Home LiteratureArticle Details
PMID: 18037229 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

sHA 14-1, a stable and ROS-free antagonist against anti-apoptotic Bcl-2 proteins, bypasses drug resistances and synergizes cancer therapies in human leukemia cell.

Cancer letters ·Vol. 259 ·No. 2 ·2008-02-08 ·Pages 198-208

Tian D, Das SG, Doshi JM, Peng J, Lin J, Xing C

Abstract

HA 14-1, a small-molecule antagonist against anti-apoptotic Bcl-2 proteins, was demonstrated to induce selective cytotoxicity toward malignant cells and to overcome drug resistance. Due to its poor stability and the reactive oxygen species (ROS) generated by its decomposition, chemical modification of HA 14-1 is needed for its future development. We have synthesized a stabilized analog of HA 14-1--sHA 14-1, which did not induce the formation of ROS. As expected from a putative antagonist against anti-apoptotic Bcl-2 proteins like HA 14-1, sHA 14-1 disrupted the binding interaction of a Bak BH3 peptide with Bcl-2 or Bcl-X(L) protein, inhibited the growth of tumor cells through the induction of apoptosis, and circumvented the drug resistance induced by the over-expression of anti-apoptotic Bcl-2 and Bcl-X(L) proteins. Interestingly, the impairment of extrinsic apoptotic pathway induced moderate resistance to sHA 14-1. The moderate resistance suggested that sHA 14-1 generated part of its apoptotic stress through the intrinsic pathway, possibly through its antagonism against anti-apoptotic Bcl-2 proteins. The resistance indicated that sHA 14-1 generated apoptotic stress through the extrinsic apoptotic pathway as well. The ability of sHA 14-1 to induce apoptotic stress through both pathways was further supported by the synergism of sHA 14-1 towards the cytotoxicities of Fas ligand and dexamethasone in Jurkat cells. Taken together, these findings suggest that sHA 14-1 may represent a promising candidate for the treatment of drug-resistant cancers either as a monotherapy or in combination with current cancer therapies.

