Skip to main content

Advertisement

SpringerLink
Log in

RETRACTED ARTICLE: Quinoxaline 1,4-dioxides induce G2/M cell cycle arrest and apoptosis in human colon cancer cells

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

This article was retracted on 08 January 2018

Abstract

We have recently shown that quinoxaline 1,4-dioxide (QdNO) derivatives, namely 2-benzoyl-3-phenyl-6,7-dichloroquinoxaline 1,4-dioxide (DCQ), 2-benzoyl-3-phenyl-quinoxaline 1,4-dioxide (BPQ) and 2-acetyl-3-methyl-quinoxaline 1,4-dioxide (AMQ), suppress the growth of T-84 human colon cancer cells. Here we show that the growth-suppressive effects of QdNOs are due to their ability to induce cell cycle arrest and/or apoptosis. While AMQ blocked more than 60% of cells at the G2/M phase without inducing apoptosis, DCQ caused a significant increase in apoptotic cells with no noticeable effects on the cycling of cells. Treatment with BPQ resulted in G2/M cell cycle arrest and induction of apoptosis. With regard to the effects of QdNOs on molecules that regulate apoptosis and the G2 to M transition, both BPQ and AMQ inhibited the expression of cyclin B, while DCQ significantly decreased the levels of Bcl-2 and increased Bax expression. Next, we investigated whether transforming growth factor-beta1 (TGF-β1) and/or extracellular signal-regulated kinase (ERK) mediate the antiproliferative and apoptotic effects of QdNOs in colon cancer cells. Interestingly, the above QdNOs increased differentially total TGFβ1 mRNA expression and decreased TGFα mRNA and ERK phosphorylation. None of these QdNOs induced changes in TGFβ-2 mRNA expression. The addition of a specific inhibitor of MEK greatly enhanced apoptosis in cells treated with DCQ, suggesting that the inhibition of ERK phosphorylation may explain, to an extent, the apoptogenic effects of this compound. Taken together, these findings provide insights into possible molecular mechanisms of growth inhibition by QdNOs that could aid in their evaluation for anticancer therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

AMQ:

2-Acetyl-3-methylquinoxaline 1,4-dioxide

BPQ:

2-Benzoyl-3-phenylquinoxaline 1,4-dioxide

DCQ:

2-Benzoyl-3-phenyl-6,7-dichloro quinoxaline 1,4-dioxide

DMEM:

Dulbecco’s modified Eagle’s medium

DMSO:

Dimethyl sulfoxide

ERK:

Extracellular signal-regulated kinase

FBS:

Fetal bovine serum

JNK:

cJUN-N terminal kinase

MAPK:

Mitogen-activated protein kinase

NGF:

Neuron growth factor

PI:

Propidium iodide

QdNO:

Quinoxaline 1,4-dioxide

TdT:

Terminal deoxynucleotide transferase

TGFα:

Transforming growth factor alpha

TGFβ:

Transforming growth factor beta

References

  1. Murthy U, Anzano MA, Greig RG (1989) Expression of TGF-alpha/EGF and TGF-beta receptors in human colon carcinoma cell lines. Int J Cancer 44:110–115

    Article  CAS  PubMed  Google Scholar 

  2. Biasi F, Tessitore L, Zanetti D, Cutrin JC, Zingaro B, Chiarpotto E, Zarkovic N, Serviddio G, Poli G (2002) Associated changes of lipid peroxidation and transforming growth factor beta1 levels in human colon cancer during tumour progression. Gut 50:361–367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Wang D, Patil S, Li W, Humphrey LE, Brattain MG, Howell GM (2002) Activation of the TGFalpha autocrine loop is downstream of IGF-I receptor activation during mitogenesis in growth factor dependent human colon carcinoma cells. Oncogene 21:2785–2796

    Article  CAS  PubMed  Google Scholar 

  4. Marshall CJ (1995) Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80:179–185

    Article  CAS  PubMed  Google Scholar 

  5. Frey RS, Mulder KM (1997) Involvement of extracellular signal-regulated kinase 2 and stress activated protein kinase/Jun N-terminal kinase activation by transforming growth factor beta in the negative growth control of breast cancer cells. Cancer Res 57:628–633

    CAS  PubMed  Google Scholar 

  6. Licato LL, Keku TO, Wurzelmann JI, Murray SC, Woosley JT, Sandler RS, Brenner DA (1997) In vivo activation of mitogen-activated protein kinases in rat intestinal neoplasia. Gastroenterology 113:1589–1598

    Article  CAS  PubMed  Google Scholar 

  7. Gredinger E, Gerber AN, Tamir Y, Tapscott SJ, Bengal E (1998) Mitogen-activated protein kinase pathway is involved in the differentiation of muscle cells. J Biol Chem 273:10436–10444

