Abstract

Background

eIF4A is an RNA helicase that forms part of the machinery of translation initiation.

Proteomic analysis demonstrated eIF4A expression to be at least two-fold greater in a radioresistant derivative of T47D breast cancer cells compared to parental cells.

Inhibition of eIF4A has previously been shown to resensitise lymphomas to chemotherapeutic agents that cause DNA damage

The objective of this work is to investigate whether small molecule inhibition of eIF4A using silvestrol sensitises breast cancer cells to radiotherapy in tissue culture.

Method

T47D cells were incubated in media containing 0 nM to 1 nM silvestrol either for 24 hours prior to irradiation at 0 Gy to 10 Gy (delivered by LINAC) or continually for six days post irradiation. MTT viability and clonogenic assays were used to quantify response.

Results

Pre-treatment of T47D cells with 1 nM silvestrol caused a 34% reduction (p = 0.014) in viability on irradiation at 2 Gy compared to treatment with a DMSO control, as assessed by MTT assay.

Maintenance of cells in 1 nM silvestrol for six days following irradiation at 2 Gy caused a 58% reduction (p = <0.01) in viability.

Clonogenic assays performed on cells maintained in 1 nM silvestrol following irradiation showed a Dose Modifying Factor (DMF) of 1.4 at 10% surviving fraction.

Conclusion

Low concentrations of silvestrol sensitise T47D breast cancer cells to radiation with minimal effect on unirradiated cells. This highlights the possible usefulness of eIF4A inhibition in potentiating radiation-induced damage at the tumour site without causing systemic toxicity.