Objective  To explore the specific mechanisms by which tetrandrine (TET) enhances the radiosensitivity of non-small cell lung cancer (NSCLC).

  Methods  Cell viability was assessed via CCK-assay, combined with the colony formation experiment to detect the effect of TET on the radiosensitivity of NSCLC under conventional or hypoxic conditions. The effect of TET on hypoxia inducible factor-1 (HIF-1α) and vascular endothelial growth factor (VEGF) in NSCLC induced by ionising radiation (IR) and hypoxia was investigated. To investigate the impact of decreased HIF-1α expression on radiosensitivity, HIF-1α was knocked down. The effect of TET on HIF-1α degradation was investigated via reverse transcription-polymerase chain reaction (RT-PCR), cycloheximide (CHX) tracking, and immunoprecipitation. The role of p53 in TET-induced radiosensitization was also explored.

  Results  While TET significantly enhances the radiosensitivity of p53-deficient NSCLC cells, it has no significant impact on the radiosensitivity of cells expressing normal level of p53. Exposure to TET after IR and hypoxia significantly inhibits HIF-1α and VEGF expression. This effect is attributable to TET-induced HIF-1α ubiquitination, which accelerates HIF-1α degradation via the ubiquitin proteasomal system. Transfection of wild-type p53 into H1299 cells attenuates the impact of TET on HIF-1α expression.

  Conclusions  Inhibition of the HIF-1α pathway by TET is achieved via promoting HIF-1α degradation, which sensitizes p53-deficient NSCLC cells to IR. The presence of p53 inhibits TET-induced HIF-1α degradation.