Differential radiation sensitization of human cervical cancer cell lines by the proteasome inhibitor velcade (bortezomib, PS-341)

Abstract

Cervical cancer is one of the deadliest cancers in women with a death toll of 230,000 worldwide each year, nearly 80% in developing countries. Radiotherapy (RT) is a major treatment modality for advanced cervical cancer but the local relapse rate is 30-44% in patients treated with RT alone and 19-25% in patients treated with concurrent chemoradiotherapy. Previous studies have shown that the transcription factor NF-kappaB is constitutively expressed in human cervical squamous cell carcinomas. NF-kappaB activation also contributes to the resistance of cervical cancer cells to apoptosis induced by chemotherapeutic agents and radiation. Therefore, inhibition of NF-kappaB in tumor cells may render them more sensitive to chemo/radiation therapies. The objective of this study is to investigate the potential of radiosensitization of NF-kappaB inhibition by Velcade in human cervical cancer cell lines. We used the human cervical cancer cell lines HeLa and SiHa. Both are highly radioresistant and chemoresistant as compared to other cervical cancer cell lines. These cells had been treated with Velcade before they were irradiated with different doses of ionizing radiation. MTT metabolic assays and clonogenic cell survival assays were performed to evaluate the effects of Velcade on radiation resistance. Inhibition of NF-kappaB by Velcade alone decreased metabolic potential (MTT) and clonogenic survival in SiHa, but not in HeLa cells. Furthermore, pre-treatment of SiHa, but not HeLa cells with Velcade enhanced radiation sensitivity. Inhibition of NF-kappaB by the proteasome inhibitor Velcade enhances radiosensitivity of certain human cervical carcinoma cancer cells in vitro. These results raise the possibility that inhibition of NF-kappaB will result in radiosensitization only in those tumor cells which are more dependent on NF-kappaB for their metabolism and survival, however, the radiosensitivity of "NF-kappaB independent" cells are not likely influenced by it.