Skip to content
2000
Volume 28, Issue 7
  • ISSN: 1386-2073
  • E-ISSN: 1875-5402

Abstract

Introduction

Omacetaxine, a semisynthetic form of Homoharringtonine (HHT), was approved for the treatment of Chronic Myeloid Leukemia (CML). Previously, we have published the synthesis of this natural alkaloid and three of its derivatives: Deoxyharringtonine (DHT), Deoxyhomoharringtonine (DHHT), and Bis(demethyl)-deoxyharringtonine (BDHT), and reported its refractory activity against the HL-60/RV+ cells over-expressing P-glycoprotein 1 (MDR1).

Methods

In this study, we have explored the extent of this resistance by first expanding the panel of established cell lines and using a panel of 21 leukemia patient-derived primary cells.

Results

Herein, we have reported consistent resistance to HTT of K562-derived cells and to mitoxantrone of MES-SA/MX2-derived cells; all of them have been found to overexpress MDR1, while we have found U87MG-ABCG2 and H69AR cells to be very sensitive to HTT. In contrast, DHT, DHHT, and BDHT seemingly overcame this resistance due to the changes made to the acyl chain of HTT, rendering the derivatives less susceptible to efflux. Surprisingly, the leukemia primary cells were very sensitive to HHT and its derivatives with low nanomolar potencies, followed by a new class of CDC7 kinase inhibitors, the anthracycline class of topoisomerase inhibitors, the DNA intercalator actinomycin-D, and the vinca alkaloid class of microtubule inhibitors. The mechanism of cell death induced by HTT and DHHT was found to be mediated caspase 3 cleavage, leading to apoptosis.

Conclusion

Taken together, our results confirm that HHT is a substrate for MDR1. It opens the door to a new opportunity to clinically evaluate HHT and its derivatives for the treatment of AML and other cancers.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cchts/10.2174/0113862073322175240823104921
2024-10-23
2025-07-15

