Shikonin Enhances Efficacy of a Gene-based Cancer Vaccine Via Induction of RANTES

Overview

Journal J Biomed Sci

Publisher Biomed Central

Specialty Biology

Date 2012 Apr 13

PMID 22494696

Citations 9

Authors

Hui-Ming Chen

Pi-Hsueh Wang

Kandan Aravindaram

Yun-Hsiang Chen

Hsiu-Hui Yu

Wen-Chin Yang

Ning-Sun Yang

Affiliations

Soon will be listed here.

Abstract

Background: Shikonin, a phytochemical purified from Lithospermum erythrorhizon, has been shown to confer diverse pharmacological activities, including accelerating granuloma formation, wound healing, anti-inflammation and others, and is explored for immune-modifier activities for vaccination in this study. Transdermal gene-based vaccine is an attractive approach for delivery of DNA transgenes encoding specific tumor antigens to host skin tissues. Skin dendritic cells (DCs), a potent antigen-presenting cell type, is known to play a critical role in transmitting and orchestrating tumor antigen-specific immunities against cancers. The present study hence employs these various components for experimentation.

Method: The mRNA and protein expression of RANTES were detected by RT-PCR and ELISA, respectively. The regional expression of RANTES and tissue damage in test skin were evaluated via immunohistochemistry assay. Fluorescein isothiocyanate sensitization assay was performed to trace the trafficking of DCs from the skin vaccination site to draining lymph nodes. Adjuvantic effect of shikonin on gene gun-delivered human gp100 (hgp100) DNA cancer vaccine was studied in a human gp100-transfected B16 (B16/hgp100) tumor model.

Results: Among various phytochemicals tested, shikonin induced the highest level of expression of RANTES in normal skin tissues. In comparison, mouse RANTES cDNA gene transfection induced a higher level of mRANTES expression for a longer period, but caused more extensive skin damage. Topical application of shikonin onto the immunization site before gene gun-mediated vaccination augmented the population of skin DCs migrating into the draining lymph nodes. A hgp100 cDNA gene vaccination regimen with shikonin pretreatment as an adjuvant in a B16/hgp100 tumor model increased cytotoxic T lymphocyte activities in splenocytes and lymph node cells on target tumor cells.

Conclusion: Together, our findings suggest that shikonin can effectively enhance anti-tumor potency of a gene-based cancer vaccine via the induction of RANTES expression at the skin immunization site.

Citing Articles

Natural Plant-Derived Compounds in Food and Cosmetics: A Paradigm of Shikonin and Its Derivatives.

Malik S, Brudzynska P, Khan M, Sytar O, Makhzoum A, Sionkowska A Materials (Basel). 2023; 16(12).

PMID: 37374560 PMC: 10304009. DOI: 10.3390/ma16124377.

Phytochemicals as Immunomodulatory Agents in Melanoma.

Tabolacci C, De Vita D, Facchiano A, Bozzuto G, Beninati S, Failla C Int J Mol Sci. 2023; 24(3).

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Cellular and Molecular Signaling as Targets for Cancer Vaccine Therapeutics.

Wei W, Shyur L, Yang N Cells. 2022; 11(9).

PMID: 35563896 PMC: 9104968. DOI: 10.3390/cells11091590.

Molecular mechanism of shikonin inhibiting tumor growth and potential application in cancer treatment.

Wang Q, Wang J, Wang J, Ju X, Zhang H Toxicol Res (Camb). 2021; 10(6):1077-1084.

PMID: 34956612 PMC: 8692723. DOI: 10.1093/toxres/tfab107.

Application of immune checkpoint targets in the anti-tumor novel drugs and traditional Chinese medicine development.

Wang Y, Zhang X, Wang Y, Zhao W, Li H, Zhang L Acta Pharm Sin B. 2021; 11(10):2957-2972.

PMID: 34729298 PMC: 8546663. DOI: 10.1016/j.apsb.2021.03.004.

References

Staniforth V, Wang S, Shyur L, Yang N . Shikonins, phytocompounds from Lithospermum erythrorhizon, inhibit the transcriptional activation of human tumor necrosis factor alpha promoter in vivo. J Biol Chem. 2003; 279(7):5877-85. DOI: 10.1074/jbc.M309185200. View

Kroeze K, Jurgens W, Doulabi B, van Milligen F, Scheper R, Gibbs S . Chemokine-mediated migration of skin-derived stem cells: predominant role for CCL5/RANTES. J Invest Dermatol. 2009; 129(6):1569-81. DOI: 10.1038/jid.2008.405. View

Jin L, Nakao A, Nakayama M, Yamaguchi N, Kojima Y, Nakano N . Induction of RANTES by TWEAK/Fn14 interaction in human keratinocytes. J Invest Dermatol. 2004; 122(5):1175-9. DOI: 10.1111/j.0022-202X.2004.22419.x. View

