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Molecular Biology Reports

, Volume 40, Issue 12, pp 6579–6585 | Cite as

Effect of combined treatment with recombinant interleukin-2 and allicin on pancreatic cancer

  • Cong-Jun Wang
  • Chao Wang
  • Jiang Han
  • Yong-Kun Wang
  • Lin Tang
  • Dong-Wei Shen
  • Yi Zhao
  • Rong-Hua XuEmail author
  • Hui ZhangEmail author
Article

Abstract

This study aimed to evaluate the efficacy of combined treatment with recombinant interleukin-2 (rIL-2) and allicin on pancreatic cancer and explore the potential immunological mechanism. A total of 60 C57/BL6 nude mice pancreatic cancer xenograft models were randomized into four groups of 15 mice per group: control group, allicin treatment group, rIL-2 treatment group, combined treatment with allicin and rIL-2 group. Mice in each group were treated with saline, rIL-2, allicin, or combination of rIL-2 and allicin by weekly i.v injection for four weeks. After four weeks of treatment, eyeballs of the mice were extracted and blood was drawn, percentages of CD4+T, CD8+T and NK cell were analyzed by FACS, IFN-γ level was detected by ELISA. One mouse in each group was sacrificed to measure the weight and volume of the tumor and prepared to the paraffin section of tumor tissue. Apoptosis of the tumor cells was analyzed by TUNEL and FACS. Other mice continued to receive treatment, survival period were compared between each group. We observed a significant suppression of xenograft growth and a significant prolonged survival time in the combined treatment with allicin and rIL-2 group (P < 0.05). The most amount of apoptotic cells were observed in the combined therapy group (P < 0.05). The percentages of CD4+T, CD8+T and NK cell and serum IFN-γ level increased significantly in the combined treatment group compared with other groups (P < 0.05). Combined treatment with allicin and rIL-2 resulted in suppression of tumor growth and prolonged survival time possibly through activation of CD4+T, CD8+T and NK cell.

Keywords

Recombinant interleukin-2 Allicin Pancreatic cancer Combined treatment 

Notes

Acknowledgments

This project is supported by Grants from the National Natural Science Foundation of China (No.30872510; 81200320; 81272534 and 81260349) the Natural Science Foundation of Hubei Province (No. 2008CDB127), and the Natural Science Foundation of Shanghai (No. 064119620 10411968400).

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standards

All human studies have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. All persons gave their informed consent prior to their inclusion in the study.

