Rxr Alpha Ligand Z-10 Induces Pml-Rara Cleavage And Apl Cell Apoptosis Through Disrupting Pml-Rara/Rxra Complex In A Camp-Independent Manner

The major oncogenic driver of acute promyelocytic leukemia (APL) is the fusion protein PML-RAR alpha originated from the chromosomal translocation t(15; 17). All-trans retinoic acid (ATRA) and arsenic trioxide cure most patients by directly targeting PML-RARa. However, major issues including the resistance of ATRA and arsenic therapy still remain in APL clinical management. Here we showed that compound Z-10, a nitro-ligand of retinoid X receptor a (RXR alpha), strongly promoted the cAMP-independent apoptosis of both ATRA-sensitive and resistant NB4 cells via the induction of caspase-mediated PML-RARa degradation. RXRa was vital for the stability of both PML-RARa and RARa likely through the interactions. The binding of Z-10 to RXR alpha dramatically inhibited the interaction of RXRa with PML-RARa but not with RAR alpha, leading to Z-10's selective induction of PML-RAR alpha but not RARa degradation. Z-36 and Z-38, two derivatives of Z-10, had improved potency of inducing PML-RAR alpha reduction and NB4 cell apoptosis. Hence, RXR alpha ligand Z-10 and its derivatives could target both ATRA-sensitive and resistant APL cells through their distinct acting mechanism, and are potential drug leads for APL treatment.