BACKGROUND: Tyrosine kinase inhibitors (TKI) such as sunitinib and pazopanib display their efficacy in a variety of solid tumours. However, their use in therapy is limited by the lack of evidence about the ability to induce cell death in cancer cells. Our aim was to evaluate cytotoxic effects induced by sunitinib and pazopanib in 5637 and J82 bladder cancer cell lines. METHODS: Cell viability was tested by MTT assay. Autophagy was evaluated by western blot using anti-LC3 and anti-p62 antibodies, acridine orange staining and FACS analysis. Oxygen radical generation and necrosis were determined by FACS analysis using DCFDA and PI staining. Cathepsin B activation was evaluated by western blot and fluorogenic Z-Arg-Arg-AMC peptide. Finally, gene expression was performed using RT-PCR Profiler array. RESULTS: We found that sunitinib treatment for 24 h triggers incomplete autophagy, impairs cathepsin B activation and stimulates a lysosomal-dependent necrosis. By contrast, treatment for 48 h with pazopanib induces cathepsin B activation and autophagic cell death, markedly reversed by CA074-Me and 3-MA, cathepsin B and autophagic inhibitors, respectively. Finally, pazopanib upregulates the α-glucosidase and downregulates the TP73 mRNA expression. CONCLUSION: Our results showing distinct cell death mechanisms activated by different TKIs, provide the biological basis for novel molecularly targeted approaches.
|Data di pubblicazione:||2013|
|Titolo:||Pazopanib and sunitinib trigger autophagic and non-autophagic death of bladder tumour cells.|
|Autore/i:||Santoni, M; Amantini, C; Morelli, Mb; Liberati, S; Farfariello, V; Nabissi, M; Bonfili, L; Eleuteri, Am; Mozzicafreddo, M; Burattini, L; Berardi, R; Cascinu, Stefano; Santoni, G.|
|Codice identificativo ISI:||WOS:000323417100028|
|Codice identificativo Scopus:||2-s2.0-84883156825|
|Citazione:||Pazopanib and sunitinib trigger autophagic and non-autophagic death of bladder tumour cells. / Santoni, M; Amantini, C; Morelli, Mb; Liberati, S; Farfariello, V; Nabissi, M; Bonfili, L; Eleuteri, Am; Mozzicafreddo, M; Burattini, L; Berardi, R; Cascinu, Stefano; Santoni, G.. - In: BRITISH JOURNAL OF CANCER. - ISSN 0007-0920. - 109(2013), pp. 1040-1050.|
|Tipologia||Articolo su rivista|
File in questo prodotto:
I documenti presenti in Iris Unimore sono rilasciati con licenza Creative Commons Attribuzione - Non commerciale - Non opere derivate 3.0 Italia, salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris