CoChat
Sign Up
Cited by 188Metal complexes synthesis and propertiesCytokine Signaling Pathways and InteractionsOrganometallic Complex Synthesis and Catalysis

Inhibition of constitutive signal transducer and activator of transcription 3 activation by novel platinum complexes with potent antitumor activity

Open access
Turkson, James, Zhang, Shumin, Palmer, Jay, Kay, Heidi, Stanko, Joseph, Mora, Linda B., Sebti, Said, Yu, Hua +1 more·2004·Molecular Cancer Therapeutics
DOI 10.1158/1535-7163.1533.3.12
Open this paper in CoChat — free accountOpen PDF

Abstract

DNA-alkylating agents that are platinum complexes induce apoptotic responses and have wide application in cancer therapy. The potential for platinum compounds to modulate signal transduction events that contribute to their therapeutic outcome has not been extensively examined. Among the signal transducer and activator of transcription (STAT) proteins, Stat3 activity is frequently up-regulated in many human tumors. Various lines of evidence have established a causal role for aberrant Stat3 activity in malignant transformation and provided validation for its targeting in the development of small-molecule inhibitors as novel cancer therapeutics. We report here that platinum-containing compounds disrupt Stat3 signaling and suppress its biological functions. The novel platinum (IV) compounds, CPA-1, CPA-7, and platinum (IV) tetrachloride block Stat3 activity in vitro at low micromolar concentrations. In malignant cells that harbor constitutively activated Stat3, CPA-1, CPA-7, and platinum (IV) tetrachloride inhibit cell growth and induce apoptosis in a manner that reflects the attenuation of persistent Stat3 activity. By contrast, cells that do not contain persistent Stat3 activity are marginally affected or are not affected by these compounds. Moreover, CPA-7 induces the regression of mouse CT26 colon tumor, which correlates with the abrogation of persistent Stat3 activity in tumors. Thus, the modulation of oncogenic signal transduction pathways, such as Stat3, may be one of the key molecular mechanisms for the antitumor effects of platinum (IV)–containing complexes.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1158/1535-7163.1533.3.12

Cites

2 of 2 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Platinum IV compounds-CPA-1, CPA-7, IS3 295, and platinum (IV) tetrachloride-can inhibit STAT3 DNA-binding activity and inhibit cancer cell line growth.

    “Platinum IV compounds—CPA-1, CPA-7, IS3 295, and platinum (IV) tetrachloride—also can inhibit STAT3 DNA-binding activity and inhibit cancer cell line growth (Turkson et al., 2004).”

    From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Turkson et al., 2004

    The Introduction and the section on inhibition of in vitro Stat3 DNA-binding activity report that CPA-1, CPA-7, and platinum(IV) tetrachloride inhibit Stat3 DNA binding; the Introduction also reports growth inhibition in malignant cell lines. Our copy does not identify IS3 295 among the compounds tested (searched: “IS3 295” and “IS3-295”), so the claim is unsupported for that compound. Page numbers were not provided. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 56

