Chemotherapeutic effect of a novel temozolomide analog on nasopharyngeal carcinoma in vitro and in vivo

Journal of Biomedical Science

Axel H. Schönthal³  Florence M. Hofman²  Jenny Nguyen³  Anupam Singh³  Stephanie J. Wetzel³  Weijun Wang¹  Hee-Yeon Cho¹  Thomas C. Chen¹ 

[1] Department of Neurosurgery, University of Southern California, Los Angeles, CA, USA;Department of Pathology, University of Southern California, Los Angeles, CA, USA;Department of Molecular Microbiology & Immunology, University of Southern California, Los Angeles, CA, USA

关键词: Chemoresistance;    Temozolomide;    Perillyl alcohol;    O6-methylguanine-DNA methyltransferase;    Nasopharyngeal carcinoma;   

Others  :  1230530
DOI  :  10.1186/s12929-015-0175-6

 received in 2015-04-27, accepted in 2015-08-01,  发布年份 2015

【 摘 要 】

Background

Many patients with nasopharyngeal carcinoma (NPC) face poor prognosis. Due to its hidden anatomical location, the tumor is usually diagnosed quite late, and despite initially successful treatment with radiation and cisplatin, many patients will relapse and succumb to the disease. New treatment options are urgently needed. We have performed preclinical studies to evaluate the potential NPC therapeutic activity of a newly developed analog of temozolomide (TMZ), an alkylating agent that is the current chemotherapeutic standard of care for patients with malignant glioma.

Results

TMZ was covalently conjugated to the natural monoterpene perillyl alcohol (POH), creating the novel fusion compound NEO212. Its impact on two NPC cell lines was studied through colony formation assays, cell death ELISA, immunoblots, and in vivo testing in tumor-bearing mice. In vitro, NEO212 effectively triggered tumor cell death, and its potency was significantly greater than that of its individual components, TMZ or POH alone. Intriguingly, merely mixing TMZ with POH also was unable to achieve the superior potency of the conjugated compound NEO212. Treatment of NPC cells with NEO212 inactivated the chemoprotective DNA repair protein MGMT (O6-methylguanine methyltransferase), resulting in significant chemosensitization of cells to a second round of drug treatment. When tested in vivo, NEO212 reduced tumor growth in treated animals.

Conclusion

Our results demonstrate anticancer activity of NEO212 in preclinical NPC models, suggesting that this novel compound should be evaluated further for the treatment of patients with NPC.

