Kanglaite stimulates anticancer immune responses and inhibits HepG2 cell transplantation‑induced tumor growth

Huang,Xinli; Qin,Jianjie; Lu,Sen

doi:10.3892/mmr.2014.2479

Kanglaite stimulates anticancer immune responses and inhibits HepG2 cell transplantation‑induced tumor growth

Authors:
- Xinli Huang
- Jianjie Qin
- Sen Lu
View Affiliations

Affiliations: Center of Liver Transplantation, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Liver Transplantation, Ministry of Health, Nanjing 210029, P.R. China
Published online on: August 11, 2014 https://doi.org/10.3892/mmr.2014.2479
Pages: 2153-2159

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Previous studies revealed that Kanglaite (KLT) exhibits antitumor and immunomodulatory activities. In the present study, we show that KLT treatment stimulated the immune response by increasing the number of T cells and natural killer (NK) cells in the blood of hepatocellular carcinoma (HCC) patients. Experiments in tumor‑bearing mice were further designed in order to explore the effects of KLT on the immune system and the underlying molecular mechanisms. The results showed that KLT improves the tumor cell transplantation‑induced reduction in the serum level of the cytokines IFN‑γ and IL‑2, and rescues the levels of CD4+ T cells in host mice. These events enhanced the cytotoxic activities of natural killer and CD8+ T cells against the hepatic HepG2 cancer cells. KLT administration further increased the mRNA level of certain nuclear factor κB (NF‑κB)‑responsive genes in CD4+ cells. The chromatin immunoprecipitation assay showed that KLT increases the association of the NF‑κB p65 subunit to the promoter regions of interleukin (IL)‑2‑ and B‑cell lymphoma (Bcl)‑2‑encoding genes in CD4+ T cells. Our study demonstrated that KLT is the main active ingredient of coix seed exhibiting anticancer and immunomodulatory properties. Induction of NF‑κB‑mediated gene transcription in CD4+ T cells is involved in the immunomodulatory activity of KLT.

