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Anti-Cancer Effects of Cordycepin on Oral Squamous Cell Carcinoma Proliferation and Apoptosis in Vitro

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DOI: 10.4236/jct.2011.22029    5,194 Downloads   10,281 Views   Citations


Cordycepin is an active component of parasitic fungus, Cordyceps militaris, and investigated for its pharmacologic efficacy. Increasing evidence supports the anti-tumoral effects of Cordycepin in various types of human solid tumors. We sought to determine the effects of Cordycepin on oral squamous cell carcinoma in vitro and in vivo. Two oral squamous cell carcinoma cell lines, KB and HSC3, were used in this study. Cells were treated with Cordycepin or diluent, followed by determinations of proliferation by sulforhodamine method and apoptosis by TUNEL assay in vitro. For in vivo experiments, tumor cells were transplanted into nude mice, followed by treatment with Cordycepin or control diluent. In addition, cells were examined for expression of adenosine receptor isotypes, and tested whether cordycepin-induced effects were mediated through adenosine receptors by combinatorial treatment of cordycepin and antagonists specific to each isotype of adenosine receptors. Two cell lines expressed protein of all types of adenosine receptors stronger than normal oral keratinocytes. Cordycepin showed anti-proliferating effect and apoptotic effect on both cell lines in vitro in a dose dependent manner. However, any adenosine receptors did not reverse the effect of cordycepin. In our in vivo experiments, cordycepin failed to decrease the tumor volume significantly, and failed to induce more apoptosis of tumor cells. Cordycepin has anti-proliferating effect and induces apoptosis not mediated by adenosine receptor on oral squamous cell carcinoma cells in vitro. However, in vivo results suggest that cordycepin in itself has a limited value as a novel chemotherapeutic agent for oral squamous cell carcinoma.

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The authors declare no conflicts of interest.

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J. Lee, S. Hong, J. Yun, H. Myoung and M. Kim, "Anti-Cancer Effects of Cordycepin on Oral Squamous Cell Carcinoma Proliferation and Apoptosis in Vitro," Journal of Cancer Therapy, Vol. 2 No. 2, 2011, pp. 224-234. doi: 10.4236/jct.2011.22029.


