harringtonines

Summary

Summary: Tetracyclic spiro-BENZAZEPINES isolated from the seeds of CEPHALOTAXUS. They are esters of the alkaloid cephalotaxine and may be effective as antineoplastic agents.

Top Publications

  1. Luo C, Tang J, Wang Y. Homoharringtonine: a new treatment option for myeloid leukemia. Hematology. 2004;9:259-70 pubmed
    ..This review will present with the preclinical research data including the action mechanism, pharmacokinetics and drug resistance of HHT as well as the result from the clinical trial with HHT in China and the United States...
  2. Cai Z, Lin M, Wuchter C, Ruppert V, Dorken B, Ludwig W, et al. Apoptotic response to homoharringtonine in human wt p53 leukemic cells is independent of reactive oxygen species generation and implicates Bax translocation, mitochondrial cytochrome c release and caspase activation. Leukemia. 2001;15:567-74 pubmed
    ..Therefore, wt p53 leukemic cells respond to HHT-specific cellular stress by induction of ROS-independent apoptotic pathway characterized by translocation of Bax, mitochondrial cytochrome c release and activation of caspases. ..
  3. Gürel G, Blaha G, Moore P, Steitz T. U2504 determines the species specificity of the A-site cleft antibiotics: the structures of tiamulin, homoharringtonine, and bruceantin bound to the ribosome. J Mol Biol. 2009;389:146-56 pubmed publisher
    ..In the ribosome, the position of U2504 is controlled by its interactions with neighboring nucleotides, whose identities vary among kingdoms. ..
  4. Quintas Cardama A, Cortes J. Omacetaxine mepesuccinate--a semisynthetic formulation of the natural antitumoral alkaloid homoharringtonine, for chronic myelocytic leukemia and other myeloid malignancies. IDrugs. 2008;11:356-72 pubmed
  5. Chen R, Guo L, Chen Y, Jiang Y, Wierda W, Plunkett W. Homoharringtonine reduced Mcl-1 expression and induced apoptosis in chronic lymphocytic leukemia. Blood. 2011;117:156-64 pubmed publisher
    ..Thus, these results provide a rationale for clinical development of HHT in CLL as single agent or in combinations. ..
  6. Allan E, Holyoake T, Craig A, Jørgensen H. Omacetaxine may have a role in chronic myeloid leukaemia eradication through downregulation of Mcl-1 and induction of apoptosis in stem/progenitor cells. Leukemia. 2011;25:985-94 pubmed publisher
    ..Thus, although omacetaxine is not leukaemia stem cell specific, its ability to induce apoptosis of leukaemic stem cells distinguishes it from TKIs and creates the potential for a curative strategy for persistent disease. ..
  7. Quintas Cardama A, Kantarjian H, Garcia Manero G, O Brien S, Faderl S, Estrov Z, et al. Phase I/II study of subcutaneous homoharringtonine in patients with chronic myeloid leukemia who have failed prior therapy. Cancer. 2007;109:248-55 pubmed
    ..Nonhematologic toxicity was mild and manageable. Subcutaneous HHT is well tolerated and may have clinical activity in patients with CML after imatinib failure. ..
  8. Kantarjian H, Cortes J. New strategies in chronic myeloid leukemia. Int J Hematol. 2006;83:289-93 pubmed
    ..Further clinical trials are needed to characterize the efficacy and safety profile of these new agents and to determine which agents improve the long-term prognosis for patients with CML who have shown resistance to imatinib. ..
  9. Marin D, Kaeda J, Andreasson C, Saunders S, Bua M, Olavarria E, et al. Phase I/II trial of adding semisynthetic homoharringtonine in chronic myeloid leukemia patients who have achieved partial or complete cytogenetic response on imatinib. Cancer. 2005;103:1850-5 pubmed
    ..The addition of sHHT should be considered for patients on imatinib who fail to obtain low levels of minimal residual disease. ..