MeSH Terms
Antineoplastic Agents/pharmacology,therapeutic use Antineoplastic Combined Chemotherapy Protocols/pharmacology,therapeutic use Apoptosis/drug effects Benzopyrans/pharmacology,therapeutic use Cell Proliferation/drug effects Cell Survival/drug effects Dose-Response Relationship, Drug Drug Resistance, Neoplasm Drug Stability Drug Synergism Fas Ligand Protein/metabolism Humans Inhibitory Concentration 50 Jurkat Cells Leukemia/drug therapy,metabolism,pathology Nitriles/pharmacology,therapeutic use Peptide Fragments/metabolism Proto-Oncogene Proteins/metabolism Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors,genetics,metabolism Reactive Oxygen Species/metabolism Signal Transduction/drug effects Transfection bcl-X Protein/antagonists & inhibitors,genetics,metabolism
Chemicals
Antineoplastic Agents BCL2L1 protein, human Bax protein (53-86) Benzopyrans Fas Ligand Protein Nitriles Peptide Fragments Proto-Oncogene Proteins Proto-Oncogene Proteins c-bcl-2 Reactive Oxygen Species bcl-X Protein ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Tian Defeng
Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.
Das Sonia G
Doshi Jignesh M
Peng Jun
Lin Jialing
Xing Chengguo
References (44)
44 references, click to expand
  1. Detection of picomole levels of hydroperoxides using a fluorescent dichlorofluorescein assay.
    Anal Biochem. 1983 Oct 1;134(1):111-6 PMID: 6660480
  2. Apoptosis: biochemical aspects and clinical implications.
    Clin Chim Acta. 2002 Dec;326(1-2):27-45 PMID: 12417095
  3. Sequential caspase-2 and caspase-8 activation upstream of mitochondria during ceramideand etoposide-induced apoptosis.
    J Biol Chem. 2004 Sep 24;279(39):40755-61 PMID: 15262979
  4. Enforced dimerization of BAX results in its translocation, mitochondrial dysfunction and apoptosis.
    EMBO J. 1998 Jul 15;17(14):3878-85 PMID: 9670005
  5. Rational design and real time, in-cell detection of the proapoptotic activity of a novel compound targeting Bcl-X(L).
    Chem Biol. 2004 Mar;11(3):389-95 PMID: 15123268
  6. Essential requirement for caspase-8/FLICE in the initiation of the Fas-induced apoptotic cascade.
    Curr Biol. 1998 Sep 10;8(18):1001-8 PMID: 9740801
  7. The small organic compound HA14-1 prevents Bcl-2 interaction with Bax to sensitize malignant glioma cells to induction of cell death.
    Cancer Res. 2006 Mar 1;66(5):2757-64 PMID: 16510597
  8. Discovery of small-molecule inhibitors of Bcl-2 through structure-based computer screening.
    J Med Chem. 2001 Dec 6;44(25):4313-24 PMID: 11728179
  9. Regulation of 17-AAG-induced apoptosis: role of Bcl-2, Bcl-XL, and Bax downstream of 17-AAG-mediated down-regulation of Akt, Raf-1, and Src kinases.
    Blood. 2003 Jul 1;102(1):269-75 PMID: 12623837
  10. A Bcr/Abl-independent, Lyn-dependent form of imatinib mesylate (STI-571) resistance is associated with altered expression of Bcl-2.
    J Biol Chem. 2004 Aug 13;279(33):34227-39 PMID: 15175350
  11. Doxorubicin activates nuclear factor of activated T-lymphocytes and Fas ligand transcription: role of mitochondrial reactive oxygen species and calcium.
    Biochem J. 2005 Jul 15;389(Pt 2):527-39 PMID: 15799720
  12. Exploitation of drug-induced Bcl-2 overexpression for restoring normal apoptosis function: a promising new approach to the treatment of multidrug resistant cancer.
    Cancer Lett. 2007 Aug 8;253(1):115-23 PMID: 17349740
  13. Peripheral benzodiazepine receptor ligands induce apoptosis and cell cycle arrest in human hepatocellular carcinoma cells and enhance chemosensitivity to paclitaxel, docetaxel, doxorubicin and the Bcl-2 inhibitor HA14-1.
    J Hepatol. 2004 Nov;41(5):799-807 PMID: 15519653
  14. An inhibitor of Bcl-2 family proteins induces regression of solid tumours.
    Nature. 2005 Jun 2;435(7042):677-81 PMID: 15902208
  15. The Bcl-2 protein family: arbiters of cell survival.
    Science. 1998 Aug 28;281(5381):1322-6 PMID: 9735050
  16. Mcl-1 down-regulation potentiates ABT-737 lethality by cooperatively inducing Bak activation and Bax translocation.
    Cancer Res. 2007 Jan 15;67(2):782-91 PMID: 17234790
  17. Pyrogallol-based molecules as potent inhibitors of the antiapoptotic Bcl-2 proteins.
    J Med Chem. 2007 Apr 19;50(8):1723-6 PMID: 17378545
  18. Degenerative disorders caused by Bcl-2 deficiency prevented by loss of its BH3-only antagonist Bim.
    Dev Cell. 2001 Nov;1(5):645-53 PMID: 11709185
  19. A novel approach for characterizing protein ligand complexes: molecular basis for specificity of small-molecule Bcl-2 inhibitors.
    J Am Chem Soc. 2002 Feb 20;124(7):1234-40 PMID: 11841292
  20. The Bcl-2 family: roles in cell survival and oncogenesis.
    Oncogene. 2003 Nov 24;22(53):8590-607 PMID: 14634621
  21. HA14-1 selectively induces apoptosis in Bcl-2-overexpressing leukemia/lymphoma cells, and enhances cytarabine-induced cell death.
    Leukemia. 2003 Nov;17(11):2074-80 PMID: 12931228
  22. Structure of Bcl-xL-Bak peptide complex: recognition between regulators of apoptosis.
    Science. 1997 Feb 14;275(5302):983-6 PMID: 9020082
  23. A novel BH3 mimetic reveals a mitogen-activated protein kinase-dependent mechanism of melanoma cell death controlled by p53 and reactive oxygen species.
    Cancer Res. 2006 Dec 1;66(23):11348-59 PMID: 17145881
  24. FADD is required for multiple signaling events downstream of the receptor Fas.
    Cell Growth Differ. 1999 Dec;10(12):797-804 PMID: 10616904
  25. Bcl-2 inhibitors sensitize tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by uncoupling of mitochondrial respiration in human leukemic CEM cells.
    Cancer Res. 2004 May 15;64(10):3607-16 PMID: 15150119
  26. The proteasome inhibitor bortezomib promotes mitochondrial injury and apoptosis induced by the small molecule Bcl-2 inhibitor HA14-1 in multiple myeloma cells.
    Leukemia. 2003 Oct;17(10):2036-45 PMID: 14513055
  27. Involvement of caspase-8 in chemotherapy-induced apoptosis of patient derived leukemia cell lines independent of the death receptor pathway and downstream from mitochondria.
    Apoptosis. 2007 Jan;12(1):181-93 PMID: 17136321
  28. Critical upstream signals of cytochrome C release induced by a novel Bcl-2 inhibitor.
    J Biol Chem. 2004 Apr 30;279(18):19133-40 PMID: 14966123
  29. The small-molecule Bcl-2 inhibitor HA14-1 interacts synergistically with flavopiridol to induce mitochondrial injury and apoptosis in human myeloma cells through a free radical-dependent and Jun NH2-terminal kinase-dependent mechanism.
    Mol Cancer Ther. 2004 Dec;3(12):1513-24 PMID: 15634644
  30. Tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis is inhibited by Bcl-2 but restored by the small molecule Bcl-2 inhibitor, HA 14-1, in human colon cancer cells.
    Clin Cancer Res. 2004 Dec 15;10(24):8284-92 PMID: 15623604
  31. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors.
    Adv Enzyme Regul. 1984;22:27-55 PMID: 6382953
  32. Proline oxidase activates both intrinsic and extrinsic pathways for apoptosis: the role of ROS/superoxides, NFAT and MEK/ERK signaling.
    Oncogene. 2006 Sep 14;25(41):5640-7 PMID: 16619034
  33. Overcoming the radioresistance of prostate cancer cells with a novel Bcl-2 inhibitor.
    Oncogene. 2007 Feb 1;26(5):652-61 PMID: 16909121
  34. Synergistic induction of apoptosis by simultaneous disruption of the Bcl-2 and MEK/MAPK pathways in acute myelogenous leukemia.
    Blood. 2002 May 1;99(9):3461-4 PMID: 11964319
  35. Antimycin A mimics a cell-death-inducing Bcl-2 homology domain 3.
    Nat Cell Biol. 2001 Feb;3(2):183-91 PMID: 11175751
  36. Structure-based discovery of an organic compound that binds Bcl-2 protein and induces apoptosis of tumor cells.
    Proc Natl Acad Sci U S A. 2000 Jun 20;97(13):7124-9 PMID: 10860979
  37. Two CD95 (APO-1/Fas) signaling pathways.
    EMBO J. 1998 Mar 16;17(6):1675-87 PMID: 9501089
  38. Discovery of a potent inhibitor of the antiapoptotic protein Bcl-xL from NMR and parallel synthesis.
    J Med Chem. 2006 Jan 26;49(2):656-63 PMID: 16420051
  39. Structure-activity relationship studies of ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (HA 14-1), an antagonist for antiapoptotic Bcl-2 proteins to overcome drug resistance in cancer.
    J Med Chem. 2006 Dec 28;49(26):7731-9 PMID: 17181155
  40. HA14-1, a small molecule Bcl-2 antagonist, induces apoptosis and modulates action of selected anticancer drugs in follicular lymphoma B cells.
    Leuk Res. 2006 Mar;30(3):322-31 PMID: 16213584
  41. Bcl-2 is a key regulator for the retinoic acid-induced apoptotic cell death in neuroblastoma.
    Oncogene. 2006 Aug 17;25(36):5046-55 PMID: 16568081
  42. Discovery, characterization, and structure-activity relationships studies of proapoptotic polyphenols targeting B-cell lymphocyte/leukemia-2 proteins.
    J Med Chem. 2003 Sep 25;46(20):4259-64 PMID: 13678404
  43. Synthetic 1,4-anthracenedione analogs induce cytochrome c release, caspase-9, -3, and -8 activities, poly(ADP-ribose) polymerase-1 cleavage and internucleosomal DNA fragmentation in HL-60 cells by a mechanism which involves caspase-2 activation but not Fas signaling.
    Biochem Pharmacol. 2004 Feb 1;67(3):523-37 PMID: 15037204
  44. Ethyl-2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H- chromene-3-carboxylate (HA 14-1), a prototype small-molecule antagonist against antiapoptotic Bcl-2 proteins, decomposes to generate reactive oxygen species that induce apoptosis.
    Mol Pharm. 2007 Nov-Dec;4(6):919-28 PMID: 17874842
Article Info
Journal
Cancer letters
Abbr.
Cancer Lett
ISSN
0304-3835
DOI
10.1016/j.canlet.2007.10.012
Published
2008-02-08
Epub
2007-00-26
Pages
198-208
Language
English
Region
Ireland
NLM ID
7600053
PMCID
PMC2693013
Subset
IM
Grants
NCI NIH HHS · R01 CA114294 · United States
NCI NIH HHS · R01 CA114294-03 · United States
NIGMS NIH HHS · R01 GM062964 · United States
NIGMS NIH HHS · R01GM062964 · United States
External Links
PubMed source DOI: 10.1016/j.canlet.2007.10.012 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2