  1. Darnell JE Jr, Kerr IM, Stark GR. Jak-STAT pathways and transcrip- tional activation in response to IFNs and other extracellular signaling proteins. Science 1994;264:1415 -21.
  2. Schindler C, Darnell JE Jr. Transcriptional responses to polypeptide ligands: the JAK-STAT pathway. Annu Rev Biochem 1995;64:621 -51.
  3. Bromberg JF, Horvath CM, Wen Z, Schreiber RD, Darnell JE Jr. Transcriptionally active Stat1 is required for the antiproliferative effects of both interferon alpha and interferon gamma. Proc Natl Acad Sci U S A 1996;93:7673 -8.
  4. Fukada T, Hibi M, Yamanaka Y, et al. Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: involvement of signal transducers and activators of transcription 3 in anti-apoptosis. Immunity 1996;5:449 -60.
  5. Darnell JE Jr. STATs and gene regulation. Science 1997;277:1630 -5.
  6. Stark GR, Kerr IM, Williams BR, Silverman RH, Schreiber RD. How cells respond to interferons. Annu Rev Biochem 1998;67:227 -64.
  7. Smithgall TE, Briggs SD, Schreiner S, Lerner EC, Cheng H, Wilson MB. Control of myeloid differentiation and survival by stats. Oncogene 2000;19:2612 -8.
  8. Akira S. Roles of signal transducers and activators of transcription 3 defined by tissue-specific gene targeting. Oncogene 2000;19:2607 -11.
  9. Hirano T, Ishihara K, Hibi M. Roles of signal transducers and activators of transcription 3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene 2000;19:2548 -56.
  10. Kotenko SV, Pestka S. Jak-Stat signal transduction pathway through the eyes of cytokine class II receptor complexes. Oncogene 2000; 19:2557 -65.
  11. Nielsen M, Kaltoft K, Nordahl M, et al. Constitutive activation of a slowly migrating isoform of Stat3 in mycosis fungoides: tyrphostin AG490 inhibits Stat3 activation and growth of mycosis fungoides tumor cell lines. Proc Natl Acad Sci U S A 1997;94:6764 -9.
  12. Turkson J, Bowman T, Garcia R, Caldenhoven E, De Groot RP, Jove R. Stat3 activation by Src induces specific gene regulation and is required for cell transformation. Mol Cell Biol 1998;18:2545 -52.
  13. Bromberg JF, Horvath CM, Besser D, Lathem WW, Darnell JE Jr. Stat3 activation is required for cellular transformation by v-src. Mol Cell Biol 1998;18:2553 -8.
  14. Grandis JR, Drenning SD, Chakraborty A, et al. Requirement of Stat3 but not Stat1 activation for epidermal growth factor receptor-mediated cell growth in vitro . J Clin Invest 1998;102:1385 -92.
  15. Catlett-Falcone R, Landowski TH, Oshiro MM, et al. Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity 1999;10:105 -15.
  16. Bromberg JF, Wrzeszczynska MH, Devgan G, et al. Stat3 as an oncogene. Cell 1999;98:295 -303.
  17. Nielsen M, Kaestel CG, Eriksen KW, et al. Inhibition of constitutively activated Stat3 correlates with altered Bcl-2/Bax expression and induction of apoptosis in mycosis fungoides tumor cells. Leukemia 1999;13:735 -8.
  18. Niu G, Heller R, Catlett-Falcone R, et al. Gene therapy with dominant- negative Stat3 suppresses growth of the murine melanoma B16 tumor in vivo. Cancer Res 1999;59:5059 -63.
  19. Grandis JR, Drenning SD, Zeng Q, et al. Constitutive activation of Stat3 signaling abrogates apoptosis in squamous cell carcinogenesis in vivo. Proc Natl Acad Sci U S A 2000;97:4227 -32.
  20. Epling-Burnette PK, Lui JH, Catlette-Falcone R, et al. Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lympho- cytes and decreased Mcl-1 expression. J Clin Invest 2001;107:351 -62.
  21. Garcia R, Bowman TL, Niu G, et al. Constitutive activation of Stat3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells. Oncogene 2001;20:2499 -513.
  22. Garcia R, Jove R. Activation of STAT transcription factors in oncogenic tyrosine kinase signaling. J Biomed Sci 1998;5:79 -85.
  23. Catlett-Falcone R, Dalton WS, Jove R. STAT proteins as novel targets for cancer therapy. Signal transducer an activator of transcription. Curr Opin Oncol 1999;11:490 -6.
  24. Turkson J, Jove R. STAT proteins: novel molecular targets for cancer drug discovery. Oncogene 2000;19:6613 -26.
  25. Song JI, Grandis JR. STAT signaling in head and neck cancer. Oncogene 2000;19:2489 -95.
  26. Coffer PJ, Koenderman L, de Groot RP. The role of STATs in myeloid differentiation and leukemia. Oncogene 2000;19:2511 -22.
  27. Lin TS, Mahajan S, Frank DA. STAT signaling in the pathogenesis and treatment of leukemias. Oncogene 2000;19:2496 -504.
  28. Yu H, Jove R. The STATs of cancer: new molecular targets come of age. Nat Rev Cancer 2004;4:97 -105.
  29. Niu G, Shain K, Huang M, et al. Overexpression of a dominant- negative signal transducer and activator of transcription 3 variant in tumor cells leads to production of soluble factors that induce apoptosis and cell cycle arrest. Cancer Res 2001;61:3276 -80.
  30. Turkson J, Ryan D, Kim JS, et al. Phosphotyrosyl peptides block Stat3-mediated DNA-binding activity, gene regulation and cell transfor- mation. J Biol Chem 2001;276:45443 -55.
  31. Turkson J, Kim JS, Zhang S, et al. Novel peptidomimetic inhibitors of signal transducer and activator of transcription 3 dimerization and biological activity. Mol Cancer Ther 2004;3:261 -9.
  32. Buettner R, Mora LB, Jove R. Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res 2002;8:945 -54.
  33. Ardizzoni A, Antonelli G, Grossi F, Tixi L, Cafferata M, Rosso R. The combination of etoposide and cisplatin in non-small-cell lung cancer (NSCLC). Ann Oncol 1999;10:S13 -7.
  34. Nitiss JL. A copper connection to the uptake of platinum anticancer drugs. Proc Natl Acad Sci U S A 2002;99:13963 -5.
  35. Bose RN. Biomolecular targets for platinum antitumor drugs. Mini Rev Med Chem 2002;2:103 -11.
  36. Persons DL, Yazlovitskaya EM, Cui W, Pelling JC. Cisplatin-induced activation of mitogen-activated protein kinases in ovarian carcinoma cells: inhibition of extracellular signal-regulated kinase activity increases sensi- tivity to cisplatin. Clin Cancer Res 1999;5:1007 -14.
  37. Sanchez-Perez I, Murguia JR, Perona R. Cisplatin induces a persistent activation of JNK that is related to cell death. Oncogene 1998;16:533 -40.
  38. Johnson PJ, Coussens PM, Danko AV, Shalloway D. Overexpressed pp60c-src can induce focus formation without complete transformation of NIH 3T3 cells. Mol Cell Biol 1985;5:1073 -83.
  39. Yu CL, Meyer DJ, Campbell GS, et al. Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein. Science 1995;269:81 -3.
  40. Wang T, Niu G, Kortylewski M, et al. Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med 2004;10:48 -54.
  41. Turkson J, Bowman T, Adnane J, et al. Requirement for Ras/Rac1- mediated p38 and c-Jun N-terminal kinase signaling in Stat3 transcriptional activity induced by the Src oncoprotein. Mol Cell Biol 1999;19:7519 -28.
  42. Burdge J, Stanko J, Palmer J. Oxidation of platinum (II) bis- (ethylenediamine) complexes with the oxides of nitrogen, NO and NO 2 : a model for the synthesis of platinum (IV) nitro compounds as potential antitumor agents. Florida Scientist 1995;58:274 -85.
  43. Palmer J, Burdge J, Stanko J. Oxidation of platinum (II) mono(- ethylenediamine) complexes with the oxides of nitrogen, NO and NO 2 : possible antitumor agents. Florida Scientist 1995;58:359 -65.
  44. Zhang Y, Turkson J, Carter-Su C, et al. Activation of Stat3 in v-Src transformed fibroblasts requires cooperation of Jak1 kinase activity. J Biol Chem 2000;275:24935 -44.
  45. Garcia R, Yu CL, Hudnall A, et al. Constitutive activation of Stat3 in fibroblasts transformed by diverse oncoproteins and in breast carcinoma cells. Cell Growth Differ 1997;8:1267 -76.
  46. Wagner BJ, Hayes TE, Hoban CJ, Cochran BH. The SIF binding element confers sis /PDGF inducibility onto the c-fos promoter. EMBO J 1990;9:4477 -84.
  47. Gouilleux F, Moritz D, Humar M, Moriggl R, Berchtold S, Groner B. Prolactin and interleukin-2 receptors in T lymphocytes signal through a MGF-STAT5-like transcription factor. Endocrinology 1995;136: 5700 -8.
  48. Seidel HM, Milocco LH, Lamb P, Darnell JE Jr., Stein RB, Rosen J. Spacing of palindromic half sites as a determinant of selective STAT (signal transducers and activators of transcription) DNA binding and transcriptional activity. Proc Natl Acad Sci U S A 1995;92:3041 -5.
  49. Croxton RL, Ma Y, Cress WD. Differences in DNA binding properties between E2F1 and E2F4 specify repression of the Mcl-1 promoter. Oncogene 2002;21:1563 -70.
  50. Liu AX, Testa JR, Hamilton TC, Jove R, Nicosia SV, Cheng JQ. AKT2, a member of the protein kinase B family, is activated by growth factors, v-Ha-ras, and v-src through phosphatidylinositol 3-kinase in human ovarian epithelial cancer cells. Cancer Res 1998;58:2973 -7.
  51. Grandis JR, Zeng Q, Drenning SD. Epidermal growth factor receptor- mediated stat3 signaling blocks apoptosis in head and neck cancer. Laryngoscope 2000;110:868 -74.
  52. Horiguchi A, Oya M, Marumo K, Murai M. STAT3, but not ERKs, mediates the IL-6-induced proliferation of renal cancer cells. Kidney Int 2002;61:926 -38.
  53. Mansouri A, Ridgeway LD, Korapati AL, et al. Sustained activation of JNK/p38 MAPK pathways in response to cisplatin leads to Fas ligand induction and cell death in ovarian carcinoma cells. J Biol Chem 2003;278:19245 -56.
  54. Zanke BW, Boudreau K, Rubie E, et al. The stress-activated protein kinase pathway mediates cell death following injury induced by cis - platinum, UV irradiation or heat. Curr Biol 1996;6:606 -13.
  55. Potapova O, Haghighi A, Bost F, et al. The Jun kinase/stress- activated protein kinase pathway functions to regulate DNA repair and inhibition of the pathway sensitizes tumor cells to cisplatin. J Biol Chem 1997;272:14041 -4.
  56. Song H, Sondak VK, Barber DL, Reid TJ, Lin J. Modulation of Janus kinase 2 by cisplatin in cancer cells. Int J Oncol 2004;24:1017 -26.

