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


CONCLUSIONS
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.
Department of Neurosurgery, University of Southern California, Los Angeles, CA, USA. tcchen@usc.edu.
Thomas C
TC
Chen
Department of Neurosurgery, University of Southern California, Los Angeles, CA, USA. heeyeonc@usc.edu.
Hee-Yeon
HY
Cho
Department of Neurosurgery, University of Southern California, Los Angeles, CA, USA. Weijun.Wang@med.usc.edu.
Weijun
W
Wang
Department of Molecular Microbiology & Immunology, University of Southern California, Los Angeles, CA, USA. stephjwetzel@gmail.com.
Stephanie J
SJ
Wetzel
Department of Molecular Microbiology & Immunology, University of Southern California, Los Angeles, CA, USA. anupamsi@usc.edu.
Anupam
A
Singh
Department of Molecular Microbiology & Immunology, University of Southern California, Los Angeles, CA, USA. nguy140@usc.edu.
Jenny
J
Nguyen
Department of Pathology, University of Southern California, Los Angeles, CA, USA. hofman@usc.edu.
Florence M
FM
Hofman
Department of Molecular Microbiology & Immunology, University of Southern California, Los Angeles, CA, USA. schontha@usc.edu.
Axel H
AH
Schönthal
D000818:Animals; D002277:Carcinoma; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
C000596794:NEO212; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide