Antitumor Alkaloids from Cephalotaxus harringtonia: Structure and Activity

Powell, Richard G.; Weisleder, David; Smith, C. R.

doi:10.1002/jps.2600610812

Cited by 206 publications

(102 citation statements)

References 6 publications

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“…Of the four alkaloids, cephalotaxine, harringtonine, isoharringtonine, and homoharringtonine (11,22), homoharringtonine seemed to be the most effective, although harringtonine and isoharringtonine were nearly as effective. The ANTIMICROB.…”

Section: Resultsmentioning

confidence: 97%

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Inhibition of Protein Synthesis in Intact HeLa Cells

Tscherne

Pestka

1975

Antimicrob Agents Chemother

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Polysome analysis has proved to be a sensitive probe for the mode of action of inhibitors of protein synthesis in intact HeLa cells. To classify the active compounds as inhibitors of initiation, elongation, or termination, their effects on the cellular polyribosome pattern were compared under three conditions. These conditions tested (i) their direct effect on the polyribosome profile; (ii) their effect on ribosome run-off produced by hypertonicity; and (iii) their effects on recovery from hypertonicity. Using this technique, diacetoxyscirpenol, 2-(4-methyl-2,6-dinitroanilino)-N-methylpropionamide, and three alkaloids, harringtonine, isoharringtonine, and homoharringtonine, were found to be inhibitors of initiation. Polysome analysis indicated that in HeLa cells 7.8 x 10-7 M pactamycin, which inhibited protein synthesis 94%, interfered with elongation as well as initiation under these conditions. Emetine, anisomycin, cycloheximide, and trichodermin each gave polysome patterns consistent with inhibition of elongation. Fusidic acid and aurintricarboxylic acid inhibited incorporation of ["CC]

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Section: Resultsmentioning

confidence: 97%

“…on May 7, 2018 by guest http://aac.asm.org/ Downloaded from latter three alkaloids have been shown to have antitumor activity (22); however, cephalotaxine, the parent compound, which had no antitumor activity, was least effective in inhibiting protein synthesis.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Protein Synthesis in Intact HeLa Cells

Tscherne

Pestka

1975

Antimicrob Agents Chemother

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“…It is currently being used as a non-first-line drug to treat acute and chronic leukemia and myelodysplastic syndrome (17)(18)(19). HHT resulted in a complete hematologic remission in 72% and cytogenetic remission in 31% of patients with late chronic-phase chronic myelogenous leukemia (CML), most of whom had not experienced a response to IFN-α therapy (20).…”

Section: Molecularmentioning

confidence: 99%

“…To determine the effect of HHT, we divided the mice into three groups (three to eight animals in each group) and injected them with P815 cells with vehicle (DMSO-containing medium), 0.5 mg/kg HHT, or 1.0 mg/kg HHT. HHT was found to be well tolerated at doses of 0.5 to 4.0 mg/kg, resulting in remarkable in vivo effects on L1210 cells in mice (19). We thus used medium doses 0.5 and 1.0 mg/kg of HHT.…”

Section: In Vivo Antitumor Effect Of Hhtmentioning

confidence: 99%

The Antitumor Activity of Homoharringtonine against Human Mast Cells Harboring the KIT D816V Mutation

Jin

Lu²,

Cao³

et al. 2010

Molecular Cancer Therapeutics

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Gain-of-function mutations of the receptor tyrosine kinase KIT play a critical role in the pathogenesis of systemic mastocytosis (SM) and gastrointestinal stromal tumors. The various juxtamembrane type of KIT mutations, including V560G, are found in 60% to 70% of patients with gastrointestinal stromal tumors; loop mutant D816V, which exists in ∼80% of SM patients, is completely resistant to imatinib. In the present study, we hypothesized that homoharringtonine (HHT), a protein synthesis inhibitor, would decrease the level of KIT protein by inhibiting translation, resulting in a decreased level of phospho-KIT and abrogating its constitutive downstream signaling. Imatinib-sensitive HMC-1.1 cells harboring the mutation V560G in the juxtamembrane domain of KIT, imatinib-resistant HMC-1.2 cells harboring both V560G and D816V mutations, and murine P815 cells were treated with HHT and analyzed in terms of growth, apoptosis, and signal transduction. The in vivo antitumor activity was evaluated by using the murine mast cell leukemia model. Our results indicated that HHT effectively inhibited the growth and induced apoptosis in cells bearing both V560G and D816V or D814Y KIT. Additionally, HHT inhibited the KIT-dependent phosphorylation of downstream signaling molecules Akt, signal transducer and activator of transcription 3 and 5, and extracellular signal-regulated kinase 1/2. Furthermore, HHT significantly prolonged the survival duration of mice with aggressive SM or mast cell leukemia by inhibiting the expansion and infiltration of imatinib-resistant mast tumor cells harboring imatinib-resistant D814Y KIT. Collectively, we show that HHT circumvents D816V KITelicited imatinib resistance. Our findings warrant a clinical trial of HHT in patients with SM harboring D816V or D814Y KIT. Mol Cancer Ther; 9(1); 211-23. ©2010 AACR.

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“…Heparinized bone marrow samples from 10 normals (five males and five females, mean age 37 years), 10 CML chronic Homoharringtonine (HHT), is a cephalotaxine alkaloid 1 phase (CML-CP) (six males and four females, mean age 39 shown to have a clinical efficacy in the treatment of de novo years) and 10 CML blastic phase (CML-BP) (four males and acute myeloid leukemia (AML) either alone or in combination six females, mean age 41 years) patients were studied after with other drugs, mainly cytosine arabinoside (Ara-C). [2][3][4][5] informed consent.…”

Section: Introductionmentioning

confidence: 99%

Effects of homoharringtonine alone and in combination with alpha interferon and cytosine arabinoside on ‘in vitro’ growth and induction of apoptosis in chronic myeloid leukemia and normal hematopoietic progenitors

et al. 1997

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CML-CP colony growth; the same activity was demonstrated by the combination of HHT with Ara-C and by the triple combination, but not by HHT + IFN-␣, on normal myeloid progenitors. Materials and methods The triple combination only was able to exert a synergistic effect in CML-BP. The induction of apoptosis resulted HHTReagents dose-dependent in CML-CP and normals; at higher drug concentrations (100-200-1000 ng/ml), HHT induced a significant increase of apoptotic cells (for normals: P = 0.04, P = 0.02 and HHT was purchased from Pharmacia, Chang Zhou, China. data. 6,8,16,17

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Antitumor Alkaloids from Cephalotaxus harringtonia: Structure and Activity

Cited by 206 publications

References 6 publications

Inhibition of Protein Synthesis in Intact HeLa Cells

Inhibition of Protein Synthesis in Intact HeLa Cells

The Antitumor Activity of Homoharringtonine against Human Mast Cells Harboring the KIT D816V Mutation

Effects of homoharringtonine alone and in combination with alpha interferon and cytosine arabinoside on ‘in vitro’ growth and induction of apoptosis in chronic myeloid leukemia and normal hematopoietic progenitors

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