Blockage of Stat3 With CDDO-Me Inhibits Tumor Cell Growth in Chordoma

Department of Orthopaedic Surgery, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Spine (Impact Factor: 2.3). 04/2010; 35(18):1668-75. DOI: 10.1097/BRS.0b013e3181c2d2b4
Source: PubMed


An experimental study to investigate the activation of Src/Stat3 pathways in chordomas and blockage of this pathway as a potential strategy for chordoma treatment.
To investigate the activation of Src/Stat3 pathway in chordomas cells and to determine the efficiency of inhibiting this pathway by 2-cyano-3,12-dioxooleana-1,9 (11)-dien-28-oic acid-methyl ester (CDDO-Me) as a potential chemotherapeutic agent for chordoma treatment.
The advent of molecularly targeted therapies has raised interest for their use in the treatment of chordomas. Unfortunately, the current understanding of molecular markers in chordomas is limited. Constitutive activation of Stat3 is a common finding in a wide spectrum of human cancers. The function of Stat3 pathway in chordomas has not been elucidated.
The expression of key components of the Src/Stat3 signaling cascade was evaluated by Western blot in chordoma tissues and chordoma cell lines. The effects of CDDO-Me on chordoma cell growth were evaluated in these chordoma cell lines by MTT assay. The expression of key components of the Src/Stat3 signaling cascade and poly (ADP-ribose) polymerase cleavage in these CDDO-Me treated cells were analyzed by Western blot and immunofluorescence. Furthermore, the synergistic effect of CDDO-Me on cisplatin and doxorubicin-induced cytotoxicity was evaluated by MTT. Finally, chordoma cells were grown in a 3-dimensional (3D) culture and treated with CDDO-Me.
The key components of the Src/Stat3 signaling cascade, including Stat3, pStat3, Src, pSrc, Bcl-xL, and Myeloid Cell Leukemia-1, were all highly expressed in chordomas. Expression of the key components of the Src/Stat3 signaling cascade was inhibited in chordoma cells after treatment with CDDO-Me. The growth of chordoma cells was inhibited and apoptosis associated poly (ADP-ribose) polymerase cleavage was detected after treatment with CDDO-Me. Additionally, CDDO-Me has a synergistic effect on cisplatin or doxorubicin-induced chordoma cell death (P < 0.001). Finally, expression of pSrc and pStat3 and chordoma cell growth was inhibited by treatment of CDDO-Me using 3D culture.
The Src/Stat3 signaling pathway was activated in chordomas. Blockage of Src/Stat3 pathway by CDDO-Me is a potential strategy for chordoma treatment and may be focus for future research.

1 Follower
16 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: The carbon-rich structures of C9Sin (n=1–5) clusters were studied by first-principles density functional calculations using the B3LYP hybrid exchange–correlation energy functional and 6-311++G(2df) basis set. By systematic investigation of the structures and energies, we found that in the structures of the carbon-rich clusters C9Sin (n=1–5), the C atoms were found to form linear (n=2), or single-ring (n=1 and 3) or double-rings (n=4 and 5) while the Si atoms prefer to attach to the carbon rings in the form of C2Si units. Based on the lowest-energy structures obtained from our calculations, the properties of the clusters such as binding energy, second difference in energy, HOMO–LUMO gap, adiabatic ionization potential (AIP), adiabatic electron affinity (AEA), vibrational frequency, bond orders and NBO charge transfer have been calculated and analyzed.
    Computational and Theoretical Chemistry 02/2011; 963(2):439-447. DOI:10.1016/j.comptc.2010.11.010 · 1.55 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Ossification of the posterior longitudinal ligament (OPLL) is a rare disease that results in progressive myeloradiculopathy related to pathological ossification of the ligament from unknown causes. Although it has long been considered a disease of Asian origin, this disorder is increasingly being recognized in European and North American populations. Herein the authors present demographic, radiographic, and comorbidity data from white patients with diagnosed OPLL as well as the outcomes of surgically treated patients. Between 1999 and 2010, OPLL was diagnosed in 36 white patients at Barrow Neurological Institute. Patients were divided into 2 groups: a group of 33 patients with cervical OPLL and a group of 3 patients with thoracic or lumbar OPLL. Fifteen of these patients who had received operative treatment were analyzed separately. Imaging analysis focused on signal changes in the spinal cord, mass occupying ratio, signs of dural penetration, spinal levels involved, and subtype of OPLL. Surgical techniques included anterior cervical decompression and fusion with corpectomy, posterior laminectomy with fusion, posterior open-door laminoplasty, and anterior corpectomy combined with posterior laminectomy and fusion. Comorbidities, cigarette smoking, and previous spine surgeries were considered. Neurological function was assessed using a modified Japanese Orthopaedic Association Scale (mJOAS). A high-intensity signal on T2-weighted MR imaging and a history of cervical spine surgery correlated with worse mJOAS scores. Furthermore, mJOAS scores decreased as the occupying rate of the OPLL mass in the spinal canal increased. On radiographic analysis, the proportion of signs of dural penetration correlated with the OPLL subtype. A high mass occupying ratio of the OPLL was directly associated with the presence of dural penetration and high-intensity signal. In the surgical group, the rate of neurological improvement associated with an anterior approach was 58% compared with 31% for a posterior laminectomy. No complications were associated with any of the 4 types of surgical procedures. In 3 cases, symptoms had worsened at the last follow-up, with only a single case of disease progression. Laminoplasty was the only technique associated with a worse clinical outcome. There were no statistical differences (p > 0.05) between the type of surgical procedure or radiographic presentation and postoperative outcome. There was also no difference between the choice of surgical procedure performed and the number of spinal levels involved with OPLL. Ossification of the posterior longitudinal ligament can no longer be viewed as a disease of the Asian population exclusively. Since OPLL among white populations is being diagnosed more frequently, surgeons must be aware of the most appropriate surgical option. The outcomes of the various surgical treatments among the different populations with OPLL appear similar. Compared with other procedures, however, anterior decompression led to the best neurological outcomes.
    Neurosurgical FOCUS 03/2011; 30(3):E11. DOI:10.3171/2010.12.FOCUS10265 · 2.11 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The management of thoracic ossification of the posterior longitudinal ligament has been studied by many spinal surgeons. Indications for operative intervention include progressive radiculopathy, myelopathy, and neurological deterioration. The ideal surgery for decompression remains highly debatable as various methods of surgical treatment of ossification of the posterior longitudinal ligament have been devised. Although numerous modifications to the 3 main approaches have been identified (anterior, posterior, or lateral), the indication for each depends on the nature of compression, the morphology of the lesion, the level of the compression, the structural alignment of the spine, and the neurological status of the patient. The authors discuss treatment techniques for thoracic ossification of the posterior longitudinal ligament, cite case examples from a single institution, and review the literature.
    Neurosurgical FOCUS 03/2011; 30(3):E16. DOI:10.3171/2010.12.FOCUS10282 · 2.11 Impact Factor
Show more