homoharringtonine and Leukemia--Myeloid

Homoharringtonine (HHT), a plant alkaloid with antitumor properties originally identified nearly 40 years ago, has a unique mechanism of action by preventing the initial elongation step of protein synthesis. HHT has been used widely in China for the treatment of chronic myeloid leukemia (CML), acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Omacetaxine, a semisynthetic form of HHT, with excellent bioavailability by the subcutaneous route, has recently been approved by FDA of the United States for the treatment of CML refractory to tyrosine kinase inhibitors. This review summarized preclinical and clinical development of HHT and omacetaxine for myeloid hematological malignancies.

Topics: Acute Disease; Antineoplastic Agents, Phytogenic; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Myelodysplastic Syndromes; Treatment Outcome

Homoharringtonine/omacetaxine is a unique agent with a long history of research development. It has been recently approved by the Food and Drug Administration for the treatment of chronic myeloid leukemia after failure of 2 or more tyrosine kinase inhibitors. Research with this agent has spanned over 40 years, with many instructive lessons to cancer research, which are summarized in this review.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents, Phytogenic; Drug Approval; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid; United States; United States Food and Drug Administration

To determine the maximum-tolerated dose (MTD), dose-limiting toxicities and pharmacokinetic of semisynthetic homoharringtonine (ssHHT), given as a twice daily subcutaneous (s.c.) injections for 9 days, in patients with advanced acute leukaemia, 18 patients with advanced acute myeloid leukaemia were included in this sequential Bayesian phase I dose-finding trial. A starting dose of 0.5 mg m(-2) day(-1) was explored with subsequent dose escalations of 1, 3, 5 and 6 mg m(-2) day(-1). Myelosuppression was constant. The MTD was estimated as the dose level of 5 mg m(-2) day(-1) for 9 consecutive days by s.c. route. Dose-limiting toxicities were hyperglycaemia with hyperosmolar coma at 3 mg m(-2), and (i) one anasarque and haematemesis, (ii) one life-threatening pulmonary aspergillosis, (iii) one skin rash and (iv) one scalp pain at dose level of 5 mg m(-2) day(-1). The mean half-life of ssHHT was 11.01+/-3.4 h, the volume of distribution at steady state was 2+/-1.4 l kg(-1) and the plasma clearance was 11.6+/-10.4 l h(-1). Eleven of the 12 patients with circulating leukaemic cells had blood blast clearance, two achieved complete remission and one with blast crisis of CMML returned in chronic phase. The recommended daily dose of ssHHT on the 9-day schedule is 5 mg m(-2) day(-1).

Topics: Acute Disease; Adult; Aged; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Harringtonines; Homoharringtonine; Humans; Injections, Subcutaneous; Leukemia, Myeloid; Male; Maximum Tolerated Dose; Middle Aged; Remission Induction; Survival Rate; Treatment Outcome

Homoharringtonine (HHT) is a natural alkaloid isolated from various Cephalotaxus species. HHT has been used to treat acute myeloid leukaemia (AML), chronic myeloid leukaemia (CML), chronic lymphocyte leukaemia and myelodysplastic syndromes. Although HHT inhibits protein synthesis and promotes apoptosis of leukaemia cells in preclinical studies, its molecular target proteins remain unknown. The aim of this study was to identify target proteins of HHT.. We have synthesized a biotinylated affinity column and used it to identify targets of HHT and confirmed the results by MS and Western blots. We also examined the effects of HHT on the target protein and determined roles of the target protein in anti-leukaemia activities of HHT through Western blots, flow cytometry and retrovirus transfection.. Myosin-9, a member of the myosin super-family, was identified as a direct interactor of HHT. Furthermore, HHT up-regulated the expression level of myosin-9 in both AML and CML cell lines in a time-dependent manner. Thus, HHT-induced apoptosis of leukaemia cells begins in 6 h and continues to increase for 24 h. There is a positive correlation between up-regulated myosin-9 expression level and increased percentage of apoptotic cells mediated by HHT. Overexpression of myosin-9 could increase the sensitivity of the leukaemia cells to the cytotoxicity of HHT and arrest cells in S and G2/M phases.. Our results indicated that myosin-9 was the target protein of HHT and played an important role in the HHT-induced apoptosis of leukaemia cells.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Chromatography, Affinity; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid; Molecular Motor Proteins; Myosin Heavy Chains; Up-Regulation

