Abstract |
Fatty acid oxidation dependency of leukemia cells has been documented in recent studies. Pharmacologic inhibition of fatty acid oxidation, thereby, displays significant effects in suppressing leukemia. 2-Bromopalmitate, a palmitate analogue, was initially identified as an inhibitor of fatty acid oxidation, and recently recognized as an inhibitor of protein palmitoylation. However, the effects of 2-Bromopalmitate on leukemia and its cellular targets remain obscure. Herein, we discover in cultured cell lines, a transplantable mouse model, and primary blasts that 2-Bromopalmitate presents synergistic differentiation induction with all-trans retinoic acid in acute promyelocytic leukemia. Moreover, 2-Bromopalmitate overcomes all-trans retinoic acid resistance in all-trans retinoic acid-resistant cells and leukemic mice. Mechanistically, 2-Bromopalmitate covalently binds at cysteine 105 and cysteine 174 of retinoic acid receptor alpha (RARα) and stabilizes RARα protein in the presence of all-trans retinoic acid which is known to induce RARα degradation, leading to enhanced transcription of RARα-target genes. Mutation of both cysteines largely abrogates the synergistic effect of 2-Bromopalmitate on all-trans retinoic acid-induced differentiation, demonstrating that 2-Bromopalmitate promotes all-trans retinoic acid-induced differentiation through binding RARα. All-trans retinoic acid-based regimens including arsenic trioxide or chemotherapy, as preferred therapy for acute promyelocytic leukemia, induce adverse events and irreversible resistance. We expect that combining all-trans retinoic acid with 2-Bromopalmitate would be a promising therapeutic strategy for acute promyelocytic leukemia, especially for overcoming all-trans retinoic acid resistance of relapsed acute promyelocytic leukemia patients.
|
Authors | Ying Lu, Jin-Song Yan, Li Xia, Kang Qin, Qian-Qian Yin, Hong-Tao Xu, Meng-Qing Gao, Xiao-Ning Qu, Yu-Ting Sun, Guo-Qiang Chen |
Journal | Haematologica
(Haematologica)
Vol. 104
Issue 1
Pg. 102-112
(01 2019)
ISSN: 1592-8721 [Electronic] Italy |
PMID | 30076181
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Copyright | Copyright© 2019 Ferrata Storti Foundation. |
Chemical References |
- Neoplasm Proteins
- Palmitates
- RARA protein, human
- Retinoic Acid Receptor alpha
- 2-bromopalmitate
- Tretinoin
|
Topics |
- Drug Delivery Systems
- Drug Resistance, Neoplasm
(drug effects)
- Humans
- Leukemia, Promyelocytic, Acute
(drug therapy, metabolism, pathology)
- Neoplasm Proteins
(agonists, metabolism)
- Palmitates
(pharmacology)
- Retinoic Acid Receptor alpha
(agonists, metabolism)
- Tretinoin
(pharmacology)
- Xenograft Model Antitumor Assays
|