    Article  CAS  PubMed  Google Scholar 

  8. Plattner R, Gupta S, Khosravi-Far R, Sato KY, Perucho M, Der CJ, Stanbridge EJ (1999) Differential contribution of the ERK and JNK mitogen-activated protein kinase cascades to Ras transformation of HT1080 fibrosarcoma and DLD-1 colon carcinoma cells. Oncogene 18:1807–1817

    Article  CAS  PubMed  Google Scholar 

  9. Taupin D, Podolsky DK (1999) Mitogen-activated protein kinase activation regulates intestinal epithelial differentiation. Gastroenterology 116:1072–1080

    Article  CAS  PubMed  Google Scholar 

  10. Sebolt-Leopold JS, Dudley DT, Herrera R, Van Becelaere K, Wiland A, Gowan RC, Tecle H, Barrett SD, Bridges A, Przybranowski S, Leopold WR, Saltiel AR (1999) Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nat Med 5:810–816

    Article  CAS  PubMed  Google Scholar 

  11. Hoshino R, Chatani Y, Yamori T, Tsuruo T, Oka H, Yoshida O, Shimada Y, Ari-i S, Wada H, Fujimoto J, Kohno M (1999) Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors. Oncogene 18:813–822

    Article  CAS  PubMed  Google Scholar 

  12. Bennett AM, Tonks NK (1997) Regulation of distinct stages of skeletal muscle differentiation by mitogen-activated protein kinase. Science 278:1288–1291

    Article  CAS  PubMed  Google Scholar 

  13. Yen A, Roberson MS, Varvayanis S, Lee AT (1998) Retinoic acid induced mitogen-activated protein [MAP]/extracellular signal-regulated kinase [ERK] kinase-dependent MAP kinase activation needed to elicit HL-60 cell differentiation and growth arrest. Cancer Res 58:3163–3172

    CAS  PubMed  Google Scholar 

  14. Yan Z, Deng X, Friedman E (2001) Oncogenic Ki-ras confers a more aggressive colon cancer phenotype through modification of transforming growth factor-beta receptor III. J Biol Chem 276:1555–1563

    Article  CAS  PubMed  Google Scholar 

  15. Akhurst RJ (2002) TGF-beta antagonists: why suppress a tumor suppressor? J Clin Invest 109:1533–1536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sebolt-Leopold JS (2000) Development of anticancer drugs targeting the MAP kinase pathway. Oncogene 19:6594–6599

    Article  CAS  PubMed  Google Scholar 

  17. Gali-Muhtasib HU, Haddadin MJ, Rahhal DN, Younes I (2001) Quinoxaline 1,4-dioxides as anticancer and hypoxia-selective drugs. Oncol Rep 8:679–684

    CAS  PubMed  Google Scholar 

  18. Haddadin MJ, Issidorides CH (1993) The Beirut reaction. Heterocycles 35:1503–1525

    Article  CAS  Google Scholar 

  19. Orlowski RZ, Small GW, Shi YY (2002) Evidence that inhibition of p44/42 mitogen-activated protein kinase signaling is a factor in proteasome inhibitor-mediated apoptosis. J Biol Chem 277:27864–27871

    Article  CAS  PubMed  Google Scholar 

  20. Reed JC (1998) Bcl-2 family proteins. Oncogene 17:3225–3236

    Article  PubMed  Google Scholar 

  21. Hennessey TD, Edwards JR (1972) Antibacterial properties of quindoxin: a new growth-promoting agent. Vet Rec 90:187–191

    Article  CAS  PubMed  Google Scholar 

  22. Priyadarsini KI, Dennis MF, Naylor MA, Stratford MRL, Wardman P (1996) Free radical intermediates in the reduction of quinoxaline N-oxide antitumor drugs: redox and prototropic reactions. J Am Chem Soc 118:5648–5654

    Article  CAS  Google Scholar 

  23. Alexandrow M, Moses H (1995) Transforming growth factor β and cell cycle regulation. Cancer Res 55:1452–1457

    CAS  PubMed  Google Scholar 

  24. Guda K, Giardina C, Nambiar P, Cui H, Rosenberg DW (2001) Aberrant transforming growth factor-beta signaling in azoxymethane-induced mouse colon tumors. Mol Carcinog 31:204–213

    Article  CAS  PubMed  Google Scholar 

  25. Hagimoto N, Kuwano K, Inoshima I, Yoshimi M, Nakamura N, Fujita M, Maeyama T, Hara N (2002) TGF-beta 1 as an enhancer of Fas-mediated apoptosis of lung epithelial cells. J Immunol 168:6470–6478