Cited by

Sorted by citations

Authors
Turkson, J., Zhang, S., Palmer, J., Kay, H., Stanko, J., Mora, L. B., Sebti, S., Yu, H., & Jove, R.
Affiliations
  • 1Molecular Oncology,
  • University of South Florida (US)
  • Moffitt Cancer Center (US)
  • 3Drug Discovery Programs, H. Lee Moffitt Cancer Center & Research Institute; and Departments of
  • 2Immunology and
ORCID
Venue
Molecular Cancer Therapeutics
Publisher
American Association for Cancer Research (AACR)
Published
2004-12-01
Volume
3
Issue
12
Pages
1533-1542
ISSN
  • 1535-7163 (ISSN-L)
  • 1538-8514
DOI
10.1158/1535-7163.1533.3.12
OpenAlex
W2134661616
Cited by
188
References
2
Citations by year
2026: 1 · 2025: 1 · 2024: 3 · 2023: 3 · 2022: 6 · 2021: 5 · 2020: 8 · 2019: 8 · 2018: 4 · 2017: 5 · 2016: 9 · 2015: 5 · 2014: 17 · 2013: 12 · 2012: 8
FWCI
6.26
Type
journal article
Language
en
Open access
Locations
  • Molecular Cancer Therapeutics (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Moffitt Cancer Center
  • National Institutes of Health
  • National Cancer Institute (R01CA055652, CA 82533, CA-55652, P01CA078038, P01CA082533, CA 78038)
Topics
  • Health Sciences › Medicine › Oncology › Metal complexes synthesis and properties
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Physical Sciences › Chemistry › Organic Chemistry › Organometallic Complex Synthesis and Catalysis
Keywords
STAT3, platinum complexes, constitutive STAT3 activation, signal transduction inhibition, anticancer activity, apoptosis, DNA alkylating agents, oncogenic signaling
MeSH terms
Animals, Antineoplastic Agents, DNA-Binding Proteins, Enzyme Activation, Female, Humans, Mice, Inbred BALB C, Neoplasms, Experimental, Organoplatinum Compounds, Phosphorylation, Tumor Cells, Cultured, Signal Transduction, Trans-Activators, Apoptosis, Chlorine Compounds, Platinum Compounds, Xenograft Model Antitumor Assays, NIH 3T3 Cells, STAT3 Transcription Factor, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review