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Cancer Chemotherapy and Pharmacology

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01.05.2010 | Original Article

LLL-3, a STAT3 inhibitor, represses BCR-ABL-positive cell proliferation, activates apoptosis and improves the effects of Imatinib mesylate

verfasst von: Andre Luiz Mencalha, B. Du Rocher, D. Salles, R. Binato, E. Abdelhay

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 6/2010

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Abstract

Purpose

The chimeric protein BCR-ABL, a constitutively active protein-tyrosine kinase, triggers downstream signalling proteins, such as STAT3, ultimately resulting in the survival of myeloid progenitors in BCR-ABL-positive leukemias. Here, we evaluated the effect of LLL-3, an inhibitor of STAT3 activity, on cell viability and its addictive effects with Imatinib mesylate (IM) treatment in BCR-ABL-positive cells.

Methods

Viability of cell lines was determined using the WST-1 assay in response to drug treatment, either LLL-3 alone or in conjunction with IM. Annexin V-FITC/PI staining, sub-G1 DNA content and Caspase-3/7 activation assays were performed to evaluate apoptosis.

Results

LLL-3 treatment decreased cell viability, triggered apoptosis and activated Caspases-3/7 in K562 cells. LLL-3 increases IM treatment to inhibited cell viability and activation of apoptosis in BCR-ABL-positive cell lines.

Conclusions

LLL-3 reduced cell viability and induced apoptosis in K562 cells. Moreover, the observed addictive effects of co-treatment with IM and LLL-3 suggest this combination has therapeutic potential.

Melo JV, Chuah C (2008) Novel agents in CML therapy: tyrosine kinase inhibitors and beyond. Hematol Am Soc Hematol Educ Program 427–435

Kurzrock R, Kantarjian HM, Druker BJ, Talpaz M (2003) Philadelphia chromosome-positive leukemias: from basic mechanisms to molecular therapeutics. Ann Intern Med 138:819–830PubMed

Chai SK, Nichols GL, Rothman P (1997) Constitutive activation of JAKs and STATs in BCR-ABL-expressing cell lines and peripheral blood cells derived from leukemic patients. J Immunol 159:4720–4728PubMed

Steelman LS, Pohnert SC, Shelton JG, Franklin RA, Bertrand FE, McCubrey JA (2004) JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia 18:189–218CrossRefPubMed

Yanada M, Ohno R, Naoe T (2008) Recent advances in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia. Int J Hematol. doi:10.1007/s12185-008-0223-z

Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL (2001) Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344:1031–1037CrossRefPubMed

Roskoski R Jr (2003) STI-571: an anticancer protein-tyrosine kinase inhibitor. Biochem Biophys Res Commun 309:709–717CrossRefPubMed

Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, Capdeville R, Talpaz M (2001) Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344:1038–1042CrossRefPubMed

Deininger M (2008) Resistance and relapse with imatinib in CML: causes and consequences. J Natl Compr Canc Netw 2:S11–S21

10.

Weisberg E, Griffin JD (2003) Resistance to imatinib (Glivec): update on clinical mechanisms. Drug Resist Updat 6:231–238CrossRefPubMed

11.

Weisberg E, Banerji L, Wright RD, Barrett R, Ray A, Moreno D, Catley L, Jiang J, Hall-Meyers E, Sauveur-Michel M, Stone R, Galinsky I, Fox E, Kung AL, Griffin JD (2008) Potentiation of antileukemic therapies by the dual PI3K/PDK-1 inhibitor, BAG956: effects on BCR-ABL- and mutant FLT3-expressing cells. Blood 111:3723–3734CrossRefPubMed

12.

Coppo P, Flamant S, De Mas V, Jarrier P, Guillier M, Bonnet ML, Lacout C, Guilhot F, Vainchenker W, Turhan AG (2006) BCR-ABL activates STAT3 via JAK and MEK pathways in human cells. Br J Haematol 134:171–179CrossRefPubMed

13.

Coppo P, Dusanter-Fourt I, Millot G, Nogueira MM, Dugray A, Bonnet ML, Mitjavila-Garcia MT, Le Pesteur D, Guilhot F, Vainchenker W, Sainteny F, Turhan AG (2003) Constitutive and specific activation of STAT3 by BCR-ABL in embryonic stem cells. Oncogene 22:4102–4110CrossRefPubMed

14.

Weber-Nordt RM, Egen C, Wehinger J, Ludwig W, Gouilleux-Gruart V, Mertelsmann R, Finke J (1996) Constitutive activation of STAT proteins in primary lymphoid and myeloid leukemia cells and in Epstein-Barr virus (EBV)-related lymphoma cell lines. Blood 88:809–816PubMed

15.

Benekli M, Xia Z, Donohue KA, Ford LA, Pixley LA, Baer MR, Baumann H, Wetzler M (2002) Constitutive activity of signal transducer and activator of transcription 3 protein in acute myeloid leukemia blasts is associated with short disease-free survival. Blood 99:252–257CrossRefPubMed

16.

Yared MA, Khoury JD, Medeiros LJ, Rassidakis GZ, Lai R (2005) Activation status of the JAK/STAT3 pathway in mantle cell lymphoma. Arch Pathol Lab Med 129:990–996PubMed

17.

Chen CL, Cen L, Kohout J, Hutzen B, Chan C, Hsieh FC, Loy A, Huang V, Cheng G, Lin J (2008) Signal transducer and activator of transcription 3 activation is associated with bladder cancer cell growth and survival. Mol Cancer 7:78CrossRefPubMed

18.