More Information

Publications61

  1. Kim T, Frick M, Le Coutre P. Omacetaxine mepesuccinate for the treatment of leukemia. Expert Opin Pharmacother. 2011;12:2381-92 pubmed publisher
    ..However, upfront combination with tyrosine kinase inhibitor represents an attractive option due their differing mechanisms of action. ..
  2. Ye X, Lin M. Homoharringtonine induces apoptosis of endothelium and down-regulates VEGF expression of K562 cells. J Zhejiang Univ Sci. 2004;5:230-4 pubmed
    ..In conclusion, we believe HHT has anti-angiogenesis potential and speculate that HHT might exert its anti-leukemia effects via reduction of angiogenesis. ..
  3. O Brien S, Giles F, Talpaz M, Cortes J, Rios M, Shan J, et al. Results of triple therapy with interferon-alpha, cytarabine, and homoharringtonine, and the impact of adding imatinib to the treatment sequence in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in early chronic phase. Cancer. 2003;98:888-93 pubmed
    ..This finding suggests that imatinib combination regimens may improve the prognosis in CML. ..
  4. Kantarjian H, Talpaz M, Santini V, Murgo A, Cheson B, O Brien S. Homoharringtonine: history, current research, and future direction. Cancer. 2001;92:1591-605 pubmed
    ..HHT and its derivatives appear to have promising activity in hematologic malignancies, a finding that needs to be pursued. ..
  5. Yinjun L, Jie J, Weilai X, Xiangming T. Homoharringtonine mediates myeloid cell apoptosis via upregulation of pro-apoptotic bax and inducing caspase-3-mediated cleavage of poly(ADP-ribose) polymerase (PARP). Am J Hematol. 2004;76:199-204 pubmed
    ..Thus, our data provide the mechanism of HHT and justify the use of HHT in the treatment of human myeloid leukemia. ..
  6. Robert F, Carrier M, Rawe S, Chen S, Lowe S, Pelletier J. Altering chemosensitivity by modulating translation elongation. PLoS ONE. 2009;4:e5428 pubmed publisher
    ..Our results indicate that depleting short-lived pro-survival factors by inhibiting their synthesis could achieve a therapeutic response in tumors harboring PTEN/AKT/mTOR pathway mutations. ..
  7. Quintas Cardama A, Kantarjian H, Cortes J. Homoharringtonine, omacetaxine mepesuccinate, and chronic myeloid leukemia circa 2009. Cancer. 2009;115:5382-93 pubmed publisher
    ..In this article, the authors discuss the current data on omacetaxine and the prospects of this agent to be integrated into the state-of-the-art treatment algorithms for CML. ..
  8. Kuroda J, Kamitsuji Y, Kimura S, Ashihara E, Kawata E, Nakagawa Y, et al. Anti-myeloma effect of homoharringtonine with concomitant targeting of the myeloma-promoting molecules, Mcl-1, XIAP, and beta-catenin. Int J Hematol. 2008;87:507-515 pubmed publisher
    ..These results suggest that HHT could constitute an attractive option for MM treatment though its ability to simultaneously target multiple tumor-promoting molecules. ..
  9. Legros L, Hayette S, Nicolini F, Raynaud S, Chabane K, Magaud J, et al. BCR-ABL(T315I) transcript disappearance in an imatinib-resistant CML patient treated with homoharringtonine: a new therapeutic challenge?. Leukemia. 2007;21:2204-6 pubmed
  10. Wetzler M, Segal D. Omacetaxine as an anticancer therapeutic: what is old is new again. Curr Pharm Des. 2011;17:59-64 pubmed
  11. Jin J, Jiang D, Mai W, Meng H, Qian W, Tong H, et al. Homoharringtonine in combination with cytarabine and aclarubicin resulted in high complete remission rate after the first induction therapy in patients with de novo acute myeloid leukemia. Leukemia. 2006;20:1361-7 pubmed
    ..The toxicities associated with HAA regimen were acceptable, and the most common toxicity was infection. This study suggested that HAA regimen might be a well-tolerable, effective induction regimen in young adult patients with AML. ..