【 授权许可】

   
2015 Chen et al.

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【 参考文献 】

• [1]Brennan B. Nasopharyngeal carcinoma. Orphanet J Rare Dis. 2006; 1:23. BioMed Central Full Text
• [2]Chaney SG, Campbell SL, Bassett E, Wu Y. Recognition and processing of cisplatin- and oxaliplatin-DNA adducts. Crit Rev Oncol Hematol. 2005; 53(1):3-11.
• [3]Chen SH, Kuo CC, Li CF, Cheung CH, Tsou TC, Chiang HC, Yang YN, Chang SL, Lin LC, Pan HY, Chang KY, Chang JY. O(6) -methylguanine DNA methyltransferase repairs platinum-DNA adducts following cisplatin treatment and predicts prognoses of nasopharyngeal carcinoma. Int J Cancer. 2015; 137(6):1291-305.
• [4]Chen TC, Cho HY, Wang W, Barath M, Sharma N, Hofman FM, Schönthal AH. A novel temozolomide-perillyl alcohol conjugate exhibits superior activity against breast cancer cells in vitro and intracranial triple-negative tumor growth in vivo. Mol Cancer Ther. 2014; 13(5):1181-93.
• [5]Chen TC, Fonseca CO, Schönthal AH. Preclinical development and clinical use of perillyl alcohol for chemoprevention and cancer therapy. Am J Cancer Res. 2015; 5(5):1580-93.
• [6]Cho HY, Wang W, Jhaveri N, Torres S, Tseng J, Leong MN, Lee DJ, Goldkorn A, Xu T, Petasis NA, Louie SG, Schönthal AH, Hofman FM, Chen TC. Perillyl alcohol for the treatment of temozolomide-resistant gliomas. Mol Cancer Ther. 2012; 11(11):2462-72.
• [7]Christmann M, Verbeek B, Roos WP, Kaina B. O(6)-Methylguanine-DNA methyltransferase (MGMT) in normal tissues and tumors: enzyme activity, promoter methylation and immunohistochemistry. Biochim Biophys Acta. 2011; 1816(2):179-90.
• [8]da Fonseca CO, Schwartsmann G, Fischer J, Nagel J, Futuro D, Quirico-Santos T, Gattass CR. Preliminary results from a phase I/II study of perillyl alcohol intranasal administration in adults with recurrent malignant gliomas. Surg Neurol. 2008; 70(3):259-66.
• [9]da Fonseca CO, Simao M, Lins IR, Caetano RO, Futuro D, Quirico-Santos T. Efficacy of monoterpene perillyl alcohol upon survival rate of patients with recurrent glioblastoma. J Cancer Res Clin Oncol. 2011; 137(2):287-93.
• [10]Grant LM, Kleiner DE, Conjeevaram HS, Vuppalanchi R, Lee WM. Clinical and histological features of idiosyncratic acute liver injury caused by temozolomide. Dig Dis Sci. 2013; 58(5):1415-21.
• [11]Haag JD, Gould MN. Mammary carcinoma regression induced by perillyl alcohol, a hydroxylated analog of limonene. Cancer Chemother Pharmacol. 1994; 34(6):477-83.
• [12]Hammond LA, Eckardt JR, Baker SD, Eckhardt SG, Dugan M, Forral K, Reidenberg P, Statkevich P, Weiss GR, Rinaldi DA, Von Hoff DD, Rowinsky EK. Phase I and pharmacokinetic study of temozolomide on a daily-for-5-days schedule in patients with advanced solid malignancies. J Clin Oncol. 1999; 17(8):2604-13.
• [13]Jang-Chun L, Jing-Min H, Yee-Min J, Dai-Wei L, Chang-Ming C, Chun-Shu L, Wen-Yen H, Yu-Fu S, Kuen-Tze L, Chao-Yueh F, Cheng-Hsiang L, Hsing-Lung C. Comparisons of quality of life for patients with nasopharyngeal carcinoma after treatment with different RT technologies. Acta Otorhinolaryngol Ital. 2014; 34(4):241-6.
• [14]Kaina B, Christmann M, Naumann S, Roos WP. MGMT: key node in the battle against genotoxicity, carcinogenicity and apoptosis induced by alkylating agents. DNA Repair (Amst). 2007; 6(8):1079-99.
• [15]Kaina B, Margison GP, Christmann M. Targeting O(6)-methylguanine-DNA methyltransferase with specific inhibitors as a strategy in cancer therapy. Cell Mol Life Sci. 2010; 67(21):3663-81.
• [16]Kwong J, Lo KW, To KF, Teo PM, Johnson PJ, Huang DP. Promoter hypermethylation of multiple genes in nasopharyngeal carcinoma. Clin Cancer Res. 2002; 8(1):131-7.
• [17]Lin CT, Chan WY, Chen W, Huang HM, Wu HC, Hsu MM, Chuang SM, Wang CC. Characterization of seven newly established nasopharyngeal carcinoma cell lines. Lab Invest. 1993; 68(6):716-27.
• [18]Lu H, Peng L, Yuan X, Hao Y, Lu Z, Chen J, Cheng J, Deng S, Gu J, Pang Q, Qin J. Concurrent chemoradiotherapy in locally advanced nasopharyngeal carcinoma: a treatment paradigm also applicable to patients in Southeast Asia. Cancer Treat Rev. 2009; 35(4):345-53.
• [19]Ma J, Liu L, Tang L, Zong J, Lin A, Lu T, Cui N, Cui C, Li L. Retropharyngeal lymph node metastasis in nasopharyngeal carcinoma: prognostic value and staging categories. Clin Cancer Res. 2007; 13(5):1445-52.
• [20]McDermott AL, Dutt SN, Watkinson JC. The aetiology of nasopharyngeal carcinoma. Clin Otolaryngol Allied Sci. 2001; 26(2):82-92.
• [21]Mills JJ, Chari RS, Boyer IJ, Gould MN, Jirtle RL. Induction of apoptosis in liver tumors by the monoterpene perillyl alcohol. Cancer Res. 1995; 55(5):979-83.
• [22]Pegg AE. Multifaceted roles of alkyltransferase and related proteins in DNA repair, DNA damage, resistance to chemotherapy, and research tools. Chem Res Toxicol. 2011; 24(5):618-39.
• [23]Pegg AE, Wiest L, Mummert C, Stine L, Moschel RC, Dolan ME. Use of antibodies to human O6-alkylguanine-DNA alkyltransferase to study the content of this protein in cells treated with O6-benzylguanine or N-methyl-N'-nitro-N-nitrosoguanidine. Carcinogenesis. 1991; 12(9):1679-83.
• [24]Pyrko P, Soriano N, Kardosh A, Liu YT, Uddin J, Petasis NA, Hofman FM, Chen CS, Chen TC, Schönthal AH. Downregulation of survivin expression and concomitant induction of apoptosis by celecoxib and its non-cyclooxygenase-2-inhibitory analog, dimethyl-celecoxib (DMC), in tumor cells in vitro and in vivo. Mol Cancer. 2006; 5(1):19. BioMed Central Full Text
• [25]Silber JR, Bobola MS, Blank A, Chamberlain MC. O(6)-methylguanine-DNA methyltransferase in glioma therapy: promise and problems. Biochim Biophys Acta. 2012; 1826(1):71-82.
• [26]Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009; 10(5):459-66.
• [27]Tsang J, Lee VH, Kwong DL. Novel therapy for nasopharyngeal carcinoma--where are we. Oral Oncol. 2014; 50(9):798-801.
• [28]Velho TR. Metastatic melanoma - a review of current and future drugs. Drugs Context. 2012; 2012:212242.
• [29]Wei WI, Sham JS. Nasopharyngeal carcinoma. Lancet. 2005; 365(9476):2041-54.
• [30]Yuri T, Danbara N, Tsujita-Kyutoku M, Kiyozuka Y, Senzaki H, Shikata N, Kanzaki H, Tsubura A. Perillyl alcohol inhibits human breast cancer cell growth in vitro and in vivo. Breast Cancer Res. 2004; 84(3):251-60.
• [31]Zhang J, Stevens MF, Bradshaw TD. Temozolomide: mechanisms of action, repair and resistance. Curr Mol Pharmacol. 2012; 5(1):102-14.