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

Abstract

BackgroundMany 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.ResultsTMZ 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.ConclusionOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12929-015-0175-6) contains supplementary material, which is available to authorized users.

Macrophages Reprogrammed In Vitro Towards the M1 Phenotype and Activated with LPS Extend Lifespan of Mice with Ehrlich Ascites Carcinoma

“…“Tumor + cisplatin” group, mice injected with EAC cells with subsequent infusion of 0.05 ml of cisplatin (0.5 mg/ml), an antitumor drug [ 29 , 30 ], on days 3, 7 and 11 experimental days. Cisplatin has been often used as a reference drug [ 31 ].…”

Computer‑aided design of temozolomide derivatives based on alkylglycerone phosphate synthase structure with isothiocyanate and their pharmacokinetic/toxicity prediction and anti‑tumor activity in vitro

“…Temozolomide (TMZ) is a novel type of glioma therapeutic drug, which is able to penetrate the blood-brain barrier to exert targeted therapeutic effects on brain tumor tissue ( 5 , 6 ). To date, studies have aimed to enhance the efficacy and reduce the toxic side effects of TMZ by reconstructing its chemical structure ( 7 , 8 ). To build on these previous studies, the present study utilized the molecular biological differences between tumor and normal cells to design TMZ derivatives with enhanced selectivity and targeting activities through rational computer-aided drug design (CADD).…”

NEO212 Inhibits Migration and Invasion of Glioma Stem Cells

“…These cytotoxic effects of TMZ decay rapidly within the first few hours of treatment. Previous studies from this laboratory showed that when we incubate TMZ in medium at 37 °C, it loses its cytotoxicity after 2 h, while NEO212 loses its cytotoxicity after 24 h of incubation at 37 °C in the medium[16, 27, 28]. To determine whether there is a relationship between the cytotoxic effects of NEO212 and its ability to block the migration of GSCs, we treated USC02 cells with NEO212 for 24 h; then the supernatant was replaced with fresh medium without the drug in half of the cell cultures, or medium with NEO212 was not removed in the other half; and the cells were incubated for an additional 48 h-period.…”