Application of Histone Deacetylase Inhibitor in Acute Myeloid Leukemia
Acute myeloid leukemia(AML)is a malignant clonal disease of hematopoietic stem cells,characterized by the proliferation of abnormal primordial cells of myeloid origin in bone marrow,blood and other tissues.At present,the standard induction therapy for AML mainly includes"3+7"standard treatment(anthracycline combined with cytarabine),allogeneic hematopoietic stem cell transplantation(Allo-HSCT)and targeted drug therapy.However,AML cells usually express high levels of P-glycoprotein,which mediates the efflux of chemotherapeutic drugs,which makes AML cells resistant to chemotherapy,resulting in many patients who are not sensitive to chemotherapy or relapse after complete remission.And some patients can not tolerate intensive therapy or lack of donors and can not use Allo-HSCT therapy.Therefore,it is of great clinical significance to find new drugs to improve the efficacy of AML patients.Epigenetic disorders play a key role in the pathogenesis of many diseases,especially cancer.Studies have shown that most AML patients have epigenetic regulatory gene mutations,such as DNMT3A,IDH and TET2,and these mutations are potentially reversible,which has become one of the therapeutic targets of AML.Histone deacetylase inhibitors(HDACi)can regulate the balance between histone acetylation and deacetylation,change the expression of proto-oncogenes or tumor suppressor genes that control cancer progression from epigenetics,and play an important role in many kinds of tumor therapy.At present,HDACi has shown the ability to induce differentiation,cell cycle arrest and apoptosis of AML cells.The mechanism may be mainly related to HDACi inducing chromatin conformation opening of tumor suppressor gene by inhibiting HDAC activity,promoting oncogene damage and preventing oncogene fusion protein from recruiting HDAC.Although the preclinical outcome of HDACi is promising,it is not as effective as the conventional therapy of AML.However,the combination strategy with various anticancer drugs is in clinical trials,showing significant anti-AML activity,improving efficacy through key targeting pathways in a typical synergistic or additive way,increasing AML sensitivity to chemotherapy,reducing tumor growth and metastasis potential,inhibiting cell mitotic activity,inducing cell apoptosis,regulating bone marrow microenvironment,which provides a good choice for the treatment of AML.Especially for those AML patients who are not suitable for intensive therapy and drug resistance to chemotherapy.This review introduces the relationship between HDAC and cancer;the classification of HDAC and its function in AML;the correlation between HDAC and AML;the clinical application of five types of HDACi;preclinical research results and clinical application progress of six kinds of HDACi in AML,such as Vrinota,Belinostat,Panobinostat,Valproic acid,Entinostat,and Chidamide,the mechanism of HDACi combined with other anticancer drugs in AML indicates that the current HDACi is mainly aimed at various subtypes of pan-HDAC inhibitors,with obvious side effects,such as fatigue,thrombocytopenia,nausea,vomiting,diarrhea.In recent years,the next generation of HDACi is mainly focused on the selectivity of analogues or isomers.Finding the best combination of HDACi and other drugs and the best timing of administration to balance the efficacy and adverse reactions is a major challenge in the treatment of AML,and the continued development of selective HDACi with less side effects and more accurate location is the key point for the development of this drug in the future.It is expected to provide reference for clinical treatment of AML.
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