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Foretinib induces G2/M cell cycle arrest, apoptosis, and invasion in human glioblastoma cells through c-MET inhibition

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Abstract

Purpose

Glioblastoma multiforme (GBM) is one of the most aggressive human cancers. The c-MET receptor tyrosine kinase (RTK) which is frequently deregulated in GBM is considered as a promising target for GBM treatment. The c-MET plays a key role in cell proliferation, cell cycle progression, invasion, angiogenesis, and metastasis. Here, we investigated the anti-tumour activity of foretinib, a c-MET inhibitor, on three human GBM cells (T98G, U87MG and U251).

Methods

Anti-proliferative effect of foretinib was determined using MTT, crystal violet staining, and clonogenic assays. PI and Annexin V/PI staining flow cytometry were used to evaluate the effects of foretinib on cell cycle and apoptosis, respectively. Scratch assay, qRT-PCR, western blot, and zymography analyses were applied to elucidate the molecular mechanisms underlying the anti-tumour activity of foretinib.

Results

Foretinib treatment reduced phosphorylation of c-MET on T98G and U251 cells, but not in U87MG cells. The highest inhibitory effect was observed in T98G cells (IC50 = 4.66 ± 0.29 µM) and the lowest one in U87MG cells (IC50 = 29.99 ± 1.31 µM). The results showed that foretinib inhibited the proliferation of GBM cells through a G2/M cell cycle arrest and mitochondrial-mediated apoptosis in association with alternation in expression of the related genes and protein-regulated G2/M phase and apoptosis. Foretinib diminished GBM cell invasion through downregulation of the proteolytic cascade of MMP2, uPA and uPAR and epithelial–mesenchymal transition (EMT)-related genes. A different GBM cell sensitivity pattern was noticeable in all experiments which demonstrated T98G as a sensitive and U87MG as a resistant phenotype to foretinib treatment.

Conclusion

The results indicated that foretinib might have the therapeutic potential against human GBM which deserve further investigation.

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Acknowledgements

This work was supported by Cancer Biology Research Center in Cancer Institute of I.R. Iran at Tehran University of Medical Sciences and also partially supported by National Institute for Medical Research Development (NIMAD) Project No. 963331. Special thanks goes to Dr. Majid Momeny and Farima Moghaddaskho for the preliminary work on this project, Dr. Mohammad Hossein Ghahremani and Dr. Amir Shadboorestan for the technical support in western blot experiments, and MS Raziyeh khoshsohbat for the administrative support.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Cancer Biology Research Center, Cancer Institute of I.R. Iran, Tehran University of Medical Sciences, Tehran, Iran

    Narges K. Gortany & Mahmoud Ghazi-Khansari

  2. Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran

    Narges K. Gortany, Homanaz Ghafari, Maryam Shekari & Mahmoud Ghazi-Khansari

  3. Department of Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Ghodratollah Panahi

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  1. Narges K. Gortany
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Gortany, N.K., Panahi, G., Ghafari, H. et al. Foretinib induces G2/M cell cycle arrest, apoptosis, and invasion in human glioblastoma cells through c-MET inhibition. Cancer Chemother Pharmacol 87, 827–842 (2021). https://doi.org/10.1007/s00280-021-04242-0

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