[1] D. M. Parkin, F. Bray, J. Ferlay and P. Pisani, “Global Cancer Statistics 2002,” CA: A Cancer Journal for Clinicians, Vol. 55, No. 2, March/April 2005, pp. 74-108. doi:10.3322/canjclin.55.2.74
[2] E. S. Kim, M. Kies and R. S. Herbst, “Novel Therapeutics for Head and Neck Cancer,” Current Opinion in Oncology, Vol. 14, No. 3, May 2002, pp. 334-342. doi:10.1097/00001622-200205000-00014
[3] G. Y. Kim, W. S. Ko, J. Y. Lee, J. O. Lee, C. H. Ryu, B. T. Choi, Y. M. Park, Y. K. Jeong, K. J. Lee, K. S. Choi, M. S. Heo and Y. H. Choi, “Water Extract of Cordyceps Militaris Enhances Maturation of Murine Bone Marrow-Derived Dendritic Cells in Vitro,” Biological & Pharmaceutical Bulletin, Vol. 29, No. 2, February 2006, pp. 354-360. doi:10.1248/bpb.29.354
[4] M. E. Rottenberg, W. Masocha, M. Ferella, F. Petitto-Assis, H. Goto, K. Kristensson, R. McCaffrey and H. Wigzell, “Treatment of African Trypanosomiasis with Cordycepin and Adenosine Deaminase Inhibitors in a Mouse Model,” Journal of Infectious Diseases, Vol. 192, No. 9, November 2005, pp. 1658-1665. doi:10.1086/496896
[5] A. M. Sugar and R. P. McCaffrey, “Antifungal Activity of 3’-Deoxyadenosine (Cordycepin),” Antimicrobial Age- nts and Chemotherapy, Vol. 42, No. 6, June 1998, pp. 1424-1427.
[6] F. L. Xu, Y. L. Lee, W. Y. Tsai, S. J. Lin, Z. Q. Yang, C. C. Yang, H. Y. Liu, L. Cheng, H. Xiao and L. Wen, “Effect of Cordycepin on Hantaan Virus 76-118 Infection of Primary Human Embryonic Pulmonary Fibroblasts— Characterization of Apoptotic Effects,” Acta Virologica, Vol. 49, No. 3, 2005, pp. 183-193.
[7] H. J. Cho, J. Y. Cho, M. H. Rhee and H. J. Park, “Cordycepin (3'-deoxyadenosine) Inhibits Human Platelet Aggregation in a Cyclic AMP- and Cyclic GMP-Dependent Manner,” European Journal of Pharmacology, Vol. 558, No. 1-3, 8 March 2007, pp. 43-51. doi:10.1016/j.ejphar.2006.11.073
[8] H. Chung, J. Y. Jung, S. D. Cho, K. A. Hong, H. J. Kim, D. H. Shin, H. Kim, H. O. Kim, D. H. Shin, H. W. Lee, L. S. Jeong and G. Kong, “The Antitumor Effect of LJ-529, a Novel Agonist to A3 Adenosine Receptor, in both Estrogen Receptor-Positive and Estrogen Receptor-Negative Human Breast Cancers,” Molecular Cancer Therapeutics, Vol. 5, No. 3, March 2006, pp. 685-692. doi:10.1158/1535-7163.MCT-05-0245
[9] Y. Koc, A. G. Urbano, E. B. Sweeney and R. McCaffrey, “Induction of Apoptosis by Cordycepin in ADA-Inhibited TdT-Positive Leukemia Cells,” Leukemia, Vol. 10, No. 6, June 1996, pp. 1019-1024.
[10] K. Nakamura, N. Yoshikawa, Y. Yamaguchi, S. Kagota, K. Shinozuka and M. Kunitomo, “Antitumor Effect of Cordycepin (3'-deoxyadenosine) on Mouse Melanoma and Lung Carcinoma Cells Involves Adenosine A3 Receptor Stimulation,” Anticancer Research, Vol. 26, No.1A, January/February 2006, pp. 43-47.
[11] F. M. Foss, “Combination Therapy with Purine Nucleoside Analogs,” Oncology (Williston Park), Vol. 14, No. 6, Supplement 2, June 2000, pp. 31-35.
[12] H. Thomadaki, C. M. Tsiapalis and A. Scorilas, “Poly- adenylate Polymerase Modulations in Human Epithelioid Cervix and Breast Cancer Cell Lines, Treated with Etoposide or Cordycepin, Follow Cell Cycle rather than Apoptosis Induction,” Biological Chemistry, Vol. 386, No. 5, May 2005, pp. 471-480. doi:10.1515/BC.2005.056
[13] N. Yoshikawa, K. Nakamura, Y. Yamaguchi, S. Kagota, K. Shinozuka and M. Kunitomo, “Antitumour Activity of Cordycepin in Mice,” Clinical and Experimental Pharmacology and Physiology, Vol. 31, No. Supplement 2, December 2004, pp. S51-53.
[14] W. C. Wu, J. R. Hsiao, Y. Y. Lian, C. Y. Lin and B. M. Huang, “The Apoptotic Effect of Cordycepin on Human OEC-M1 Oral Cancer Cell Line,” Cancer Chemotherapy and Pharmacology, Vol. 60, No. 1, June 2007, pp. 103-111. doi:10.1007/s00280-006-0354-y
[15] A. J. Nordone and E. B. Pivorun, “Cytosolic Calcium Responses to Extracellular Adenosine 5',5" '-P1,P4-Tetraphosphate in PC12 Cells,” Pharmacology Biochemistry and Behavior, Vol. 52, No. 1, September 1995, pp. 85-91. doi:10.1016/0091-3057(95)00018-R
[16] G. Ohana, S. Bar-Yehuda, F. Barer and P. Fishman, “Differential Effect of Adenosine on Tumor and Normal Cell Growth: Focus on the A3 Adenosine Receptor,” Journal of Cellular Physiology, Vol. 186, No. 1, January 2001, pp. 19-23. doi:10.1002/1097-4652(200101)186:1<19::AID-JCP1011>3.0.CO;2-3
[17] S. Merighi, K. Varani, S. Gessi, E. Cattabriga, V. Iannotta, C. Ulouglu, E. Leung and P. A. Borea, “Pharmacological and Biochemical Characterization of Adenosine Receptors in the Human Malignant Melanoma A375 Cell Line,” British Journal of Pharmacology, Vol. 134, No. 6, November 2001, pp. 1215-1226. doi:10.1038/sj.bjp.0704352