  12. Ni D, Ho D, Vijjeswarapu M, Felix E, Rhea P, Newman R. Metabolism of homoharringtonine, a cytotoxic component of the evergreen plant Cephalotaxus harringtonia. J Exp Ther Oncol. 2003;3:47-52 pubmed
    ..The lethal dose of HHT affecting 50% (LD50) of mice was 6.7 mg/kg, but HHT-acid produced no apparent toxic effects at doses up to 280 mg/kg...
  13. Tang R, Faussat A, Majdak P, Marzac C, Dubrulle S, Marjanovic Z, et al. Semisynthetic homoharringtonine induces apoptosis via inhibition of protein synthesis and triggers rapid myeloid cell leukemia-1 down-regulation in myeloid leukemia cells. Mol Cancer Ther. 2006;5:723-31 pubmed
    ..We suggest that the inhibition of protein synthesis and resulting Mcl-1 turnover play a key role in the apoptosis induced by ssHHT. Our results encourage further clinical trials for the use of ssHHT in acute myelogenous leukemia. ..
  14. Quintas Cardama A, Cortes J. Homoharringtonine for the treatment of chronic myelogenous leukemia. Expert Opin Pharmacother. 2008;9:1029-37 pubmed publisher
    ..These encouraging results have propelled the development of several Phase II/III trials both in Europe and in the US to further delineate the activity of omacetaxine mepesuccinate in patients with CML who are resistant to TKI therapy. ..
  15. Hegde V, Campitelli M, Quinn R, Camp D. Synthesis of novel molecular probes inspired by harringtonolide. Org Biomol Chem. 2011;9:4570-9 pubmed publisher
    ..The scaffold may be useful in drug discovery or in the preparation of additional molecular probes for chemical biology...
  16. Wu L, Li X, Su J, Chang C, He Q, Zhang X, et al. Effect of low-dose cytarabine, homoharringtonine and granulocyte colony-stimulating factor priming regimen on patients with advanced myelodysplastic syndrome or acute myeloid leukemia transformed from myelodysplastic syndrome. Leuk Lymphoma. 2009;50:1461-7 pubmed publisher
    ..Stronger and alternative subsequent chemotherapy is necessary for patients with CR to maintain longer CR and better OS. ..
  17. Li W, Wang X. Novel formal synthesis of cephalotaxine via a facile Friedel-Crafts cyclization. Org Lett. 2007;9:1211-4 pubmed
    ..A remarkable stereoelectronic effect of the methylenedioxy substituent (R) and an interesting skeletal isomerization of the CET core ring system (B, X = H2) were observed. ..
  18. Cortes J, Lipton J, Rea D, Digumarti R, Chuah C, Nanda N, et al. Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation. Blood. 2012;120:2573-80 pubmed
    ..Omacetaxine may provide a safe and effective treatment for CML patients with T315I mutation. This study is registered at www.clinicaltrials.gov as NCT00375219. ..
  19. Fang B, Li N, Song Y, Han Q, Zhao R. Standard-dose imatinib plus low-dose homoharringtonine and granulocyte colony-stimulating factor is an effective induction therapy for patients with chronic myeloid leukemia in myeloid blast crisis who have failed prior single-agent therapy with imat. Ann Hematol. 2010;89:1099-105 pubmed publisher
    ..We conclude that the GHI regimen may overcome disease-poor response to conventional doses of imatinib and this approach deserves further evaluation as frontline therapy for newly diagnosed CML. ..
  20. Zhang Z, Li W. A facile total synthesis of hainanensine via an unusual rearrangement--annulation cascade. Org Lett. 2010;12:1649-51 pubmed publisher
    ..A facile total synthesis of hainanensine (1), a structurally unique Cephalotaxus alkaloid, via an effective acid-mediated rearrangement/Friedel-Crafts annulation cascade (7a/7b --> 8a/8b), is described. ..
  21. Ye L, Cao W, Shi Y, Deng Z, Tao S, Ji P, et al. [Effect of homoharringtonine on expression of NF-?B and BCL-2 proteins in K562 cells]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2013;21:78-81 pubmed publisher
    ..05). It is concluded that HHT may inhibit the proliferation of K562 cells, and down-regulating expression levels of BCL-2 and NF-?B may be one of its anti-CML mechanisms. ..
