Ribonucleotide reductase inhibitors enhance cidofovir‐induced apoptosis in EBV‐positive nasopharyngeal carcinoma xenografts

Abstract

In nasopharyngeal carcinoma (NPC), Epstein-Barr virus (EBV) infection is mainly latent, and the tumor cells contain episomal viral DNA. We have shown that the acyclic nucleoside phosphonate analog, cidofovir [(S)-1-(3-hydroxy-2-(phosphonylmethoxypropyl)cytosine] (HPMPC), inhibits growth of NPC xenografts in nude mice by causing apoptosis. The ribonucleotide reductase (RR) inhibitors, hydroxyurea and didox (3,4-dihydroxybenzohydroxamic acid), have been demonstrated to inhibit neoplastic growth and are used as antiviral and anticancer agents. Here we show that RR inhibitors enhance the antitumor effect of cidofovir in EBV-transformed epithelial cells. MTT assays indicate that hydroxyurea and didox enhance cidofovir-induced cell toxicity in NPC-KT cells, an EBVpositive epithelial cell line derived from NPC. The effect is due to enhancement of apoptosis through the caspase cascade as shown by pronounced cleavage of poly(ADP-ribose) polymerase. Finally, hydroxyurea strikingly enhanced the cidofovir-induced growthinhibitory effect on NPC grown in athymic mice. The results suggest that RR inhibitors should enhance the antitumor effect of acyclic nucleoside phosphonate analogs on NPC. ' 2005 Wiley-Liss, Inc.

Didox and resveratrol sensitize colorectal cancer cells to doxorubicin via activating apoptosis and ameliorating P-glycoprotein activity

“…Moreover, DID synergizes the anti-tumor effect of temozolomide54, carmustine40 and cidofovir34 against malignant brain tumor cells, DAOY human medulloblastoma cells and Epstein-Barr virus (EBV)-positive nasopharyngeal carcinoma xenografts, respectively. DOX-induced cytotoxicity is partly attributed to the generation of reactive oxygen species and free radicals55.…”

“…Ribonucleotide reductase enzyme has been considered potential target for cancer chemotherapy31. DID showed anti-tumor effects in a variety of experimental systems, and several human tumor xenografts323334. It may exert its anti-tumor effect via the activation of various apoptosis pathways35.…”

Electric Cell-Substrate Impedance Sensing To Monitor Viral Growth and Study Cellular Responses to Infection with Alphaherpesviruses in Real Time

“…The MTT assay was used to assess cidofovir toxicity in a manner similar to that previous described (41, 42). Briefly, 20,000 cells were plated into duplicate wells of a 96-well plate.…”

HF-EPR, Raman, UV/VIS Light Spectroscopic, and DFT Studies of the Ribonucleotide Reductase R2 Tyrosyl Radical from Epstein-Barr Virus

“…The virus may induce development of several diseases such as infectious mononucleosis, and is associated with neoplasms, including lymphomas and carcinomas [13]. In this context, the viral RNR is an important drug target for EBV [14], [15]. Certain small organic molecules are potential inhibitors of herpes viral RNRs and thus can be employed for the treatment of herpes viral infections by targeting the R2 tyrosyl radical site.…”