title: Bortezomib sensitizes human acute myeloid leukemia cells to all-trans-retinoic acid-induced differentiation by modifying the RARα/STAT1 axis.
abstract: All-trans-retinoic acid (ATRA) has held great promise for differentiation-based therapy but reportedly downregulates retinoic acid receptor-α (RARα) in a proteasome-dependent manner, which leads to decreased acute myeloid leukemia (AML) cell differentiation efficiency. Therefore, research strategies that seek to further sensitize cells to retinoids and extend the range of retinoid-affected myeloid malignancies beyond acute promyelocytic leukemia (APL) are key investigative avenues. Here, we show that bortezomib, the first proteasome inhibitor approved for newly diagnosed and relapsed multiple myeloma, exhibited strong synergism with ATRA to promote HL60 and NB4 AML cell differentiation. We observed that bortezomib sensitized AML cells to ATRA-induced morphologic, biochemical, and functional changes, indicative of myeloid differentiation without cell death. In addition, treatment of human leukemia HL60 xenografts with bortezomib and ATRA together did not increase bortezomib-induced progressive weight loss but resulted in significant tumor growth inhibition in addition to increased differentiation (P < 0.05). These enhanced differentiation effects were accompanied by RARα stabilization and STAT1 activation. Taken together, our study was the first to evaluate bortezomib and ATRA synergy in AML cell differentiation and to assess new opportunities for bortezomib and ATRA combination as a promising approach for future differentiation therapy.
authors.affiliation: Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Hangzhou 310058, China.
authors.forename: Meidan
authors.initials: M
authors.lastname: Ying
authors.forename: Xinglu
authors.initials: X
authors.lastname: Zhou
authors.forename: Like
authors.initials: L
authors.lastname: Zhong
authors.forename: Nengming
authors.initials: N
authors.lastname: Lin
authors.forename: Hui
authors.initials: H
authors.lastname: Jing
authors.forename: Peihua
authors.initials: P
authors.lastname: Luo
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Yang
authors.forename: Hua
authors.initials: H
authors.lastname: Song
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
authors.forename: Qiaojun
authors.initials: Q
authors.lastname: He
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D000069286:Bortezomib; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology*; D011897:Random Allocation; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D014212:Tretinoin / Q000008:administration & dosage / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D001897:Boronic Acids; D011719:Pyrazines; C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D014212:Tretinoin; D000069286:Bortezomib