of BiotechnologyNational Taiwan UniversityTaipeiTaiwan, ROC
  4. 4.Department of Life SciencesNational Central UniversityZhongliTaiwan, ROC
  5. 5.Department of Allergy and VaccinologyIGE Therapeutics, Inc.San DiegoUSA
  6. 6.Department of Molecular BiologyThe Scripps Research InstituteSan DiegoUSA
  7. 7.Graduate Institute of BiotechnologyNational Chung Hsing UniversityTaichungTaiwan, ROC

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