Xu Lin, Zeng Zhiping, Zhang Weidong, Ren Gaoang, Ling Xiaobin, Huang Fengyu, Xie Peizhen, Su Ying, Zhang Xiao-Kun, Zhou Hu
School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, Fujian, China.
Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
Oncotarget. 2017 Feb 14;8(7):12311-12322. doi: 10.18632/oncotarget.14812.
The major oncogenic driver of acute promyelocytic leukemia (APL) is the fusion protein PML-RARα originated from the chromosomal translocation t(15;17). All-trans retinoic acid (ATRA) and arsenic trioxide cure most patients by directly targeting PML-RARα. 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 α (RXRα), strongly promoted the cAMP-independent apoptosis of both ATRA- sensitive and resistant NB4 cells via the induction of caspase-mediated PML-RARα degradation. RXRα was vital for the stability of both PML-RARα and RARα likely through the interactions. The binding of Z-10 to RXRα dramatically inhibited the interaction of RXRα with PML-RARα but not with RARα, leading to Z-10's selective induction of PML-RARα but not RARα degradation. Z-36 and Z-38, two derivatives of Z-10, had improved potency of inducing PML-RARα reduction and NB4 cell apoptosis. Hence, RXRα 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.
急性早幼粒细胞白血病（APL）的主要致癌驱动因素是源自染色体易位t(15;17)的融合蛋白PML-RARα。全反式维甲酸（ATRA）和三氧化二砷通过直接作用于PML-RARα治愈了大多数患者。然而，APL临床治疗中仍存在包括ATRA和砷剂治疗耐药等主要问题。在此我们发现，化合物Z-10，一种视黄酸X受体α（RXRα）的硝基配体，通过诱导半胱天冬酶介导的PML-RARα降解，强烈促进了对ATRA敏感和耐药的NB4细胞的非cAMP依赖性凋亡。RXRα可能通过相互作用对PML-RARα和RARα的稳定性至关重要。Z-10与RXRα的结合显著抑制了RXRα与PML-RARα的相互作用，但不影响其与RARα的相互作用，导致Z-10选择性诱导PML-RARα而非RARα的降解。Z-36和Z-38是Z-10的两种衍生物，具有更强的诱导PML-RARα减少和NB4细胞凋亡的能力。因此，RXRα配体Z-10及其衍生物可通过其独特的作用机制靶向对ATRA敏感和耐药的APL细胞，是APL治疗潜在的药物先导物。