[18] P. Fishman, S. Bar-Yehuda, E. Ardon, L. Rath-Wolfson, F. Barrer, A. Ochaion and L. Madi, “Targeting the A3 Adenosine Receptor for Cancer Therapy: Inhibition of Prostate Carcinoma Cell Growth by A3AR Agonist,” Anticancer Research, Vol. 23, No. 3A, May/June 2003, pp. 2077-2083.
[19] J. Lu, A. Pierron and K. Ravid, “An Adenosine Analogue, IB-MECA, Down-Regulates Estrogen Receptor Alpha and Suppresses Human Breast Cancer Cell Proliferation,” Cancer Research, Vol. 63, No. 19, 1 October 2003, pp. 6413-6423.
[20] M. Panjehpour and F. Karami-Tehrani, “An Adenosine Analog (IB-MECA) Inhibits Anchorage-Dependent Cell Growth of Various Human Breast Cancer Cell Lines,” International Journal of Biochemistry & Cell Biology, Vol. 36, No. 8, August 2004, pp. 1502-1509. doi:10.1016/j.biocel.2003.12.001
[21] P. T. Phelps, J. C. Anthes and C. Correll, “Characterization of Adenosine Receptors in the Human Bladder Carcinoma T24 Cell Line,” European Journal of Pharmacology, Vol. 536, No. 1-2, April 2006, pp. 28-37. doi:10.1016/j.ejphar.2006.02.046
[22] S. Gessi, E. Cattabriga, A. Avitabile, R. Gafa, G. Lanza, L. Cavazzini, N. Bianchi, R. Gambari, C. Feo, A. Liboni, S. Gullini, E. Leung, S. Mac-Lennan and P. A. Borea, “Elevated Expression of A3 Adenosine Receptors in Human Colorectal Cancer is Reflected in Peripheral Blood Cells,” Clinical Cancer Research, Vol. 10, No. 17, 1 September 2004, pp. 5895-5901. doi:10.1158/1078-0432.CCR-1134-03
[23] L. Madi, A. Ochaion, L. Rath-Wolfson, S. Bar-Yehuda, A. Erlanger, G. Ohana, A. Harish, O. Merimski, F. Barer and P. Fishman, “The A3 Adenosine Receptor is Highly Expressed in Tumor Versus Normal Cells: Potential Target for Tumor Growth Inhibition,” Clinical Cancer Research, Vol. 10, No. 13, 1 July 2004, pp. 4472-4479. doi:10.1158/1078-0432.CCR-03-0651
[24] P. Fishman, S. Bar-Yehuda, F. Barer, L. Madi, A. S. Multani and S. Pathak, “The A3 Adenosine Receptor as a New Target for Cancer Therapy and Chemoprotection,” Experimental Cell Research, Vol. 269, No. 2, October 2001, pp. 230-236. doi:10.1006/excr.2001.5327
[25] P. Fishman, S. Bar-Yehuda, G. Ohana, F. Barer, A. Ochaion, A. Erlanger and L. Madi, “An Agonist to the A3 Adenosine Receptor Inhibits Colon Carcinoma Growth in Mice via Modulation of GSK-3 Beta and NF-kappa B,” Oncogene, Vol. 23, No. 14, 1 April 2004, pp. 2465-2471. doi:10.1038/sj.onc.1207355
[26] P. Fishman, L. Madi, S. Bar-Yehuda, F. Barer, L. Del Valle and K. Khalili, “Evidence for Involvement of Wnt Signaling Pathway in IB-MECA Mediated Suppression of Melanoma Cells,” Oncogene, Vol. 21, No. 25, June 2002, pp. 4060-4064. doi:10.1038/sj.onc.1205531
[27] Y. Kohno, Y. Sei, M. Koshiba, H. O. Kim and K. A. Jacobson, “Induction of Apoptosis in HL-60 Human Promyelocytic Leukemia Cells by Adenosine A(3) Receptor Agonists,” Biochemical and Biophysical Research Communications, Vol. 219, No. 3, February 1996, pp. 904-910. doi:10.1006/bbrc.1996.0331
[28] Y. Yao, Y. Sei, M. P. Abbracchio, J. L. Jiang, Y. C. Kim and K. A. Jacobson, “Adenosine A3 Receptor Agonists Protect HL-60 and U-937 Cells from Apoptosis Induced by A3 Antagonists,” Biochemical and Biophysical Research Communications, Vol. 232, No. 2, March 1997, pp. 317-322. doi:10.1006/bbrc.1997.6290
[29] E. J. Lee, H. Y. Min, H. J. Chung, E. J. Park, D. H. Shin, L. S. Jeong and S. K. Lee, “A Novel Adenosine Analog, Thio-Cl-IB-MECA, Induces G0/G1 Cell Cycle Arrest and Apoptosis in Human Promyelocytic Leukemia HL-60 Cells,” Biochemical Pharmacology, Vol. 70, No. 6, September 2005, pp. 918-924.
[30] C. Schneider, H. Wiendl and A. Ogilvie, “Biphasic Cytotoxic Mechanism of Extracellular ATP on U-937 Human Histiocytic Leukemia Cells: Involvement of Adenosine Generation,” Biochemica et Biophysica Acta (BBA)-Molecular Cell Research, Vol. 1538, No. 2-3, April 2001, pp. 190-205.
[31] L. F. Wu, G. P. Li, J. L. Feng and Z. J. Pu, “Molecular Mechanisms of Adenosine-Induced Apoptosis in Human HepG2 Cells,” Acta Pharmacologica Sinica, Vol. 27, No. 4, April 2006, pp. 477-484. doi:10.1111/j.1745-7254.2006.00302.x
[32] S. G. Kim, G. Ravi, C. Hoffmann, Y. J. Jung, M. Kim, A. Chen and K. A. Jacobson, “P53-Independent Induction of Fas and Apoptosis in Leukemic Cells by an Adenosine Derivative, Cl-IB-MECA,” Biochemical Pharmacology, Vol. 63, No. 5, March 2002, pp. 871-80. doi:10.1016/S0006-2952(02)00839-0

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