Lieblein JC, Ball S, Hutzen B, Sasser AK, Lin HJ, Huang TH, Hall BM, Lin J (2008) STAT3 can be activated through paracrine signaling in breast epithelial cells. BMC Cancer 8:302CrossRefPubMed

19.

Abdulghani J, Gu L, Dagvadorj A, Lutz J, Leiby B, Bonuccelli G, Lisanti MP, Zellweger T, Alanen K, Mirtti T, Visakorpi T, Bubendorf L, Nevalainen MT (2008) Stat3 promotes metastatic progression of prostate cancer. Am J Pathol 172:1717–1728CrossRefPubMed

20.

Liu B, Ren Z, Shi Y, Guan C, Pan Z, Zong Z (2008) Activation of signal transducers and activators of transcription 3 and overexpression of its target gene CyclinD1 in laryngeal carcinomas. Laryngoscope 118:1976–1980CrossRefPubMed

21.

Germain D, Frank DA (2007) Targeting the cytoplasmic and nuclear functions of signal transducers and activators of transcription 3 for cancer therapy. Clin Cancer Res 13:5665–5669CrossRefPubMed

22.

Fletcher S, Turkson J, Gunning PT (2008) Molecular approaches towards the inhibition of the signal transducer and activator of transcription 3 (Stat3) protein. ChemMedChem 3:1159–1168CrossRefPubMed

23.

Aziz MH, Dreckschmidt NE, Verma AK (2008) Plumbagin, a medicinal plant-derived naphthoquinone, is a novel inhibitor of the growth and invasion of hormone-refractory prostate cancer. Cancer Res 68:9024–9032CrossRefPubMed

24.

Hao W, Hu Y, Niu C, Huang X, Chang CP, Gibbons J, Xu J (2008) Discovery of the catechol structural moiety as a Stat3 SH2 domain inhibitor by virtual screening. Bioorg Med Chem Lett 18:4988–4992CrossRefPubMed

25.

Bhasin D, Cisek K, Pandharkar T, Regan N, Li C, Pandit B, Lin J, Li PK (2008) Design, synthesis, and studies of small molecule STAT3 inhibitors. Bioorg Med Chem Lett 18:391–395CrossRefPubMed

26.

Sirard C, Laneuville P, Dick JE (1994) Expression of bcr-abl abrogates factor-dependent growth of human hematopoietic M07E cells by an autocrine mechanism. Blood 83:1575–1585PubMed

27.

Nicoletti I, Migliorati G, Pagliaccil MC, Grignani F, Riccardi C (1991) A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J Immunol Methods 139:271–279CrossRefPubMed

28.

Turkson J, Kim JS, Zhang S, Yuan J, Huang M, Glenn M, Haura E, Sebti S, Hamilton AD, Jove R (2004) Novel peptidomimetic inhibitors of signal transducer and activator of transcription 3 dimerization and biological activity. Mol Cancer Ther 3:261–269PubMed

29.

Lizard G, Miguet C, Gueldry S, Monier S, Gambert P (1997) Flow cytometry measurement of DNA fragmentation in the course of cell death via apoptosis. New techniques for evaluation of DNA status for the pathologist. Ann Pathol 17:61–66PubMed

30.

Raguz S, Yagüe E (2008) Resistance to chemotherapy: new treatments and novel insights into an old problem. Br J Cancer 99:387–391CrossRefPubMed

31.

Song H, Wang R, Wang S, Lin J (2005) A low-molecular-weight compound discovered through virtual database screening inhibits Stat3 function in breast cancer cells. Proc Natl Acad Sci USA 102:4700–4705CrossRefPubMed

32.

Xie SQ, Hu GQ, Zhang ZQ, Xu M, Ji BS (2008) Anti-tumour effects of HL-37, a novel anthracene derivative, in vivo and in vitro. J Pharm Pharmacol 60:213–219CrossRefPubMed

33.

Weisberg E, Griffin JD (2003) Resistance to imatinib (Glivec): update on clinical mechanisms. Drug Resist Updat 6:231–238CrossRefPubMed

34.

Aggarwal BB, Sethi G, Ahn KS, Sandur SK, Pandey MK, Kunnumakkara AB, Sung B, Ichikawa H (2006) Targeting signal-transducer-and-activator-of-transcription-3 for prevention and therapy of cancer: modern target but ancient solution. Ann N Y Acad Sci 1091:151–169CrossRefPubMed

35.

Bewry NN, Nair RR, Emmons MF, Boulware D, Pinilla-Ibarz J, Hazlehurst LA (2008) Stat3 contributes to resistance toward BCR-ABL inhibitors in a bone marrow microenvironment model of drug resistance. Mol Cancer Ther 7:3169–3175CrossRefPubMed

36.

Ye D, Wolff N, Li L, Zhang S, Ilaria RL Jr (2006) STAT5 signaling is required for the efficient induction and maintenance of CML in mice. Blood 7:4917–4925CrossRef

Titel: LLL-3, a STAT3 inhibitor, represses BCR-ABL-positive cell proliferation, activates apoptosis and improves the effects of Imatinib mesylate
verfasst von: Andre Luiz Mencalha
B. Du Rocher
D. Salles
R. Binato
E. Abdelhay
Publikationsdatum: 01.05.2010
Verlag: Springer-Verlag
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 6/2010
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-009-1109-3

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Springer Medizin

LLL-3, a STAT3 inhibitor, represses BCR-ABL-positive cell proliferation, activates apoptosis and improves the effects of Imatinib mesylate

Abstract

Purpose

Methods

Results

Conclusions

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Springer Medizin

Abstract

Purpose

Methods

Results

Conclusions

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