References

  1. 1.
    Fleischauer AT, Arab L (2001) Garlic and cancer: a critical review of the epidemiologic literature. J Nutr 131(3):1032s–1040sPubMedGoogle Scholar
  2. 2.
    Lamm DL, Riggs DR (2001) Enhanced immunocompetence by garlic: role in bladder cancer and other malignancies. J Nutr 131(3):1067s–1070sPubMedGoogle Scholar
  3. 3.
    Ghazanfari T, Hassan ZM, Ebtekar M, Ahmadiani A, Naderi G, Azar A (2000) Garlic induces a shift in cytokine pattern in Leishmania major-infected BALB/c mice. Scand J Immunol 52(5):491–495PubMedCrossRefGoogle Scholar
  4. 4.
    Leong KH, Ramshaw IA, Ramsay AJ (1997) Interleukin-7 enhances cell-mediated immune responses in vivo in an interleukin-2-dependent manner. Viral Immunol 10(1):1–9PubMedCrossRefGoogle Scholar
  5. 5.
    Watson J, Mochizuki D (1980) Interleukin 2: a class of T cell growth factors. Immunol Rev 51:257–278PubMedCrossRefGoogle Scholar
  6. 6.
    Bleackley RC, Barr PJ, Havele C, Hooton J, Ng J, Meier M, Merryweather JP, Gibbs C, Paetkau V (1985) Biologic activities of recombinant human interleukin-2 on murine lymphocytes. Lymphokine Res 4(2):117–131PubMedGoogle Scholar
  7. 7.
    Bosetti C, Bertuccio P, Negri E, La Vecchia C, Zeegers MP, Boffetta P (2012) Pancreatic cancer: overview of descriptive epidemiology. Mol Carcinog 51(1):3–13. doi: 10.1002/Mc.20785 PubMedCrossRefGoogle Scholar
  8. 8.
    Rozen P, Liphshitz I, Rosner G, Barchana M, Lachter J, Pel S, Shohat T, Santo E, Consortium IPC (2009) Pancreatic cancer in Israel: the epidemiology, possibilities of prevention, early detection and screening. Isr Med Assoc J 11(12):710–713Google Scholar
  9. 9.
    Jemal A, Siegel R, Ward E, Hao YP, Xu JQ, Thun MJ (2009) Cancer Statistics, 2009. CA Cancer J Clin 59(4):225–249. doi: 10.3322/Caac.20006 PubMedCrossRefGoogle Scholar
  10. 10.
    Kleeff J, Michalski C, Friess H, Buchler MW (2006) Pancreatic cancer - From bench to 5-year survival. Pancreas 33(2):111–118PubMedCrossRefGoogle Scholar
  11. 11.
    Brasiuniene B, Juozaityte E (2007) The effect of combined treatment methods on survival and toxicity in patients with pancreatic cancer. Medicina-Lithuania 43(9):716–725Google Scholar
  12. 12.
    von Bernstorff W, Voss M, Freichel S, Schmid A, Vogel I, Johnk C, Henne-Bruns D, Kremer B, Kalthoff H (2001) Systemic and local immunosuppression in pancreatic cancer patients. Clin Cancer Res 7(3):925s–932sGoogle Scholar
  13. 13.
    Plate JMD, Harris JE (2000) Immune cell functions in pancreatic cancer. Crit Rev Immunol 20(5):375–392PubMedCrossRefGoogle Scholar
  14. 14.
    Koido S, Homma S, Hara E, Namiki Y, Takahara A, Komita H, Nagasaki E, Ito M, Ohkusa T, Gong J, Tajiri H (2010) Regulation of tumor immunity by tumor/dendritic cell fusions. Clin Dev Immunol 2010:516768PubMedCrossRefGoogle Scholar
  15. 15.
    Koido S, Homma S, Hara E, Namiki Y, Takahara A, Komita H, Nagasaki E, Ito M, Ohkusa T, Gong J, Tajiri H (2010) Regulation of tumor immunity by tumor/dendritic cell fusions. Clin Dev Immunol 2010:516768. doi: 10.1155/2010/516768 PubMedCrossRefGoogle Scholar
  16. 16.
    Mougiakakos D, Choudhury A, Lladser A, Kiessling R, Johansson CC (2010) Regulatory T cells in cancer. Adv Cancer Res 107:57–117. doi: 10.1016/S0065-230X(10)07003-X PubMedCrossRefGoogle Scholar
  17. 17.
    Shevach EM (2009) Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity 30(5):636–645. doi: 10.1016/j.immuni.2009.04.010 PubMedCrossRefGoogle Scholar
  18. 18.
    Singh SV, Powolny AA, Stan SD, Xiao D, Arlotti JA, Warin R, Hahm ER, Marynowski SW, Bommareddy A, Potter DM, Dhir R (2008) Garlic constituent diallyl trisulfide prevents development of poorly differentiated prostate cancer and pulmonary metastasis multiplicity in TRAMP mice. Cancer Res 68(22):9503–9511. doi: 10.1158/0008-5472.Can-08-1677 PubMedCrossRefGoogle Scholar
  19. 19.