    Article  CAS  PubMed  Google Scholar 

  26. Kim BC, Mamura M, Choi KS, Calabretta B, Kim SJ (2002) Transforming growth factor beta 1 induces apoptosis through cleavage of BAD in a Smad3-dependent mechanism in FaO hepatoma cells. Mol Cell Biol 22:1369–1378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME (1995) Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 270:1326–1331

    Article  CAS  PubMed  Google Scholar 

  28. Wilson DJ, Alessandrini A, Budd RC (1999) MEK1 activation rescues Jurkat T cells from Fas-induced apoptosis. Cell Immunol 194:67–77

    Article  CAS  PubMed  Google Scholar 

  29. Yang GH., Jarvis BB, Chung YJ, Pestka JJ (2000) Apoptosis induction by the satratoxins and other trichothecene mycotoxins: relationship to ERK, p38 MAPK, and SAPK/JNK activation. Toxicol Appl Pharmacol 164:149–160

    Article  CAS  PubMed  Google Scholar 

  30. Qiao D, Stratagouleas ED, Martinez JD (2001) Activation and role of mitogen-activated protein kinases in deoxycholic acid-induced apoptosis. Carcinogenesis 22:35–41

    Article  CAS  PubMed  Google Scholar 

  31. Rice PL, Goldberg RJ, Ray EC, Driggers LJ, Ahnen DJ (2001) Inhibition of extracellular signal-regulated kinase 1/2 phosphorylation and induction of apoptosis by sulindac metabolites. Cancer Res 61:1541–1547

    CAS  PubMed  Google Scholar 

  32. Carnesecchi S, Bradaia A, Fischer B, Coelho D, Scholler-Guinard M, Gosse F, Raul F (2002) Perturbation by geraniol of cell membrane permeability and signal transduction pathways in human colon cancer cells. J Pharmacol Exp Ther 303:711–715

    Article  CAS  PubMed  Google Scholar 

  33. Diab-Assaf M, Haddadin MJ, Yared P, Al-Assaad C, Gali-Muhtasib HU (2002) Quinoxaline 1,4-dioxides: hypoxia selective therapeutic agents. Mol Carcinog 33:198–205

    Article  Google Scholar 

Download references

Acknowledgements

We thank members of the Central Research Science Laboratory, Dr. Youssef Mouneimne and Ms. Rania El-Usta for their help in the use of the flow cytometer and assistance with the graphic presentations. This work was supported by the University Research Board of the American University of Beirut, the Royalties of the Beirut Reaction and the Lebanese National Council for Scientific Research.

Author information

Authors and Affiliations

  1. Department of Biology, American University of Beirut, Beirut, Lebanon

    Hala U. Gali-Muhtasib & Mona Diab-Assaf

  2. Department of Chemistry, American University of Beirut, Beirut, Lebanon

    Makhluf J. Haddadin

Authors
  1. Hala U. Gali-Muhtasib
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mona Diab-Assaf
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Makhluf J. Haddadin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hala U. Gali-Muhtasib.

Additional information

The authors have retracted this article [1] because of overlap in images within the publication and with another previously published article [2]. It was brought to our attention that there are inconsistencies in Figs. 3, 5 and 6. The left middle panel in Fig. 3, labeled "Ctrl", is the same as the left panel in Fig. 6, labeled "PD98059", except that the latter is flipped upside down and right-left. In Fig. 5, the gel in the middle left panel labeled TGF-β2 has been cropped in two different ways and used in Figs. 2 and 3 of Harakeh et al [2]. This has been investigated by the Internal Research Integrity panel of the American University of Beirut who recommended retraction of the article as the original data are not available. *All authors agree to this retraction.

1. Gali-Muhtasib HU, Diab-Assaf M, Haddadin MJ. Quinoxaline 1,4-dioxides induce G2/M cell cycle arrest and apoptosis in human colon cancer cells. Cancer Chemother Pharmacol. 2005 Apr;55(4):369-78. doi:10.1007/s00280-004-0907-x

2. Harakeh S, Diab-Assef M, El-Sabban M, Haddadin M, Gali-Muhtasib H. Inhibition of proliferation and induction of apoptosis by 2-benzoyl-3-phenyl-6,7-dichloroquinoxaline 1,4-dioxide in adult T-cell leukemia cells. Chem Biol Interact. 2004 Jul 20;148(3):101-13. doi:10.1016/j.cbi.2004.05.002

An erratum to this article can be found online at http://dx.doi.org/10.1007/s00280-017-3515-2.

About this article

Cite this article

Gali-Muhtasib, H.U., Diab-Assaf, M. & Haddadin, M.J. RETRACTED ARTICLE: Quinoxaline 1,4-dioxides induce G2/M cell cycle arrest and apoptosis in human colon cancer cells. Cancer Chemother Pharmacol 55, 369–378 (2005). https://doi.org/10.1007/s00280-004-0907-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-004-0907-x

Keywords

Search

Navigation