Table 3.

Preclinical and clinical studies regarding the efficacy of HHT and OM in AML: mechanisms and synergistic interactions

Types of studies
Preclinical studies using cell lines (in vitro) or animal model (in vivo)
Experimental model	Mechanisms	Results	References
HL-60 cells (In vitro)	↓ Protein synthesis Synergy with l-β-d-arabinofuranosylcytosine	↓ Protein synthesis Synergistic effect with DNA synthesis inhibitor	[67]
AML cells (In vitro)	↑ Bax	↑ Apoptosis No cross-resistance with DNR and cytarabine	[68]
HL60 HL60/MRP cells (In vitro)	↑MCL-1 turnover ↑Mitochondrial disruption ↑Caspases	↑ Apoptosis through mitochondrial pathway	[69]
AML cell lines Xenograft mice (In vitro/In vivo)	↓ MMP ↓ Mcl-1 ↓ c-KIT levels ↑Caspase-3	↑ Apoptosis Prolonged t(8;21) leukemia mouse survival ↑Synergy with oridonin	[61]
AML cells (In vitro)	↓ PI3K/AKT ↓WNT/β‐catenin signalling	↑ Apoptosis ↑Caspase-3 mediated cleavage of AML1–ETO oncoprotein ↑synergy with aclarubicin	[71, 72]
AML cell lines Primary AML cells (In vitro)	↑ ROS synthesis Restriction of antioxidant defence	Synergistic cytotoxicity with etoposide ↑ Apoptosis	[73]
FLT3–ITD positive cell lines Primary leukemia cells (In vitro)	↓STAT5/Pim-2/C-Myc ↑ Cell cycle arrest	↑ Apoptosis Alone or in combination: ↑ Sensitivity to chemotherapeuthic drugs	[74, 83]
AML cells Xenograft mice (In vitro/In vivo)	: ↓ MMP, ↓ Mcl-1, ↓ PI3K–AKT/MAPK/ERK pathways	↓ AML progression Prolonged survival in mice Synergistic effect with venetoclax	[70]

Clinical studies
Cancer type	Study design	Primary outcomes	References
R/R-AML	Combination of HHT with venetoclax and azacitidine (HVA) Focus on patients with allo-HSCT	Better treatment response Well tolerated	[79]
R/R-AML	Single-center Phase II study with 46 patients HHT with aclarubicin and cytarabine (HAA)	80% achieved Complete Remission (CR) 42% OS rate	[80]
De Novo AML	National, multicenter, randomized, double-blinded, prospective Phase III clinical trial; HAA regimen	High CR rate Prolonged OS Suggested as a treatment option for young and newly diagnosed patients	[56, 81]

AML: Acute Myeloid Leukemia; Bax: Bcl-2-associated X protein; CR: Complete Remission; DNR: Daunorubicin; FLT3–ITD: FMS-like tyrosine kinase 3–internal tandem duplication; HHT: Homoharringtonine; HVA: HHT, Venetoclax, and Azacitidine combination; HAA: HHT, Aclarubicin, and Cytarabine combination; MCL-1: Myeloid cell leukemia 1; MMP: Mitochondrial membrane potential; OM: Omacetaxine Mepesuccinate; OS: Overall Survival; PI3K–AKT: Phosphoinositide 3-kinase–Protein kinase B; R/R-AML: Refractory/Relapsed Acute Myeloid Leukemia; ROS: Reactive oxygen species; STAT5/Pim-2/C-Myc: Signal transducer and activator of transcription 5 / Proviral integration site for Moloney murine leukemia virus-2/Cellular Myelocytomatosis; allo-HSCT: Allogeneic Hematopoietic Stem Cell Transplantation