  22. Ingolia N, Lareau L, Weissman J. Ribosome profiling of mouse embryonic stem cells reveals the complexity and dynamics of mammalian proteomes. Cell. 2011;147:789-802 pubmed publisher
    ..We also define a class of short, polycistronic ribosome-associated coding RNAs (sprcRNAs) that encode small proteins. Our studies reveal an unanticipated complexity to mammalian proteomes. ..
  23. Chen Y, Hu Y, Michaels S, Segal D, Brown D, Li S. Inhibitory effects of omacetaxine on leukemic stem cells and BCR-ABL-induced chronic myeloid leukemia and acute lymphoblastic leukemia in mice. Leukemia. 2009;23:1446-54 pubmed publisher
    ..Treatment with omacetaxine decreased the number of leukemia stem cells and prolonged the survival of mice with BCR-ABL-induced CML or B-ALL. ..
  24. Robert F, Mills J, Agenor A, Wang D, Dimarco S, Cencic R, et al. Targeting protein synthesis in a Myc/mTOR-driven model of anorexia-cachexia syndrome delays its onset and prolongs survival. Cancer Res. 2012;72:747-56 pubmed publisher
    ..Together, our findings suggest a new paradigm to treat ACS by strategies which target protein synthesis to block the production of procachexic factors...
  25. Taniguchi T, Ishibashi H. Short synthesis of (-)-cephalotaxine using a radical cascade. Org Lett. 2008;10:4129-31 pubmed publisher
    ..The short total synthesis of (-)-cephalotaxine is described. The concise construction of the pentacyclic core of this alkaloid was achieved by a radical cascade involving 7-endo and 5-endo cyclizations. ..
  26. Kano Y, Akutsu M, Tsunoda S, Mano H, Sato Y, Honma Y, et al. In vitro cytotoxic effects of a tyrosine kinase inhibitor STI571 in combination with commonly used antileukemic agents. Blood. 2001;97:1999-2007 pubmed
    ..Although there are gaps between in vitro studies and clinical trials, the present findings provide useful information for the establishment of clinical protocols involving STI571. (Blood. 2001;97:1999-2007) ..
  27. Tang J, Xue H, Pan C, Chen J, Gu L, Zhao H. A homoharringtonine-based regimen for childhood acute myelogenous leukemia. Med Pediatr Oncol. 2003;41:70-2 pubmed
  28. Ye X, Chai Y, Li X, Wu K. [Studies on the synthesis and antitumor activity of the derivatives of cephalotaxine alkaloid esters]. Yao Xue Xue Bao. 2004;39:429-33 pubmed
    ..The seven new esters were studied for antitumor activity, the results showed that the antitumor activity was influenced by the substituentes on C3'-N. It might provide some rational basis for further structral modification. ..
  29. Chen Y, Ma X, Zhang W, Liu J, Cao X, He A. [Efficiency of GHA priming chemotherapy on patients with refractory acute myeloid leukemia and myelodysplastic syndrome and its relationship with expression of costimulatory molecule B7.1]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2008;16:1002-5 pubmed
    ..It is a new chemotherapy protocol with better effect and low toxicity. Efficiency of GHA priming chemotherapy may be correlated with B7.1 expression. Its mechanism is worthy to be further explored. ..
  30. Ji Y, Zhang W, Chen Y, Zhao X, He A, Liu J, et al. [Efficiency of GHA priming therapy on patients with acute monocytic leukemia and its mechanism]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2010;18:213-8 pubmed
    ..GHA priming therapy can down regulate the expression of MLAA 34. MLAA-34 is a novel anti-apoptotic factor of acute monocytic leukemia. ..
  31. Zhang W, Wang F, Chen Y, Cao X, He A, Liu J, et al. Combination chemotherapy with low-dose cytarabine, homoharringtonine, and granulocyte colony-stimulating factor priming in patients with relapsed or refractory acute myeloid leukemia. Am J Hematol. 2008;83:185-8 pubmed
    ..Further studies are necessary to elucidate optimum dose and schedule for this regimen to enhance the treatment efficacy of relapsed or refractory AML patients. ..