  • From This Site

    /content/journals/cchts/10.2174/0113862073322175240823104921
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Pérard-ViretJ. QuteishatL. AlsalimR. RoyerJ. DumasF. Cephalotaxus Alkaloids.Alkaloids Chem. Biol.20177820535210.1016/bs.alkal.2017.07.00128838429
     [Google Scholar]
  2. PowellR.G. WeislederD. SmithC.R.Jr RohwedderW.K. Structures of harringtonine, isoharringtonine, and homoharringtonine.Tetrahedron Lett.1970111181581810.1016/S0040‑4039(01)97839‑65436615
     [Google Scholar]
  3. FresnoM. JiménezA. VázquezD. Inhibition of translation in eukaryotic systems by harringtonine.Eur. J. Biochem.197772232333010.1111/j.1432‑1033.1977.tb11256.x319998
     [Google Scholar]
  4. GürelG. BlahaG. MooreP.B. SteitzT.A. 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.2009389114615610.1016/j.jmb.2009.04.00519362093
     [Google Scholar]
  5. HuangM.T. Harringtonine, an inhibitor of initiation of protein biosynthesis.Mol. Pharmacol.19751155115191237080
     [Google Scholar]
  6. RobertF. CarrierM. RaweS. ChenS. LoweS. PelletierJ. Altering chemosensitivity by modulating translation elongation.PLoS One200945e542810.1371/journal.pone.000542819412536
     [Google Scholar]
  7. PowellR.G. WeislederD. SmithC.R.Jr Antitumor alkaloids for Cephalataxus harringtonia: Structure and activity.J. Pharm. Sci.19726181227123010.1002/jps.26006108125050371
     [Google Scholar]
  8. KantarjianH.M. TalpazM. SantiniV. MurgoA. ChesonB. O’BrienS.M. Homoharringtonine.Cancer20019261591160510.1002/1097‑0142(20010915)92:6<1591::AID‑CNCR1485>3.0.CO;2‑U11745238
     [Google Scholar]
  9. FeldmanE.J. SeiterK.P. AhmedT. BaskindP. ArlinZ.A. Homoharringtonine in patients with myelodysplastic syndrome (MDS) and MDS evolving to acute myeloid leukemia.Leukemia199610140428558935
     [Google Scholar]
  10. O’BrienS. KantarjianH. KeatingM. BeranM. KollerC. RobertsonL.E. HesterJ. RiosM.B. AndreeffM. TalpazM. Homoharringtonine therapy induces responses in patients with chronic myelogenous leukemia in late chronic phase.Blood19958693322332610.1182/blood.V86.9.3322.bloodjournal86933227579434
     [Google Scholar]
  11. O’BrienS. KantarjianH. KollerC. FeldmanE. BeranM. AndreeffM. GiraltS. ChesonB. KeatingM. FreireichE. RiosM.B. TalpazM. Sequential homoharringtonine and interferon-alpha in the treatment of early chronic phase chronic myelogenous leukemia.Blood199993124149415310.1182/blood.V93.12.414910361112
     [Google Scholar]
  12. O’BrienS. TalpazM. CortesJ. ShanJ. GilesF.J. FaderlS. ThomasD. Garcia-ManeroG. MallardS. Beth RiosM. KollerC. KornblauS. AndreeffM. MurgoA. KeatingM. KantarjianH.M. Simultaneous homoharringtonine and interferon‐α in the treatment of patients with chronic‐phase chronic myelogenous leukemia.Cancer20029472024203210.1002/cncr.1043611932905
     [Google Scholar]
  13. FeldmanE. ArlinZ. AhmedT. MittelmanA. PuccioC. ChunH. CookP. BaskindP. Homoharringtonine is safe and effective for patients with acute myelogenous leukemia.Leukemia1992611118511881434802
     [Google Scholar]
  14. FeldmanE. ArlinZ. AhmedT. MittelmanA. PuccioC. ChunH. CookP. BaskindP. Homoharringtonine in combination with cytarabine for patients with acute myelogenous leukemia.Leukemia1992611118911911434803
     [Google Scholar]
  15. CovelliA. Modulation of multidrug resistance (MDR) in hematological malignancies.Ann. Oncol.199910Suppl. 6S53S6010.1093/annonc/10.suppl_6.S5310676553
     [Google Scholar]
  16. ChoiY. YuA.M. ABC transporters in multidrug resistance and pharmacokinetics, and strategies for drug development.Curr. Pharm. Des.201420579380710.2174/13816128200514021416521223688078
     [Google Scholar]
  17. SharomF.J. ABC multidrug transporters: Structure, function and role in chemoresistance.Pharmacogenomics20089110512710.2217/14622416.9.1.10518154452
     [Google Scholar]
  18. RussoD. MicheluttiA. MelliC. DamianiD. MichieliM.G. CandoniA. ZhouD.C. MarieJ.P. ZittounR. BaccaraniM. MDR-related P170-glycoprotein modulates cytotoxic activity of homoharringtonine.Leukemia1995935135167885049
     [Google Scholar]
  19. EckelbargerJ.D. WilmotJ.T. EppersonM.T. ThakurC.S. ShumD. AntczakC. TarassishinL. DjaballahH. GinD.Y. Synthesis of antiproliferative cephalotaxus esters and their evaluation against several human hematopoietic and solid tumor cell lines: Uncovering differential susceptibilities to multidrug resistance.Chemistry200814144293430610.1002/chem.20070199818366032
     [Google Scholar]
  20. ZhouD.C. RamondS. ViguieF. FaussatA.M. ZittounR. MarieJ.P. Sequential emergence ofMRP- andMDR1-gene over-expression as well asMDR1-gene translocation in homoharringtonine-selected K562 human leukemia cell lines.Int. J. Cancer199665336537110.1002/(SICI)1097‑0215(19960126)65:3<365::AID‑IJC15>3.0.CO;2‑98575859
     [Google Scholar]
  21. NijhawanD. FangM. TraerE. ZhongQ. GaoW. DuF. WangX. Elimination of Mcl-1 is required for the initiation of apoptosis following ultraviolet irradiation.Genes Dev.200317121475148610.1101/gad.109390312783855
     [Google Scholar]