View Figures

View References

1	Nordenstedt H, White DL and El-Serag HB: The changing pattern of epidemiology in hepatocellular carcinoma. Dig Liver Dis. 42(Suppl 3): S206–S214. 2010. View Article : Google Scholar : PubMed/NCBI
2	Clavien PA, Petrowsky H, DeOliveira ML and Graf R: Strategies for safer liver surgery and partial liver transplantation. N Engl J Med. 356:1545–1559. 2007. View Article : Google Scholar : PubMed/NCBI
3	Brunocilla PR, Brunello F, Carucci P, et al: Sorafenib in hepatocellular carcinoma: prospective study on adverse events, quality of life, and related feasibility under daily conditions. Med Oncol. 30:3452013. View Article : Google Scholar
4	Pawlik TM, Reyes DK, Cosgrove D, Kamel IR, Bhagat N and Geschwind JF: Phase II trial of sorafenib combined with concurrent transarterial chemoembolization with drug-eluting beads for hepatocellular carcinoma. J Clin Oncol. 29:3960–3967. 2011. View Article : Google Scholar : PubMed/NCBI
5	Vasievich EA and Huang L: The suppressive tumor microenvironment: a challenge in cancer immunotherapy. Mol Pharm. 8:635–641. 2011. View Article : Google Scholar : PubMed/NCBI
6	Pardee AD and Butterfield LH: Immunotherapy of hepatocellular carcinoma: unique challenges and clinical opportunities. Oncoimmunology. 1:48–55. 2012. View Article : Google Scholar : PubMed/NCBI
7	Ormandy LA, Farber A, Cantz T, et al: Direct ex vivo analysis of dendritic cells in patients with hepatocellular carcinoma. World J Gastroenterol. 12:3275–3282. 2006.
8	Hoechst B, Voigtlaender T, Ormandy L, et al: Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor. Hepatology. 50:799–807. 2009. View Article : Google Scholar : PubMed/NCBI
9	Teitz-Tennenbaum S, Li Q, Okuyama R, et al: Mechanisms involved in radiation enhancement of intratumoral dendritic cell therapy. J Immunother. 31:345–358. 2008. View Article : Google Scholar
10	Krusch M, Salih J, Schlicke M, et al: The kinase inhibitors sunitinib and sorafenib differentially affect NK cell antitumor reactivity in vitro. J Immunol. 183:8286–8294. 2009. View Article : Google Scholar : PubMed/NCBI
11	Zhang QB, Sun HC, Zhang KZ, et al: Suppression of natural killer cells by sorafenib contributes to prometastatic effects in hepatocellular carcinoma. PLoS One. 8:e559452013. View Article : Google Scholar : PubMed/NCBI
12	Lu Y, Li CS and Dong Q: Chinese herb related molecules of cancer-cell-apoptosis: a minireview of progress between Kanglaite injection and related genes. J Exp Clin Cancer Res. 27:312008. View Article : Google Scholar : PubMed/NCBI
13	Zhan YP, Huang XE, Cao J, et al: Clinical safety and efficacy of Kanglaite® (Coix Seed Oil) injection combined with chemotherapy in treating patients with gastric cancer. Asian Pac J Cancer Prev. 13:5319–5321. 2012.
14	Pan P, Wu Y, Guo ZY, Wang R, Wang YJ and Yuan YF: Antitumor activity and immunomodulatory effects of the intraperitoneal administration of Kanglaite in vivo in Lewis lung carcinoma. J Ethnopharmacol. 143:680–685. 2012. View Article : Google Scholar
15	Wullaert A, Bonnet MC and Pasparakis M: NF-κB in the regulation of epithelial homeostasis and inflammation. Cell Res. 21:146–158. 2011.
16	Porta C, Larghi P, Rimoldi M, et al: Cellular and molecular pathways linking inflammation and cancer. Immunobiology. 214:761–777. 2009. View Article : Google Scholar : PubMed/NCBI
17	Zhang Y, Yu G, Wang D, Hu Y and Lei W: ERK1/2 activation plays important roles in the opposite effects of Trichostatin A in non-cancer and cancer cells. Toxicon. 57:932–937. 2011. View Article : Google Scholar
18	Lee S, Ra J, Song JY, et al: Extracts from Citrus unshiu promote immune-mediated inhibition of tumor growth in a murine renal cell carcinoma model. J Ethnopharmacol. 133:973–979. 2011.
19	Wang J, Tong X, Li P, Cao H and Su W: Immuno-enhancement effects of shenqi fuzheng injection on cyclophosphamide-induced immunosuppression in Balb/c mice. J Ethnopharmacol. 139:788–795. 2012. View Article : Google Scholar : PubMed/NCBI
20	Huang H, Hao S, Li F, Ye Z, Yang J and Xiang J: CD4+ Th1 cells promote CD8+ Tc1 cell survival, memory response, tumor localization and therapy by targeted delivery of interleukin 2 via acquired pMHC I complexes. Immunology. 120:148–159. 2007. View Article : Google Scholar
21	Rakhra K, Bachireddy P, Zabuawala T, et al: CD4⁺ T cells contribute to the remodeling of the microenvironment required for sustained tumor regression upon oncogene inactivation. Cancer Cell. 18:485–498. 2010.
22	Chaput N, Darrasse-Jeze G, Bergot AS, et al: Regulatory T cells prevent CD8 T cell maturation by inhibiting CD4 Th cells at tumor sites. J Immunol. 179:4969–4978. 2007. View Article : Google Scholar : PubMed/NCBI
23	Biswas K, Richmond A, Rayman P, et al: GM2 expression in renal cell carcinoma: potential role in tumor-induced T-cell dysfunction. Cancer Res. 66:6816–6825. 2006. View Article : Google Scholar : PubMed/NCBI
24	Cui G and Florholmen J: Polarization of cytokine profile from Th1 into Th2 along colorectal adenoma-carcinoma sequence: implications for the biotherapeutic target? Inflamm Allergy Drug Targets. 7:94–97. 2008. View Article : Google Scholar
25	Grimm M, Gasser M, Bueter M, et al: Evaluation of immunological escape mechanisms in a mouse model of colorectal liver metastases. BMC Cancer. 10:822010. View Article : Google Scholar : PubMed/NCBI
26	Baldwin AS: Regulation of cell death and autophagy by IKK and NF-κB: critical mechanisms in immune function and cancer. Immunol Rev. 246:327–345. 2012.
27	Shi Y, Feng Y, Kang J, et al: Critical regulation of CD4⁺ T cell survival and autoimmunity by β-arrestin 1. Nat Immunol. 8:817–824. 2007.
28	Weil R and Israel A: T-cell-receptor- and B-cell-receptor-mediated activation of NF-kappaB in lymphocytes. Curr Opin Immunol. 16:374–381. 2004. View Article : Google Scholar : PubMed/NCBI