Homoharringtonine, omacetaxine mepesuccinate, and chronic myeloid leukemia circa 2009

Quintás‐Cardama, Alfonso; Kantarjian, Hagop M.; Cortés, Jorge E.

doi:10.1002/cncr.24601

Cited by 99 publications

(65 citation statements)

References 76 publications

(100 reference statements)

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“…Homoharringtonine (HHT, Synribo), originally a plant alkaloid, was recently approved for the therapy of chronic myeloid leukemia (CML) resistant to tyrosine-kinase inhibitors (14). Molecular mechanisms of antitumor activity of HHT appear to be multifactorial, and include downregulation of short-lived proteins, including MCL1 (15).…”

Section: Introductionmentioning

confidence: 99%

Targeting of BCL2 Family Proteins with ABT-199 and Homoharringtonine Reveals BCL2- and MCL1-Dependent Subgroups of Diffuse Large B-Cell Lymphoma

Klánová

Anděra

Bražina

et al. 2016

Clinical Cancer Research

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Purpose: To investigate the roles of BCL2, MCL1, and BCL-XL in the survival of diffuse large B-cell lymphoma (DLBCL).Experimental designs: Immunohistochemical analysis of 105 primary DLBCL samples, and Western blot analysis of 18 DLBCL cell lines for the expression of BCL2, MCL1, and BCL-XL. Pharmacologic targeting of BCL2, MCL1, and BCL-XL with ABT-199, homoharringtonine (HHT), and ABT-737. Analysis of DLBCL clones with manipulated expressions of BCL2, MCL1, and BCL-XL. Immunoprecipitation of MCL1 complexes in selected DLBCL cell lines. Experimental therapy aimed at inhibition of BCL2 and MCL1 using ABT-199 and HHT, single agent, or in combination, in vitro and in vivo on primary cell-based murine xenograft models of DLBCL.Results: By the pharmacologic targeting of BCL2, MCL1, and BCL-XL, we demonstrated that DLBCL can be divided into BCL2-dependent and MCL1-dependent subgroups with a less pronounced role left for BCL-XL. Derived DLBCL clones with manipulated expressions of BCL2, MCL1, and BCL-XL, as well as the immunoprecipitation experiments, which analyzed MCL1 protein complexes, confirmed these findings at the molecular level. We demonstrated that concurrent inhibition of BCL2 and MCL1 with ABT-199 and HHT induced significant synthetic lethality in most BCL2-expressing DLBCL cell lines. The marked cytotoxic synergy between ABT-199 and HHT was also confirmed in vivo using primary cell-based murine xenograft models of DLBCL.Conclusions: As homoharringtonine is a clinically approved antileukemia drug, and ABT-199 is in advanced phases of diverse clinical trials, our data might have direct implications for novel concepts of early clinical trials in patients with aggressive DLBCL.

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Section: Introductionmentioning

confidence: 99%

Targeting of BCL2 Family Proteins with ABT-199 and Homoharringtonine Reveals BCL2- and MCL1-Dependent Subgroups of Diffuse Large B-Cell Lymphoma

Klánová

Anděra

Bražina

et al. 2016

Clinical Cancer Research

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“…45 It has clinical activity against resistant CML, including cells containing the T315I mutation. 46,47 Its precise mechanism of action is not known, though several potential pathways are thought to be involved.…”

Section: Alternatives To Tyrosine Kinase Inhibitors Omacetaxinementioning

confidence: 99%

Chronic Myeloid Leukemia— What Else is there Beyond Protein Kinase Inhibitors?

Jabbour¹

2014

Oncology &Amp; Hematology Review (US)

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Chronic myeloid leukemia (CML) is induced by the BCR-ABL oncogene. The advent of BCR-ABL tyrosine kinase inhibitors (TKIs) has redefined treatment goals in CML starting with imatinib and followed by the newer TKI inhibitors including dasatinib, nilotinib, bosutinib, and ponatinib.However, a significant proportion of patients do not achieve a satisfactory response to TKIs and resistance remains an unmet need in the in the treatment of CML. Furthermore, disease eradication with TKIs may pose a significant challenge: minimal residual disease (MRD) remains detectable following treatment with these agents. Recently, several new molecular targets have been proposed in CML, and several drugs are in clinical development. Omacetaxine, a protein translation inhibitor, has shown the potential to substantially reduce MRD in animal models and has demonstrated clinical activity in phase II clinical trials regardless of patients' BCR-ABL T313I mutation status. The broad range of therapeutic effects associated with interferon may reduce resistance and relapse, and has resulted in a resurgence of interest in this therapy. In addition, several other therapeutic targets are currently undergoing clinical investigation. KeywordsChronic myeloid leukemia, imatinib, omacetaxine, tyrosine kinase inhibitors Disclosure: Elias Jabbour, MD, has received consultancy fees from Ariad, BMS, Novartis, Pfizer, and TEVA.

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“…Homoharringtonine (16) may be obtained also from several other Cephalotaxus species. The mechanism of action of compounds 16 and 17 is unusual, and they promote apoptosis and inhibit protein synthesis at the ribosomal level (58,59). Clinical studies of a mixture of homoharringtonine (16) (62,63).…”

Section: Selected Antineoplastic Plant-derived Single Chemical Entitimentioning

confidence: 99%

Discovery of new anticancer agents from higher plants

Kinghorn¹

2012

Front Biosci

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Homoharringtonine, omacetaxine mepesuccinate, and chronic myeloid leukemia circa 2009

Cited by 99 publications

References 76 publications

Targeting of BCL2 Family Proteins with ABT-199 and Homoharringtonine Reveals BCL2- and MCL1-Dependent Subgroups of Diffuse Large B-Cell Lymphoma

Targeting of BCL2 Family Proteins with ABT-199 and Homoharringtonine Reveals BCL2- and MCL1-Dependent Subgroups of Diffuse Large B-Cell Lymphoma

Chronic Myeloid Leukemia— What Else is there Beyond Protein Kinase Inhibitors?

Discovery of new anticancer agents from higher plants

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