    Sun L, Wang X (2003) Effects of allicin on both telomerase activity and apoptosis in gastric cancer SGC-7901 cells. World J Gastroenterol 9(9):1930–1934PubMedGoogle Scholar
  20. 20.
    Xiao D, Lew KL, Kim YA, Zeng Y, Hahm ER, Dhir R, Singh SV (2006) Diallyl trisulfide suppresses growth of PC-3 human prostate cancer xenograft in vivo in association with Bax and Bak induction. Clin Cancer Res 12(22):6836–6843. doi: 10.1158/1078-0432.Ccr-06-1273 PubMedCrossRefGoogle Scholar
  21. 21.
    Ishikawa H, Saeki T, Otani T, Suzuki T, Shimozuma K, Nishino H, Fukuda S, Morimoto K (2006) Aged garlic extract prevents a decline of NK cell number and activity in patients with advanced cancer. J Nutr 136(3):816s–820sPubMedGoogle Scholar
  22. 22.
    Lake RA, Robinson BWS (2005) Immunotherapy and chemotherapy—a practical partnership. Nat Rev Cancer 5(5):397–405. doi: 10.1038/Nrc1613 PubMedCrossRefGoogle Scholar
  23. 23.
    Degrate L, Nobili C, Franciosi C, Caprotti R, Brivio F, Romano F, Leone BE, Trezzi R, Uggeri F (2009) Interleukin-2 immunotherapy action on innate immunity cells in peripheral blood and tumoral tissue of pancreatic adenocarcinoma patients. Langenbecks Arch Surg 394(1):115–121. doi: 10.1007/s00423-008-0393-4 PubMedCrossRefGoogle Scholar
  24. 24.
    Kim S, Iizuka K, Aguila HL, Weissman IL, Yokoyama WM (2000) In vivo natural killer cell activities revealed by natural killer cell-deficient mice. Proc Natl Acad Sci USA 97(6):2731–2736PubMedCrossRefGoogle Scholar
  25. 25.
    Butt MS, Sultan MT, Butt MS, Iqbal J (2009) Garlic: nature’s protection against physiological threats. Crit Rev Food Sci Nutr 49(6):538–551. doi: 10.1080/10408390802145344 PubMedCrossRefGoogle Scholar
  26. 26.
    Patya M, Zahalka MA, Vanichkin A, Rabinkov A, Miron T, Mirelman D, Wilchek M, Lander HM, Novogrodsky A (2004) Allicin stimulates lymphocytes and elicits an antitumor effect: a possible role of p21ras. Int Immunol 16(2):275–281. doi: 10.1093/intimm/dxh038 PubMedCrossRefGoogle Scholar
  27. 27.
    Tang X-l Jz-y, Cai S-y (2008) Enhanced effect of CD8+T cells activated by tumor lysate-pulsed DCs on killing autologous tumor cells. Chinese J Pathophysiol 1000–4718Google Scholar
  28. 28.
    Chavez AR, Buchser W, Basse PH, Liang X, Appleman LJ, Maranchie JK, Zeh H, de Vera ME, Lotze MT (2009) Pharmacologic administration of interleukin-2. Ann N Y Acad Sci 1182:14–27. doi: 10.1111/j.1749-6632.2009.05160.x PubMedCrossRefGoogle Scholar
  29. 29.
    Krastev Z, Koltchakov V, Tomova R, Deredjian S, Alexiev A, Popov D, Tomov B, Koten JW, Jacobs J, Den Otter W (2005) Locoregional IL-2 low dose applications for gastrointestinal tumors. World J Gastroenterol 11(35):5525–5529PubMedGoogle Scholar
  30. 30.
    Duluc D, Tan F, Scotet M, Blanchard S, Fremaux I, Garo E, Horvat B, Eid P, Delneste Y, Jeannin P (2009) PolyI:C plus IL-2 or IL-12 induce IFN-gamma production by human NK cells via autocrine IFN-beta. Eur J Immunol 39(10):2877–2884. doi: 10.1002/eji.200838610 PubMedCrossRefGoogle Scholar
  31. 31.
    Wulff S, Pries R, Wollenberg B (2010) Cytokine release of human NK cells solely triggered with Poly I:C. Cell Immunol 263(2):135–137. doi: 10.1016/j.cellimm.2010.03.020 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Cong-Jun Wang
    • 1
  • Chao Wang
    • 1
  • Jiang Han
    • 2
  • Yong-Kun Wang
    • 1
  • Lin Tang
    • 1
  • Dong-Wei Shen
    • 1
  • Yi Zhao
    • 1
  • Rong-Hua Xu
    • 3
    Email author
  • Hui Zhang
    • 1
    Email author
  1. 1.Department of General SurgeryShanghai East Hospital, Tongji University School of MedicineShanghaiChina
  2. 2.Department of General SurgeryPudong New Area Zhoupu HospitalShanghaiChina
  3. 3.Department of Oncology SurgeryThe Affiliated Hospital of Hainan Medical CollegeHaikou, Hainan ProvinceChina

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