Combination Bcl-2 Antisense and Radiation Therapy for Nasopharyngeal Cancer

Abstract

Purpose: A wide variety of tumors depend on the dysregulation of Bcl-2 family proteins for survival. The resulting apoptotic block can often provide a mechanism for resistance to anticancer treatments, such as chemotherapy and radiation.This current study evaluates the efficacy of combining systemically delivered Bcl-2 phosphorothioate antisense (Bcl-2 ASO) and radiation for nasopharyngeal cancer therapy. Results: Antisense uptake was unaffected by 0, 3, or 6 Gy radiation. Radiation decreased the fraction of viable C666-1cells to 60%, with a further decrease to 40% in combination with Bcl-2 ASO. Despite a modest in vitro effect, Bcl-2 ASO alone caused the regression of established xenograft tumors in mice, extending survival by 15 days in a C666-1and by 6 days in a C15 model. The survival times for mice treated with both Bcl-2 ASO and radiation increased by 52 days in C666-1and by 20 days in C15 tumors. This combination resulted in a more-than-additive effect in C666-1tumors. Less impressive gains observed in C15 tumors might be attributable to higher expression of antiapoptotic Bcl-2 family proteins and limited drug distribution in the tumor. Retreatment of C666-1 tumors with the Bcl-2 ASO-radiation combination, however, was effective, resulting in mice surviving for >80 days relative to untreated controls. Conclusions:Our results show that the Bcl-2 ASO and radiation combination is a highly potent therapy for nasopharyngeal cancer. Further examination of combination therapy with radiation and other Bcl-2 family^targeted anticancer agents in both preclinical and clinical settings is definitely warranted.

Potential use of alexidine dihydrochloride as an apoptosis-promoting anticancer agent

“…All cell lines were cultured according to specifications. C666-1 (human undifferentiated nasopharyngeal cancer) cells were cultured in RPMI 1640 supplemented with 10% fetal bovine serum (Wisent, Inc., St. Bruno, Quebec, Canada) and antibiotics (100 mg/L penicillin and 100 mg/L streptomycin) as previously described (8,15). All experiments were conducted when cells were in an exponential growth phase.…”

“…Our group has extensive experience in identifying new molecular therapies that improve outcome for head and neck cancers, ranging from adenoviral (8 -14) to antisense oligonucleotide (15) approaches. To this end, we have recently done a cell-based, phenotype-driven, cell viability -based high-throughput screen for novel head and neck cancer cytotoxics (16).…”

Multiple dysregulated pathways in nasopharyngeal carcinoma revealed by gene expression profiling

“…This observation suggests that blockage of mitochondrial-mediated apoptosis is the result of an unstable balance of simultaneous coexpression of both pro-and antiapoptotic genes and is consistent with our previous data demonstrating that apoptosis can be induced in 2 NPC xenograft models by merely increasing the expression of Bim s or FasL, or by silencing the expression of Bcl-2. 7,9,10 Several mutations and changes in the expression of genes involved in Wnt/b-catenin pathway have been associated with different cancers, including breast, lung, prostate, bladder and colorectal malignancies. [32][33][34] The observation that b-catenin is activated and localized to the nucleus in NPC biopsies, through the activation of the PI3K/Akt pathway mediated by the EBV latent proteins LMP1 and LMP2A, 35,36 suggests that dysregulation of the Wnt/b-catenin cascade may be relevant to the establishment of NPC.…”

“…Our group has had a long-time interest in developing molecular therapies for NPC, [6][7][8][9][10] which have focused primarily on antiapoptotic strategies. To explore novel potential therapeutic targets and to attain a better understanding of the pathways involved in NPC development, we performed a gene expression profile study using primary human NPC samples and analyzed in silico the interaction between the differentially expressed genes to prioritize and guide their validation.…”

A new curcumin analogue exhibits enhanced antitumor activity in nasopharyngeal carcinoma

“…Chemotherapy and radiotherapy are the main treatment strategies for NPC (2); however, radioresistance remains a serious obstacle to successful treatment in the clinic (2,3). To develop better approaches, it is important to seek innovative therapeutics for NPC.…”