Vitamin K2 sensitizes the efficacy of venetoclax in acute myeloid leukemia by targeting the NOXA-MCL-1 pathway
Fig 6
Effect of NOXA-knockout in HL-60 and SKM-1 cells on the cytotoxicity and MCL-1 repression by VK2 and VEN combination treatment.
(A, B) Control and NOXA knockout (KO) HL-60 and SKM-1 cells were treated with VK2 with/without VEN at indicated concentrations, and the viable cell numbers were assessed by CellTiter Blue assay. Data are presented as the mean ± SD. *p<0.05 vs. VEN 0 nM. The synergistic effect of VK2 and VEN combined treatment on each cell proliferative inhibition was statistically analyzed using Combenefit software. (C, D) After treatment with VK2 with/without VEN for 48 h, cellular proteins were separated by SDS-PAGE and immunoblotted with anti-NOXA, anti-MCL-1, and anti-PARP Abs. Immunoblotting with anti-GAPDH mAb was performed as an internal control. (E) Proposal scheme of the molecular mechanism of VK2 for sensitization to VEN in AML cells. VEN-treatment specifically inhibits BCL-2 but not MCL-1 [36]. VK2-treatment induces mitochondrial ROS production leading to up-regulation of NOXA, which results in inhibition and/or repression of MCL-1 to relieve BAK inhibition. Thus, concomitant treatment with VEN plus VK2 results in simultaneous inhibition of BCL-2 and MCL-1. This appears to enhance BAK- and/or BAK/BAX-mediated apoptosis induction in AML cells.