Homoharringtonine exhibits antagonistic effects on both dose and time in inhibiting IL-6-induced STAT3 phosphorylation. Through mechanisms, homoharringtonine (HHT) causes apoptosis while suppressing colony formation, cell proliferation, and survival. Homoharringtonine's cytotoxicity was investigated using gefitinib-controlled human non-small cell lung cancer (NSCLC) cell lines, A549 (wild-type EGFR) and NCI-H1975 (type EGFR of H1975, L858R, and T790M). Using an IC50 of 3.7 μM, the MTT experiment revealed that homoharringtonine was mildly hazardous to A549 cells. With an IC50 of 0.7 μM, homoharringtonine more highly sensitively affected H1975 cells. Using the MTT assay, homoharringtonine exhibited dose- and time-dependent inhibition of A549 and H1975 cell growth and proliferation. Homoharringtonine dramatically reduced the clonogenic potential of A549 and H1975 cells at dose and time [1] according to the trypan blue intermittent test.

Homoharringtonine (10 mg/kg) successfully stopped the growth of tumors as compared to gefitinib or vehicle control (P<0.05). Furthermore, mice treated with homoharringtonine (HHT) did not lose body weight, suggesting that homoharringtonine has no discernible effect. Every mouse was put to sleep, separated, examined, and tumor samples were gathered. Western blot of tumor-expressing cells will be used to ascertain whether homoharringtonine reduces STAT3 phosphorylation. When compared to the vehicle control or gefitinib treatment groups, the homoharringtonine-treated group exhibited a substantial decrease in both STAT3 phosphorylation and MCL1 levels. In parallel, treatment with harringtonine suppressed the phosphorylation amplifiers for ERK1/2 and AKT1/2/3, which is in line with the results above. Tumor tissues were frozen, and sections were diluted at 10 μM for fluorescence histochemistry in order to investigate STAT3 phosphorylation in deeper detail in xenograft tumor samples that were treated differently. therapy with homoharringtonine suppressed STAT3 phosphorylation more than either gefitinib therapy or tumor immune control [1].

Absorption, Distribution and Excretion
Homoharringtonine absorption was not quantified, but maximum concentration is reached after about 30 mins.
The main route of elimination for homoharringtonine is still unknown, but renal elimination is less than 15%.
Homoharringtonine has a steady state Vd of 141 ± 93.4 L.
Clearance for homoharringtonine was not quantified.

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Metabolism / Metabolites
Homoharringtonine has undergoes little hepatic metabolism and is mostly metabolized to 4’-DMHHT by plasma esterase hydrolysis.

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Biological Half-Life
Homoharringtonine has a half life of about 6 hours after subcutaneous administration.

Protein Binding
Plasma protein binding is equal or less than 50%.

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Toxicity Data
Mouse(ip): LD50: 1960 ug/kg
Mouse(ip): LD50: 6.5 mg/kg

[1]. Homoharringtonine induces apoptosis and inhibits STAT3 via IL-6/JAK1/STAT3 signal pathway in Gefitinib-resistant lung cancer cells. Sci Rep. 2015 Jul 13;5:8477.

Omacetaxine mepesuccinate is a cephalotaxine-derived alkaloid ester obtained from Cephalotaxus harringtonia; used for the treatment of chronic or accelerated phase chronic myeloid leukaemia. It has a role as an antineoplastic agent, a protein synthesis inhibitor, an apoptosis inducer and an anticoronaviral agent. It is an alkaloid ester, a tertiary alcohol, an organic heteropentacyclic compound and an enol ether. It is functionally related to a cephalotaxine.
Omacetaxine mepesuccinate (formerly known as HHT or Homoharringtonine), is a cephalotaxine ester and protein synthesis inhibitor with established clinical activity as a single agent in hematological malignancies. Omacetaxine mepesuccinate is synthesized from cephalotaxine, which is an extract from the leaves of the plant, Cephalotaxus species. In October 2005, omacetaxine mepesuccinate received Orphan Drug designation from the EMEA for the treatment of chronic myeloid leukemia (CML). Then in March 2006, it received Orphan Drug status from the FDA for the treatment of CML. In November 2006, omacetaxine mepesuccinate, for the treatment of CML, was granted Fast Track designation by the FDA. Most recently, in October 2012, omacetaxine mepesuccinate was marketed under the brand name Synribo and FDA approved for patients who are intolerant and/or resistant to two or more tyrosine kinase inhibitors used to treat accelerated or chronic phase CML.
Omacetaxine mepesuccinate has been reported in Cephalotaxus fortunei and Cephalotaxus harringtonia with data available.
Omacetaxine Mepesuccinate is a semisynthetic formulation of the cytotoxic plant alkaloid homoharringtonine isolated from the evergreen tree Cephalotaxus with potential antineoplastic activity. Omacetaxine binds to the 80S ribosome in eukaryotic cells and inhibits protein synthesis by interfering with chain elongation. This agent also induces differentiation and apoptosis in some cancer cell types.
Semisynthetic derivative of harringtonine that acts as a protein synthesis inhibitor and induces APOPTOSIS in tumor cells. It is used in the treatment of MYELOID LEUKEMIA, CHRONIC.
See also: Omacetaxine (has active moiety).

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Drug Indication
Used in patients who are intolerant and/or resistant to two or more tyrosine kinase inhibitors used to treat accelerated or chronic phase CML.
FDA Label
Philadelphia chromosome positive chronic myeloid leukaemia in patients who have the T315I Bcr-Abl kinase domain mutation and who are resistant to prior imatinib therapy.

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Mechanism of Action
Homoharringtonine inhibits protein synthesis by not directly binding to Bcr-Abl. It binds to the A-site cleft in the large ribosomal subunit, which affects chain elongation and prevents protein synthesis.

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Pharmacodynamics
The pharmacodynamics of homoharringtonine is not fully understood. It is known that homoharringtonine is involved with protein synthesis inhibition and this leads to its antineoplastic activity.

C29H39NO9

545.6213

545.262

26833-87-4

285033

Off-white to yellow solid powder

1.3±0.1 g/cm3

713.1±60.0 °C at 760 mmHg

144-146ºC

385.1±32.9 °C

0.0±2.4 mmHg at 25°C

1.605

2.7

2

10

11

39

968

4

CC(C)(CCC[C@@](CC(=O)OC)(C(=O)O[C@H]1[C@H]2C3=CC4=C(C=C3CCN5[C@@]2(CCC5)C=C1OC)OCO4)O)O

HYFHYPWGAURHIV-JFIAXGOJSA-N

InChI=1S/C29H39NO9/c1-27(2,33)8-5-10-29(34,16-23(31)36-4)26(32)39-25-22(35-3)15-28-9-6-11-30(28)12-7-18-13-20-21(38-17-37-20)14-19(18)24(25)28/h13-15,24-25,33-34H,5-12,16-17H2,1-4H3/t24-,25-,28+,29-/m1/s1

(S)-1-((11bS,12S,14aR)-13-methoxy-2,3,5,6,11b,12-hexahydro-1H-[1,3]dioxolo[4',5'

Omacetaxine mepesuccinate Synribo CGX-635 Myelostat CGX635Ceflatonin homoharringtonine, 3H-labeled, (3(R))-isomer

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 50 mg/mL (~91.64 mM)
H2O : ~1.4 mg/mL (~2.57 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.58 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (4.58 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (4.58 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 1.67 mg/mL (3.06 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication (<60°C).

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 (Please use freshly prepared in vivo formulations for optimal results.)