Elsevier

Neuroscience

Volume 168, Issue 2, 30 June 2010, Pages 514-522
Neuroscience

Neurodegeneration, Neuroprotection and Disease-Oriented Neuroscience
Research Paper
Inhibition of metalloproteinases derived from tumours: new insights in the treatment of human glioblastoma

https://doi.org/10.1016/j.neuroscience.2010.03.064Get rights and content

Abstract

Glioblastoma multiforme is the most commonly diagnosed malignant primary brain tumour in adults. Invasive behaviour is the pathological hallmark of malignant gliomas; consequently, its inhibition has been suggested as a therapeutic strategy. Tumour cell-derived gelatinases (matrix metalloproteinase-2, matrix metalloproteinase-9) can be considered prime factors in glioma invasiveness: their expression correlates with the progression and the degree of malignancy. Thus, broad spectrum matrix metalloproteinase inhibitors (MMP inhibitors) have been included in clinical trials. In the present study, the invasiveness, viability and progression of the human glioma cell line U87MG were investigated following treatment with N-O-isopropyl sulfonamido-based hydroxamates (compounds 1 and 2) as MMP-2 inhibitors used at nanomolar concentration. A standard broad spectrum MMP-inhibitor belonging to the classical tertiary sulfonamido-based hydroxamates family (CGS_27023A) was used too. The compounds 1 and 2 resulted in potent inhibition of cell invasiveness (P<0.0001) without affecting viability. In some clinical trials, the combined therapy of temozolomide (an alkylating agent used in glioma treatment) plus marimastat (a broad spectrum MMP inhibitor) has provided evidence of the importance of MMPs to tumor progression and invasiveness. On this basis, the effect on U87MG cells of a combined treatment with temozolomide, plus each of the two MMP inhibitors at nanomolar concentration, was investigated. The obtained data demonstrated the inhibition of cell invasiveness and viability after treatment. These results can help in developing clinical combined therapy using MMP inhibitors that, at low doses, increase the anticancer efficacy of chemotherapeutic drugs, probably without causing the side effects typical of broad-spectrum MMP inhibitors.

Section snippets

Commercial suppliers

Temozolomide and gelatin (type A) were purchased from Sigma-Aldrich (St. Louis, MO, USA). Cell culture media and growth supplements were obtained from Cambrex Bio Science, Walkersville, Inc. (Walkersville, MD, USA). Bio-Rad Protein Assays were purchased from Bio-Rad (Hercules, CA, USA). Trypan Blue was from Sigma/RBI (Natick, MA, USA). Cell Titer 96 Aqueous One Solution Cell Proliferation assays were obtained from Promega (Milan, Italy). RayBio® Human MMP-2 ELISA kit was from RayBiotech Inc

Results

The N-isopropoxy-biphenylsulfonamide hydroxamic acids 1 and 2 (Fig. 1) were employed in cell treatment experiments.

In test tube assays, nanomolar concentrations of compounds 1 and 2 resulted to selectively inhibit the activity of the human recombinant matrix metalloproteinases, MMP-2, MMP-9 and MMP-12 (Table 1).

The ability of the compounds to affect MMP-2 activity at such concentrations (12 nM compound 1, 1 nM compound 2 and 25 nM CGS_27023A) prompted us to investigate their ability to affect

Discussion

Gliomas are the most prevalent primary brain tumours. Between gliomas, GBM (World Health Organization Grade IV astrocytoma) is the most common and aggressive primary brain tumor in adults, and the median survival of 12 months for patients has not changed during the last few years (Desjardins et al., 2005). Therefore, new approaches are essential for the treatment of these patients, especially because the occurrence of gliomas is increasing (Hess et al., 2004, Johannesen et al., 2004). Invasive

Conclusion

In conclusion, taken together, these data suggest that this combination of drugs may have good therapeutic potential for the treatment of brain tumours. The ability of glioma cells to proliferate quickly and to infiltrate the surrounding brain tissues, escaping current therapeutic modalities, could be minimized using the combined treatment. These co-treatments could block the growth of the tumour by means of an alkylating agent, such as TMZ, and could stop the invasiveness through MMP-2

Acknowledgments

This study was supported by the Italian Ministry of University and Scientific Research (PRIN 2007). The authors thank Dr. Marina Fabbi from National Institute for Cancer Research of Genoa for providing the human U87MG cell line.

References (42)

  • A. Albini et al.