Tuting T, Storkus W, Falo Jr L . DNA immunization targeting the skin: molecular control of adaptive immunity. J Invest Dermatol. 1998; 111(2):183-8. DOI: 10.1046/j.1523-1747.1998.00261.x. View

Kaith B, Kaith N, Chauhan N . Anti-inflammatory effect of Arnebia euchroma root extracts in rats. J Ethnopharmacol. 1996; 55(1):77-80. DOI: 10.1016/s0378-8741(96)01477-8. View

Warfel A, Thorbecke G, Belsito D . Langerhans cells as outposts of the dendritic cell system. Adv Exp Med Biol. 1993; 329:469-80. DOI: 10.1007/978-1-4615-2930-9_79. View

Ozaki Y, Ohno A, Saito Y, Satake M . Accelerative effect of shikonin, alkannin and acetylshikonin on the proliferation of granulation tissue in rats. Biol Pharm Bull. 1994; 17(8):1075-7. DOI: 10.1248/bpb.17.1075. View

Nakaya K, Miyasaka T . A shikonin derivative, beta-hydroxyisovalerylshikonin, is an ATP-non-competitive inhibitor of protein tyrosine kinases. Anticancer Drugs. 2003; 14(9):683-93. DOI: 10.1097/00001813-200310000-00002. View

Davis H, McCluskie M . DNA vaccines for viral diseases. Microbes Infect. 1999; 1(1):7-21. DOI: 10.1016/s1286-4579(99)80009-4. View

10.

Yang H, Zhou P, Huang H, Chen D, Ma N, Cui Q . Shikonin exerts antitumor activity via proteasome inhibition and cell death induction in vitro and in vivo. Int J Cancer. 2009; 124(10):2450-9. PMC: 2707765. DOI: 10.1002/ijc.24195. View

11.

Chen X, Murakami T, Oppenheim J, Howard O . Triptolide, a constituent of immunosuppressive Chinese herbal medicine, is a potent suppressor of dendritic-cell maturation and trafficking. Blood. 2005; 106(7):2409-16. PMC: 1569904. DOI: 10.1182/blood-2005-03-0854. View

12.

Stoitzner P, Holzmann S, McLellan A, Ivarsson L, Stossel H, Kapp M . Visualization and characterization of migratory Langerhans cells in murine skin and lymph nodes by antibodies against Langerin/CD207. J Invest Dermatol. 2003; 120(2):266-74. DOI: 10.1046/j.1523-1747.2003.12042.x. View

13.

Xiang J, Huang H, Liu Y . A new dynamic model of CD8+ T effector cell responses via CD4+ T helper-antigen-presenting cells. J Immunol. 2005; 174(12):7497-505. DOI: 10.4049/jimmunol.174.12.7497. View

14.

Hou Y, Guo T, Wu C, He X, Zhao M . Effect of shikonin on human breast cancer cells proliferation and apoptosis in vitro. Yakugaku Zasshi. 2006; 126(12):1383-6. DOI: 10.1248/yakushi.126.1383. View

15.

Raz E, Carson D, Parker S, Parr T, Abai A, Aichinger G . Intradermal gene immunization: the possible role of DNA uptake in the induction of cellular immunity to viruses. Proc Natl Acad Sci U S A. 1994; 91(20):9519-23. PMC: 44844. DOI: 10.1073/pnas.91.20.9519. View

16.

Aravindaram K, Yu H, Lan C, Wang P, Chen Y, Chen H . Transgenic expression of human gp100 and RANTES at specific time points for suppression of melanoma. Gene Ther. 2009; 16(11):1329-39. DOI: 10.1038/gt.2009.90. View

17.

Chiu S, Tsao S, Hwang P, Vanisree S, Chen Y, Yang N . Differential functional genomic effects of anti-inflammatory phytocompounds on immune signaling. BMC Genomics. 2010; 11:513. PMC: 2997007. DOI: 10.1186/1471-2164-11-513. View

18.

Zhang S, Zhang Y . Novel chemotactic-antigen DNA vaccine against cancer. Future Oncol. 2008; 4(2):299-303. DOI: 10.2217/14796694.4.2.299. View

19.

Appay V, Rowland-Jones S . RANTES: a versatile and controversial chemokine. Trends Immunol. 2001; 22(2):83-7. DOI: 10.1016/s1471-4906(00)01812-3. View

20.

Gurunathan S, Klinman D, Seder R . DNA vaccines: immunology, application, and optimization*. Annu Rev Immunol. 2000; 18:927-74. DOI: 10.1146/annurev.immunol.18.1.927. View