  32. Lou Y, Qian W, Jin J. Homoharringtonine induces apoptosis and growth arrest in human myeloma cells. Leuk Lymphoma. 2007;48:1400-6 pubmed
    ..The results also demonstrate that HHT potentiates dexamethasone-induced killing of MM cells. These findings indicate that HHT may be effective in the treatment of MM. ..
  33. Sun Q, Meng F, Fu Y, Li L. [Induction of apoptosis in HL-60 cells by bortezomib alone or in combination with harringtonine in vitro]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2007;15:233-6 pubmed
    ..It is concluded that the bortezomib can induce HL-60 cells apoptosis in a time-and-dose-dependent manner and synergistic effectiveness can be found when bortezomib combined with harringtonine. ..
  34. Wu L, Li X, Chang C, Xu F, He Q, Wu D, et al. Efficacy and toxicity of decitabine versus CHG regimen (low-dose cytarabine, homoharringtonine and granulocyte colony-stimulating factor) in patients with higher risk myelodysplastic syndrome: a retrospective study. Leuk Lymphoma. 2016;57:1367-74 pubmed publisher
    ..In conclusion, both decitabine and CHG regimen are effective for higher risk MDS; there is no cross resistance between the regimens. Decitabine might be a better choice for patients with poor karyotypes. ..
  35. Li W, Ma B. A novel formal total synthesis of cephalotaxine. J Org Chem. 2005;70:3277-80 pubmed
  36. Marenah L, Allan E, Mountford J, Holyoake T, Jørgensen H, Elliott M. Investigation into omacetaxine solution stability for in vitro study. Biomed Chromatogr. 2012;26:545-7 pubmed publisher
  37. Visani G, Isidori A. Resistant chronic myeloid leukemia beyond tyrosine-kinase inhibitor therapy: which role for omacetaxine?. Expert Opin Pharmacother. 2014;15:1-3 pubmed publisher
    ..Therefore, the activity of this compound is independent from the presence of BCR-ABL1 mutations, which makes it an attractive option for the treatment of CML patients after TKI failure. ..
  38. Wu C, Shen H, Xia D. [Harringtonine induces apoptosis in NB4 cells through down-regulation of Mcl-1]. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2013;42:431-6 pubmed
    ..HT inhibits cell growth and induces apoptosis in NB4 cells and primarily cultured APL cells, which may be associated with down-regulation of Mcl-1. ..
  39. Bell B, Chang M, Weinstein H. A phase II study of Homoharringtonine for the treatment of children with refractory or recurrent acute myelogenous leukemia: a pediatric oncology group study. Med Pediatr Oncol. 2001;37:103-7 pubmed
    ..This agent warrants further clinical evaluation in combination with other agents or perhaps biologic response modifiers which will hopefully lead to useful therapeutic options. Med Pediatr Oncol 2001;37:103-107. ..
  40. Nazha A, Kantarjian H, Cortes J, Quintas Cardama A. Omacetaxine mepesuccinate (synribo) - newly launched in chronic myeloid leukemia. Expert Opin Pharmacother. 2013;14:1977-86 pubmed publisher
    ..The development of an oral formulation of omacetaxine would greatly facilitate its use and provide an attractive option for TKI-based combinatorial strategies. ..
  41. Klanova M, Andera L, Brazina J, Svadlenka J, Benesova S, Soukup J, et al. Targeting of BCL2 Family Proteins with ABT-199 and Homoharringtonine Reveals BCL2- and MCL1-Dependent Subgroups of Diffuse Large B-Cell Lymphoma. Clin Cancer Res. 2016;22:1138-49 pubmed publisher
  42. Cortes J, Giles F. New agents in chronic myelogenous leukemia. J Natl Compr Canc Netw. 2003;1:501-12 pubmed
    ..If this is successful, complete eradication of disease may become a reality for the majority of patients with CML. ..