    The chemoinvasion assay: a method to assess tumor and endothelial cell invasion and its modulation

    Nat Protoc

    (2007)
  • M. Brada et al.

    Phase I dose-escalation and pharmacokinetic study of temozolomide (SCH 52365) for refractory or relapsing malignancies

    Br J Cancer

    (1999)
  • B. Cauwe et al.

    The biochemical, biological, and pathological kaleidoscope of cell surface substrates processed by matrix metalloproteinases

    Crit Rev Biochem Mol Biol

    (2007)
  • A.R. Dehdashti et al.

    New trends in the medical management of glioblastoma multiforme: the role of temozolomide chemotherapy

    Neurosurg Focus

    (2006)
  • A. Desjardins et al.

    Chemotherapy and novel therapeutic approaches in malignant glioma

    Front Biosci

    (2005)
  • P.A. Forsyth et al.

    Gelatinase-A (MMP-2), gelatinase-B (MMP-9) and membrane type matrix metalloproteinase-1 (MT1-MMP) are involved in different aspects of the pathophysiology of malignant gliomas

    Br J Cancer

    (1999)
  • A. Giese et al.

    Cost of migration: invasion of malignant gliomas and implications for treatment

    J Clin Oncol

    (2003)
  • M.D. Groves et al.

    Phase II trial of temozolomide plus the matrix metalloproteinase inhibitor, marimastat, in recurrent and progressive glioblastoma multiforme

    J Clin Oncol

    (2002)
  • J. Heino

    Biology of tumor cell invasion: interplay of cell adhesion and matrix degradation

    Int J Cancer

    (1996)
  • K.R. Hess et al.

    Adult glioma incidence trends in the United States, 1977–2000

    Cancer

    (2004)
  • Y. Hirose et al.

    p53 effects both the duration of G2/M arrest and the fate of temozolomide-treated human glioblastoma cells

    Cancer Res

    (2001)
  • Cited by (42)

    • Inhibition of human glioblastoma multiforme cells by 10,11-dehydrocurvularin through the MMP-2 and PI3K/AKT signaling pathways

      2022, European Journal of Pharmacology
      Citation Excerpt :

      Because MMP-2 can degrade the extracellular matrix and promote tumor cell invasion, it is regarded as the main feature of malignant invasion and migration of tumor cells (Cheng et al., 2017; Westermarck and Khri, 1999; Yang et al., 2010; Yoon et al., 2003). At present, there have been a large number of clinical trials targeting PI3K/AKT pathways drugs such as perifosine, BKM120, and PX-866 (Gabelloni et al., 2010); there are also studies on a broad spectrum matrix metalloproteinase (MMP) inhibitor such as marimastat and N–O-isopropyl sulfonamide hydroxamates (Li et al., 2016). Therefore, inhibiting the protein levels of the PI3K/AKT signaling pathways and MMP-2 could be a robust solution to inhibit tumor cell proliferation, invasion, and migration.

    • Extracellular proteolysis in glioblastoma progression and therapeutics

      2020, Biochimica et Biophysica Acta - Reviews on Cancer
      Citation Excerpt :

      For instance, inhibitors such as the N-O-isopropyl sulfonamido-based hydroxamate compounds (code CGS-27023A) were found to reduce MMP-2 at mRNA and protein levels. In combination with Temozolomide, they also reduce invasiveness and cell viability in vitro and importantly, they work at low concentrations, which would help to reduce toxicity [130]. Recent technologies for improved therapies have now been suggested for MMPs.

    • A drug-delivering-drug strategy for combined treatment of metastatic breast cancer

      2018, Nanomedicine: Nanotechnology, Biology, and Medicine
      Citation Excerpt :

      The viability from CPNs, β-CN-PTX-Ns and Taxol was dose-dependent and, importantly, the CPNs displayed a more profound cytotoxicity to 4T1 cells. By inhibiting the activity and expression of extracellular MMPs at mRNA and protein levels, using an MMP inhibitor, even at nanomolar concentrations, increased the cytotoxicity of an anti-tumor drug against cancer cells,31,32 implying a potential synergism. To assess the synergistic effect between PTX and MATT, the combination index (CI) was calculated based on the cytotoxicity of CPNs (Figure S4, B), with CI < 1 indicating synergistic effects.32

    View all citing articles on Scopus
    1

    These authors contributed equally for this manuscript.

    View full text