CUL3 and cancer: As a result, DI-591/DI-404 cause the accumulation of NRF2, a CUL-3 substrate, in a dose-dependent manner in multiple cancer cell lines.456 However, DI-591/DI-404 fail to show any cytotoxicity in both human cancer cells at concentrations up to 20 μM, suggesting the dispensable functions of CRL3 activity in determining cell survival.