  43. Akard L, Kantarjian H, Nicolini F, Wetzler M, Lipton J, Baccarani M, et al. Incidence and management of myelosuppression in patients with chronic- and accelerated-phase chronic myeloid leukemia treated with omacetaxine mepesuccinate. Leuk Lymphoma. 2016;57:654-65 pubmed publisher
    ..Concerns regarding myelosuppression, observed with many cancer treatments, should not prevent eligible patients from receiving omacetaxine, particularly CML patients with unsatisfactory responses to multiple lines of prior treatment. ..
  44. Zhang M, Liu N, Tang W. Stereoselective total synthesis of hainanolidol and harringtonolide via oxidopyrylium-based [5 + 2] cycloaddition. J Am Chem Soc. 2013;135:12434-8 pubmed publisher
    ..Conversion of cycloheptadiene to tropone was realized by a sequential [4 + 2] cycloaddition, Kornblum-DeLaMare rearrangement, and double elimination. The biomimetic synthesis of harringtonolide from hainanolidol was also confirmed. ..
  45. Zhang M, Li Y, Zhang H, Xue S. BAPTA blocks DNA fragmentation and chromatin condensation downstream of caspase-3 and DFF activation in HT-induced apoptosis in HL-60 cells. Apoptosis. 2001;6:291-7 pubmed
    ..These data suggest a novel role for intracellular calcium in regulating apoptotic nuclease that causes DNA fragmentation and chromatin condensation. ..
  46. Zhou F, Tan W, Ma Y, Chen B, Zhu P, Xu X, et al. [Establishment of human homoharringtonine-resistant SKM-1 cell line and its biological characteristics]. Zhonghua Xue Ye Xue Za Zhi. 2012;33:433-8 pubmed
    ..619:1 \[(1.91 ± 0.30)×10(-4) vs (3.08 ± 0.21)×10(-4), P < 0.05\]. A HHT-resistant cell line SKM-1/HHT was established. The prominent overexpression of mdr1 may be the main cause for multidrug resistance. ..
  47. Kulkarni H, Goring H, Diego V, Cole S, Walder K, Collier G, et al. Association of differential gene expression with imatinib mesylate and omacetaxine mepesuccinate toxicity in lymphoblastoid cell lines. BMC Med Genomics. 2012;5:37 pubmed publisher
  48. Koseki Y, Sato H, Watanabe Y, Nagasaka T. A formal total synthesis of (+/-)-cephalotaxine using sequential N-acyliminium ion reactions. Org Lett. 2002;4:885-8 pubmed
  49. Esmieu W, Worden S, Catterick D, Wilson C, Hayes C. A formal synthesis of (-)-cephalotaxine. Org Lett. 2008;10:3045-8 pubmed publisher
    ..4]azanonane core D/E-ring system. A Heck-type cyclization was used to close the tetrahydroazepine C-ring and a selective epoxidation-rearrangement sequence was used to elaborate the E-ring. ..
  50. Romero M, Serrano M, Efferth T, Alvarez M, Marin J. Effect of cantharidin, cephalotaxine and homoharringtonine on "in vitro" models of hepatitis B virus (HBV) and bovine viral diarrhoea virus (BVDV) replication. Planta Med. 2007;73:552-8 pubmed
  51. Watanabe K, Ito S, Yamamoto S. Studies on membrane-associated prostaglandin E synthase-2 with reference to production of 12L-hydroxy-5,8,10-heptadecatrienoic acid (HHT). Biochem Biophys Res Commun. 2008;367:782-6 pubmed publisher
    ..Thus, native mPGE synthase-2 enzymatically catalyzes only the conversion of PGH(2) to PGE(2), but not to HHT, and heme is not involved in this reaction. ..
  52. Tang J, Liu Y, Chen J, Xue H, Pan C, Gu L. Homoharringtonine as a backbone drug for the treatment of newly diagnosed pediatric acute myeloid leukemia: a report from a single institution in China. Int J Hematol. 2011;93:610-617 pubmed publisher
    ..Other toxicities, including nausea, vomiting, diarrhea, and mucositis, were mild. HHT-including protocols may emerge as useful therapeutic options in future clinical trials. ..