As phospho-eIF4E (p-eIF4E), unlike total eIF4E (t-eIF4E) essential for normal cells, is specifically required by cancer cells, it is an attractive, yet unrealized, target for anti-tumor intervention. Here we identify a small molecule, homoharringtonine (HHT), that antagonizes p-eIF4E function and eradicates acute myeloid leukemia (AML) expressing high level of p-eIF4E in vitro and in vivo. HHT selectively reduces p-eIF4E levels of leukemia cells without affecting t-eIF4E. HHT targets the phosphorylated serine 209 residue of p-eIF4E and induces p-eIF4E oligomerization, which enhances its interaction with the small ubiquitin-like protein modifier (SUMO)-conjugating enzyme UBC9, resulting in proteasome-dependent degradation of p-eIF4E via SUMO2/3-mediated SUMOylation. These results suggest that the phosphorylated serine 209 residue of p-eIF4E might be a potential target for developing small molecule-based new therapies for leukemia.

Topics: Acute Disease; Animals; Antineoplastic Agents, Phytogenic; Blotting, Western; Cell Line, Tumor; Dose-Response Relationship, Drug; Eukaryotic Initiation Factor-4E; Harringtonines; Homoharringtonine; Humans; Interleukin Receptor Common gamma Subunit; Leukemia, Myeloid; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Molecular Structure; Phosphorylation; Proteasome Endopeptidase Complex; Protein Multimerization; Proteolysis; Serine; Small Ubiquitin-Related Modifier Proteins; Sumoylation; Tumor Cells, Cultured; Ubiquitins; Xenograft Model Antitumor Assays

Homoharringtonine (HHT) is a plant alkaloid with antileukemia activity that is currently being used for treatment of acute, chronic leukemias and MDS. In this study, we show that HHT can induce apoptosis in a variety of human myeloid leukemia cell lines (U937, HL-60, HEL, THP, and K562). U937 and HL60 cells undergo rapid apoptosis on treatment with HHT, as indicated by increased annexin V binding capacity, caspase-3 activation, and cleavage of poly(ADP-ribose) polymerase (PARP). In addition, the expression of bax is upregulated during HHT-induced cell death, whereas the expression of bcl-2 is only slightly decreased. Importantly, treatment of primary leukemic cells, obtained from acute myeloid leukemia patients, resulted in rapid apoptosis. Thus, our data provide the mechanism of HHT and justify the use of HHT in the treatment of human myeloid leukemia.

Topics: Annexin A5; Apoptosis; bcl-2-Associated X Protein; Blotting, Western; Caspase 3; Caspases; Cell Division; Gene Expression; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Reverse Transcriptase Polymerase Chain Reaction; Tumor Cells, Cultured

Continuous infusion of homoharringtonine was administered to 17 children with refractory leukemia. Ten children with acute lymphoblastic leukemia received a total of 18 courses and seven children with acute nonlymphoblastic leukemia had a total of 13 courses. Doses were escalated from 1.65 to 8.5 mg/m2 for 5-10 consecutive days. Side effects included mild nausea and vomiting and transient changes in liver enzymes. Mucositis and diarrhea were more frequently seen at higher dose levels. Grade 3 hypotension and pain were seen at doses of 7 mg/m2 for 10 days. This is considered to be the maximum tolerated dose in this limited phase I trial. None of these previously heavily treated patients achieved a marrow remission.

Topics: Adolescent; Alkaloids; Blast Crisis; Child; Child, Preschool; Female; Harringtonines; Homoharringtonine; Humans; Infant; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Male