Enhanced Anti-Tumor Activity of Triptolide in Combination with Irradiation for the Treatment of Oral Cancer

Abstract

Advanced oral cancer has a poor prognosis because of the lack of an effective treatment. We explored the efficiency of combined treatment with triptolide and ionizing radiation for treating oral cancer. Human tongue cancer cells were treated with triptolide, ionizing radiation, or triptolide plus ionizing radiation. Cell proliferation, cell cycle arrest, and apoptotic influences were analyzed by FACS and immunohistochemistry. Tumor potency was examined in an in vivo human tongue cancer cells xenograft mouse model. Our results demonstrated that triptolide caused a marked reduction in colony number that was further enhanced with increasing doses of ionizing radiation. Triptolide increased apoptosis and decreased the expression of anti-apoptotic proteins. In vivo, combination treatment synergistically reduced tumor weight and volume possibly via the induction of apoptosis and reduction in anti-apoptotic protein expression. In conclusion, triptolide plus ionizing radiation treatment had synergistic anti-tumor effects, especially in vivo, and may be a promising combined modality therapy for advanced oral cancer.

Key words

triptolide - ionizing radiation - human tongue cancer cells - Tripterygium wilfordii - Celastraceae

• References

• 1 Pentenero M, Gandolfo S, Carrozzo M. Importance of tumor thickness and depth of invasion in nodal involvement and prognosis of oral squamous cell carcinoma: a review of the literature. Head Neck 2005; 27: 1080-1091
• 2 Chen YJ, Lin SC, Kao T, Chang CS, Hong PS, Shieh TM, Chang KW. Genome-wide profiling of oral squamous cell carcinoma. J Pathol 2004; 204: 326-332
• 3 Daley T, Darling M. Nonsquamous cell malignant tumours of the oral cavity: an overview. J Can Dent Assoc 2003; 69: 577-582
• 4 Lyons AJ, Jones J. Cell adhesion molecules, the extracellular matrix and oral squamous carcinoma. Int J Oral Maxillofac Surg 2007; 36: 671-679
• 5 Greenberg JS, El Naggar AK, Mo V, Roberts D, Myers JN. Disparity in pathologic and clinical lymph node staging in oral tongue carcinoma. Implication for therapeutic decision making. Cancer 2003; 98: 508-515
• 6 Thomas GJ, Speight PM. Cell adhesion molecules and oral cancer. Crit Rev Oral Biol Med 2001; 12: 479-498
• 7 Huang HS, Chen TC, Chen RH, Huang KF, Huang FC, Jhan JR, Chen CL, Lee CC, Lo Y, Lin JJ. Synthesis, cytotoxicity and human telomerase inhibition activities of a series of 1,2-heteroannelated anthraquinones and anthra[1,2-d]imidazole-6,11-dione homologues. Bioorg Med Chem 2009; 17: 7418-7428
• 8 Chen YW, Lin GJ, Chuang YP, Chia WT, Hueng DY, Lin CK, Nieh S, Sytwu HK. Triptolide circumvents drug-resistant effect and enhances 5-fluorouracil antitumor effect on KB cells. Anticancer Drugs 2010; 21: 502-513
• 9 Kramer S, Gelber RD, Snow JB, Marcial VA, Lowry LD, Davis LW, Chandler R. Combined radiation therapy and surgery in the management of advanced head and neck cancer: final report of study 73-03 of the Radiation Therapy Oncology Group. Head Neck Surg 1987; 10: 19-30
• 10 Psyrri A, Fountzilas G. Advances in the treatment of locally advanced non-nasopharyngeal squamous cell carcinoma of the head and neck region. Med Oncol 2006; 23: 1-15
• 11 Brinker AM, Ma J, Lipsky PE, Raskin I. Medicinal chemistry and pharmacology of genus Tripterygium (Celastraceae). Phytochemistry 2007; 68: 732-766
• 12 Chang WT, Kang JJ, Lee KY, Wei K, Anderson E, Gotmare S, Ross JA, Rosen GD. Triptolide and chemotherapy cooperate in tumor cell apoptosis. A role for the p 53 pathway. J Biol Chem 2001; 276: 2221-2227
• 13 Yang S, Chen J, Guo Z, Xu XM, Wang L, Pei XF, Yang J, Underhill CB, Zhang L. Triptolide inhibits the growth and metastasis of solid tumors. Mol Cancer Ther 2003; 2: 65-72
• 14 Tang XY, Zhu YQ, Tao WH, Wei B, Lin XL. Synergistic effect of triptolide combined with 5-fluorouracil on colon carcinoma. Postgrad Med J 2007; 83: 338-343
• 15 Lo JF, Yu CC, Chiou SH, Huang CY, Jan CI, Lin SC, Liu CJ, Hu WY, Yu YH. The epithelial-mesenchymal transition mediator S100A4 maintains cancer-initiating cells in head and neck cancers. Cancer Res 2011; 71: 1912-1923
• 16 Cui YH, Liang HJ, Zhang QQ, Li SQ, Li XR, Huo XQ, Yang QH, Li WW, Gu JF, Hua QL, Lu P, Miao ZH. Radiosensitivity enhancement by arsenic trioxide in conjunction with hyperthermia in the EC-1 esophageal carcinoma cell line. Asian Pac J Cancer Prev 2012; 13: 1693-1697