Targeting DHODH reveals therapeutic opportunities in ATRA-resistant acute promyelocytic leukemia

Tingyuan Yang; Xiayu Shi; Shiliang Li; Zhenjiang Zhao; Junyi Wang; Panpan Yu; Honglin Li; Rui Wang; Zhuo Chen

doi:10.1016/j.biopha.2023.115314

Targeting DHODH reveals therapeutic opportunities in ATRA-resistant acute promyelocytic leukemia

Biomed Pharmacother. 2023 Oct:166:115314. doi: 10.1016/j.biopha.2023.115314. Epub 2023 Aug 12.

Authors

Tingyuan Yang¹, Xiayu Shi¹, Shiliang Li¹, Zhenjiang Zhao¹, Junyi Wang¹, Panpan Yu¹, Honglin Li², Rui Wang³, Zhuo Chen⁴

Affiliations

¹ Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China.
² Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China; Innovation Center for AI and Drug Discovery, East China Normal University, Shanghai 200062, China; Lingang Laboratory, Shanghai 200031, China. Electronic address: hlli@ecust.edu.cn.
³ Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China. Electronic address: ruiwang@ecust.edu.cn.
⁴ Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China. Electronic address: chenzhuo@ecust.edu.cn.

PMID: 37579695
DOI: 10.1016/j.biopha.2023.115314

Abstract

Although all-trans retinoic acid (ATRA)-induced differentiation has transformed acute promyelocytic leukemia (APL) from the most fatal to the most curable hematological disease, resistance to ATRA in high-risk APL patients remains a clinical challenge. In this paper, we discovered that dihydroorotate dehydrogenase (DHODH) inhibition overcame ATRA resistance. 416, a potent DHODH inhibitor previously obtained in our group, inhibited the occurrence of APL in cells and model mice. Excitingly, 416 effectively overcame ATRA resistance in vitro and in vivo by inducing apoptosis and differentiation. Further mechanistic studies showed that PML/RARα lost the regulation of Bcl-2 and c-Myc in NB4-R1 cells, which probably contributed to ATRA resistance. Notably, 416 maintained its Bcl-2 and c-Myc down-regulation effect in NB4-R1 cells and overcome ATRA resistance by inhibiting DHODH. In conclusion, our study highlights the potential of 416 for APL therapy and overcoming ATRA resistance, supporting the further development of DHODH inhibitors for clinical use in refractory and relapsed APL.

Keywords: APL; ATRA resistance; Biological evaluation; DHODH; Mechanism of action.

MeSH terms

Animals
Antineoplastic Agents* / pharmacology
Antineoplastic Agents* / therapeutic use
Cell Differentiation
Dihydroorotate Dehydrogenase* / antagonists & inhibitors
Dihydroorotate Dehydrogenase* / genetics
Dihydroorotate Dehydrogenase* / metabolism
Drug Resistance, Neoplasm*
Leukemia, Promyelocytic, Acute* / drug therapy
Leukemia, Promyelocytic, Acute* / genetics
Leukemia, Promyelocytic, Acute* / metabolism
Mice
Tretinoin* / pharmacology
Tretinoin* / therapeutic use

Substances

Antineoplastic Agents
Dihydroorotate Dehydrogenase
Tretinoin