All-Trans-Retinoic Acid Combined With Valproic Acid Can Promote Differentiation in Myeloid Leukemia Cells by an Autophagy Dependent Mechanism

Frontiers in Oncology

Tracey R. O’Donovan¹  Sharon L. McKenna¹  Mary R. Cahill²  Nina Orfali³  Dalyia N. Benjamin⁵  Kristian B. Laursen⁵  Lorraine J. Gudas⁵  Nigel P. Mongan⁶ 

[1] Cancer Research, University College Cork, Cork, Ireland;Department of Haematology, Cork University Hospital, Cork, Ireland;Department of Haematology, St James’s Hospital, Dublin, Ireland;Department of Haematology, Tallaght University Hospital, Dublin, Ireland;Department of Pharmacology, Weill Cornell Medical College of Cornell University, New York, NY, United States;Faculty of Medicine and Health Science, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom;

关键词: APL;    AML;    ATRA;    valproic acid;    autophagy;    differentiation;   

DOI  :  10.3389/fonc.2022.848517

来源: DOAJ

【 摘 要 】

Acute myeloid leukemia (AML) is an aggressive blood cancer with an overall survival of 30%. One form of AML, acute promyelocytic leukemia (APL) has become more than 90% curable with differentiation therapy, consisting of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). Application of differentiation therapy to other AML subtypes would be a major treatment advance. Recent studies have indicated that autophagy plays a key role in the differentiation of ATRA-responsive APL cells. In this study, we have investigated whether differentiation could be enhanced in ATRA resistant cells by promoting autophagy induction with valproic acid (VPA). ATRA sensitive (NB4) and resistant leukemia cells (NB4R and THP-1) were co-treated with ATRA and valproic acid, followed by assessment of autophagy and differentiation. The combination of VPA and ATRA induced autophagic flux and promoted differentiation in ATRA-sensitive and -resistant cell lines. shRNA knockdown of ATG7 and TFEB autophagy regulators impaired both autophagy and differentiation, demonstrating the importance of autophagy in the combination treatment. These data suggest that ATRA combined with valproic acid can promote differentiation in myeloid leukemia cells by mechanism involving autophagy.

【 授权许可】

Unknown