Arsenic trioxide potentiates sensitivity of multiple myeloma cells to lenalidomide by upregulating cereblon expression levels

The mechanism of the anti-myeloma effect of the immunomodulatory drug lenalidomide relies upon the binding of lenalidomide or an analogue to cereblon (CRBN) ubiquitin ligase, which inhibits it and results in the degradation of Ikaros-family zinc finger proteins 1 and 3 (IKZF1 and IKZF3). To determine whether the traditional Chinese medicine arsenic trioxide, could potentiate sensitivity of multiple myeloma (MM) cells to lenalidomide and identify the mechanism by which this happens, the present study investigated how arsenic trioxide affected CRBN on MM cell lines and examined the anti-myeloma effect and mechanism in the combination of arsenic trioxide and lenalidomide. The present study revealed that arsenic trioxide upregulates the transcription and protein levels of CRBN, the anti-myeloma target of lenalidomide, thus potentiating the sensitivity of multiple myeloma cells to lenalidomide and enhancing the lenalidomide-dependent degradation of IKZF1 and IKZF3. The results of the present study indicate that clinical trials of this combination therapy could take place within the near future, with the aim of improving MM patient outcome.