  22. MaL. KrishnamacharyN. PerbalB. CenterM.S. HL-60 cells isolated for resistance to vincristine are defective in 12-O-tetradecanoylphorbol-13-acetate induced differentiation and the formation of a functional AP-1 complex.Oncol. Res.1992472912981450490
     [Google Scholar]
  23. HarkerW.G. SladeD.L. DaltonW.S. MeltzerP.S. TrentJ.M. Multidrug resistance in mitoxantrone-selected HL-60 leukemia cells in the absence of P-glycoprotein overexpression.Cancer Res.19894916454245492568172
     [Google Scholar]
  24. MonvilleC. FagesC. FeyensA.M. d’HondtV. GuilletC. VernallisA. GascanH. PeschanskiM. Astroglial expression of the P-glycoprotein is controlled by intracellular CNTF.BMC Cell Biol.200231202910.1186/1471‑2121‑3‑2012150717
     [Google Scholar]
  25. AntczakC. WeeB. RaduC. BhinderB. HollandE.C. DjaballahH. A high-content assay strategy for the identification and profiling of ABCG2 modulators in live cells.Assay Drug Dev. Technol.2014121284210.1089/adt.2013.52123992118
     [Google Scholar]
  26. WeeB. PietrasA. OzawaT. BazzoliE. PodlahaO. AntczakC. WestermarkB. NelanderS. UhrbomL. Forsberg-NilssonK. DjaballahH. MichorF. HollandE.C. ABCG2 regulates self-renewal and stem cell marker expression but not tumorigenicity or radiation resistance of glioma cells.Sci. Rep.2016612595610.1038/srep2595627456282
     [Google Scholar]
  27. MirskiS.E. GerlachJ.H. ColeS.P. Multidrug resistance in a human small cell lung cancer cell line selected in adriamycin.Cancer Res.19874710259425982436751
     [Google Scholar]
  28. ColeS.P.C. ChandaE.R. DickeF.P. GerlachJ.H. MirskiS.E. Non-P-glycoprotein-mediated multidrug resistance in a small cell lung cancer cell line: Evidence for decreased susceptibility to drug-induced DNA damage and reduced levels of topoisomerase II.Cancer Res.19915113334533521675932
     [Google Scholar]
  29. NazhaA. KantarjianH. CortesJ. Quintás-CardamaA. Omacetaxine mepesuccinate (synribo) – newly launched in chronic myeloid leukemia.Expert Opin. Pharmacother.201314141977198610.1517/14656566.2013.82146423875628
     [Google Scholar]
  30. MillerT.P. GroganT.M. DaltonW.S. SpierC.M. ScheperR.J. SalmonS.E. P-glycoprotein expression in malignant lymphoma and reversal of clinical drug resistance with chemotherapy plus high-dose verapamil.J. Clin. Oncol.199191172410.1200/JCO.1991.9.1.171670642
     [Google Scholar]
  31. ChabnerB.A. FojoA. Multidrug resistance: P-glycoprotein and its allies--the elusive foes.J. Natl. Cancer Inst.1989811291091310.1093/jnci/81.12.9102567356
     [Google Scholar]
  32. ShumD. SantosR. DjaballahH. High-throughput profiling of leukemia cells for the identification of novel chemical scaffold signatures predicting disease-specific sensitivities.Cancer Res.2007679Suppl.5560
     [Google Scholar]
  33. FrattiniM.G. DjaballahH. CDC7 kinase inhibitors and uses thereof.US Patent US009782386B22010
  34. RossD.D. Novel mechanisms of drug resistance in leukemia.Leukemia200014346747310.1038/sj.leu.240169410720143
     [Google Scholar]
  35. AbolhodaA. WilsonA.E. RossH. DanenbergP.V. BurtM. ScottoK.W. Rapid activation of MDR1 gene expression in human metastatic sarcoma after in vivo exposure to doxorubicin.Clin. Cancer Res.19995113352335610589744
     [Google Scholar]
  36. GottesmanM.M. FojoT. BatesS.E. Multidrug resistance in cancer: Role of ATP–dependent transporters.Nat. Rev. Cancer200221485810.1038/nrc70611902585
     [Google Scholar]
  37. EfferthT. SauerbreyA. HalatschM.E. RossD.D. GebhartE. Molecular modes of action of cephalotaxine and homoharringtonine from the coniferous tree Cephalotaxus hainanensis in human tumor cell lines.Naunyn Schmiedebergs Arch. Pharmacol.20033671566710.1007/s00210‑002‑0632‑012616342
     [Google Scholar]
  38. TangR. FaussatA.M. MajdakP. MarzacC. DubrulleS. MarjanovicZ. LegrandO. MarieJ.P. 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.20065372373110.1158/1535‑7163.MCT‑05‑016416546987
     [Google Scholar]
  39. ChenR. GuoL. ChenY. JiangY. WierdaW.G. PlunkettW. Homoharringtonine reduced Mcl-1 expression and induced apoptosis in chronic lymphocytic leukemia.Blood2011117115616410.1182/blood‑2010‑01‑26280820971952
     [Google Scholar]
  40. ChenR. GandhiV. PlunkettW. A sequential blockade strategy for the design of combination therapies to overcome oncogene addiction in chronic myelogenous leukemia.Cancer Res.20066622109591096610.1158/0008‑5472.CAN‑06‑121617108134
     [Google Scholar]
/content/journals/cchts/10.2174/0113862073322175240823104921
Loading
Antiproliferative Activity of Cephalotaxus Esters: Overcoming Chemoresistance
Comb Chem High Throughput Screen 28, 1264 (2025); https://doi.org/10.2174/0113862073322175240823104921
/content/journals/cchts/10.2174/0113862073322175240823104921
/content/journals/cchts/10.2174/0113862073322175240823104921
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher's website along with the published article.

file format download Download

  • Article Type:     Research Article
Keyword(s): AML; Cancer; CML; drug resistance; homoharringtonine; leukemia; MDR; natural products

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test