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
Absorption of homoharringtonine was not quantitatively analyzed, but maximum concentration was reached approximately 30 minutes later. The primary elimination pathway of homoharringtonine is unclear, but renal elimination was less than 15%. The steady-state volume of distribution (Vd) of homoharringtonine was 141 ± 93.4 L. The clearance of homoharringtonine was not quantitatively analyzed. Metabolism/Metabolites Homoharringtonine is minimally metabolized in the liver, primarily through hydrolysis by plasma esterases to 4'-dimethylhomoharringtonine (4'-DMHHT). Biological Half-Life Following subcutaneous injection, the half-life of homoharringtonine is approximately 6 hours.

Protein Binding
Plasma protein binding rate ≤50%. Toxicity Data Mice (intraperitoneal injection): LD50: 1960 μg/kg Mice (intraperitoneal injection): 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 an alkaloid ester derived from cephalotaxine (Cephalotaxus harringtonia) and used to treat chronic or accelerated phase chronic myeloid leukemia. It possesses antitumor, protein synthesis inhibitory, apoptosis-inducing, and anticoronavirus activities. It is an alkaloid ester, tertiary alcohol, organic heteropentane compound, and enol ether. Its function is similar to that of cephalotaxine. Omacetaxine mepesuccinate (formerly known as HHT or high-harringtonine) is a cephalotaxine ester and protein synthesis inhibitor, and its clinical activity as a single agent in hematologic malignancies has been demonstrated. Omacetaxine mepesuccinate is synthesized from cephalotaxine, which is extracted from the leaves of plants in the genus Taxus. In October 2005, omaxitabine mepiquat succinate received Orphan Drug Designation from the European Medicines Agency (EMEA) for the treatment of chronic myeloid leukemia (CML). Subsequently, in March 2006, it received Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) for the treatment of CML. In November 2006, omaxitabine mepiquat succinate received Fast Track Designation from the FDA for the treatment of CML. Most recently, in October 2012, omaxitabine methyl ester succinate, marketed under the brand name Synribo, was approved by the FDA for the treatment of patients with accelerated or chronic phase CML who are intolerant and/or resistant to two or more tyrosine kinase inhibitors. Omaxitabine methyl ester succinate has been reported to be found in Taxus chinensis (Cephalotaxus fortunei) and Taxus harringtonia, and relevant data are available. Omaxistatin methyl succinate is a semi-synthetic preparation of goharingtonine, a cytotoxic plant alkaloid isolated from the evergreen tree Taxus, and possesses potential antitumor activity. Omaxistatin binds to the 80S ribosome in eukaryotic cells, inhibiting protein synthesis by interfering with chain elongation. This drug can also induce differentiation and apoptosis in certain cancer cell types. A semi-synthetic derivative of haringtonine, it acts as a protein synthesis inhibitor, inducing apoptosis in tumor cells. Used to treat chronic myeloid leukemia. See also: Omaxistatin (with the active moiety).

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Drug Indications
For patients who are intolerant and/or resistant to two or more tyrosine kinase inhibitors used to treat accelerated or chronic phase chronic myeloid leukemia.
FDA Label
Philadelphia chromosome-positive chronic myeloid leukemia, for patients carrying the T315I Bcr-Abl kinase domain mutation and resistant to prior imatinib treatment. Mechanism of Action Homoharringtonine inhibits protein synthesis by not directly binding to Bcr-Abl. It binds to the A-site cleft of the large ribosomal subunit, affecting chain elongation and preventing protein synthesis. Pharmacodynamics The pharmacodynamics of homoharringtonine is not fully elucidated. Homoharringtonine is known to participate in protein synthesis inhibition, which contributes to its antitumor 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.)